Stuart MacGregor

Cost-Effectiveness of Polygenic Risk Profiling for Primary Open-Angle Glaucoma in the United Kingdom and Australia

Publisher: Elsevier BV

Date: 2021

DOI: 10.2139/SSRN.3761840

Is Genetic Risk for Sleep Apnoea Causally Linked With Glaucoma Susceptibility?

Publisher: Elsevier BV

Date: 2021

DOI: 10.2139/SSRN.3821797

WALLABY pre-pilot and pilot survey

Publisher: Oxford University Press (OUP)

Date: 12-11-2023

DOI: 10.1093/MNRAS/STAC3246

Abstract: The WALLABY pilot survey has been conducted using the Australian SKA Pathfinder (ASKAP). The integrated 21-cm H i line spectra are formed in a very different manner compared to usual single-dish spectra Tully–Fisher measurements. It is thus extremely important to ensure that slight differences (e.g. biases due to missing flux) are quantified and understood in order to maximise the use of the large amount of data becoming available soon. This article is based on four fields for which the data are scientifically interesting by themselves. The pilot data discussed here consist of 614 galaxy spectra at a rest wavelength of 21 cm. Of these spectra, 472 are of high enough quality to be used to potentially derive distances using the Tully–Fisher relation. We further restrict the s le to the 251 galaxies whose inclination is sufficiently close to edge-on. For these, we derive Tully–Fisher distances using the deprojected WALLABY velocity widths combined with infrared (WISE W1) magnitudes. The resulting Tully–Fisher distances for the Eridanus, Hydra, Norma, and NGC4636 clusters are 21.5, 53.5, 69.4, and 23.0 Mpc, respectively, with uncertainties of 5–10 per cent, which are better or equivalent to the ones obtained in studies using data obtained with giant single dish telescopes. The pilot survey data show the benefits of WALLABY over previous giant single-dish telescope surveys. WALLABY is expected to detect around half a million galaxies with a mean redshift of $z = 0.05 (200\\, \\mathrm{Mpc})$. This study suggests that about 200 000 Tully–Fisher distances might result from the survey.

Attitudes Toward Glaucoma Genetic Risk Assessment in Unaffected Individuals

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 28-10-2022

DOI: 10.1167/TVST.11.10.38

Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma

Publisher: Springer Science and Business Media LLC

Date: 27-07-2018

DOI: 10.1038/S41588-018-0176-Y

Abstract: Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide

Normal-tension glaucoma is associated with cognitive impairment

Publisher: BMJ

Date: 29-03-2022

DOI: 10.1136/BJOPHTHALMOL-2020-317461

Abstract: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. The authors completed a case–control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly s led from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of /22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.

High Polygenic Risk Is Associated with Earlier Trabeculectomy in Patients with Primary Open-Angle Glaucoma

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.OGLA.2022.06.009

Abstract: To evaluate the association between a polygenic risk score (PRS) for Primary Open Angle Glaucoma (POAG) and the age of first trabeculectomy and the need for bilateral trabeculectomy. The ocular surgical history was reviewed for nine hundred and three genotyped participants with POAG from the Australian New Zealand Registry of Advanced Glaucoma (ANZRAG). Age of diagnosis, age of trabeculectomy and laterality of trabeculectomy were recorded. Multivariate linear regression analyses correlated glaucoma PRS with age of trabeculectomy and laterality of trabeculectomy. For descriptive purposes, participants were additionally stratified into top decile, intermediate group (10 A higher PRS was associated with a younger age at first trabeculectomy (beta: -1.94 years/SD 95% CI: [-0.41, -3.47] P=0.014). Participants in the top decile underwent their first trabeculectomy approximately 7 years earlier than participants in the lowest decile (mean difference: -7.04 years [2.82, 11.26]). Participants in the top decile were 1.41 fold more likely to require bilateral trabeculectomy than participants in the bottom decile (OR: 1.41 [1.06, 1.91] P=0.021). This report identified clinically relevant correlations between glaucoma PRS and need for surgical intervention in glaucoma. Further work is required to investigate the association between PRS and other clinical endpoints, such as treatment initiation.

Is schizophrenia linked to chromosome 1q?

Publisher: American Association for the Advancement of Science (AAAS)

Date: 20-12-2002

DOI: 10.1126/SCIENCE.1076508

Platinum Sensitivity–Related Germline Polymorphism Discovered via a Cell-Based Approach and Analysis of Its Association with Outcome in Ovarian Cancer Patients

Publisher: American Association for Cancer Research (AACR)

Date: 14-08-2011

DOI: 10.1158/1078-0432.CCR-11-0724

Abstract: Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy. Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P & 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts. Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res 17(16) 5490–500. ©2011 AACR.

WALLABY Pilot Survey

Publisher: American Astronomical Society

Date: 05-2023

DOI: 10.3847/1538-4357/ACC1E3

Abstract: We report on the commensal ASKAP detection of a fast radio burst (FRB), FRB 20211127I, and the detection of neutral hydrogen (H i ) emission in the FRB host galaxy, WALLABY J131913–185018 (hereafter W13–18). This collaboration between the CRAFT and WALLABY survey teams marks the fifth, and most distant, FRB host galaxy detected in H i , not including the Milky Way. We find that W13–18 has an H i mass of M HI = 6.5 × 10 9 M ⊙ , an H i -to-stellar mass ratio of 2.17, and coincides with a continuum radio source of flux density at 1.4 GHz of 1.3 mJy. The H i global spectrum of W13–18 appears to be asymmetric, albeit the H i observation has a low signal-to-noise ratio (S/N), and the galaxy itself appears modestly undisturbed. These properties are compared to the early literature of H i emission detected in other FRB hosts to date, where either the H i global spectra were strongly asymmetric, or there were clearly disrupted H i intensity map distributions. W13–18 lacks a sufficient S/N to determine whether it is significantly less asymmetric in its H i distribution than previous ex les of FRB host galaxies. However, there are no strong signs of a major interaction in the optical image of the host galaxy that would stimulate a burst of star formation and hence the production of putative FRB progenitors related to massive stars and their compact remnants.

Identification of a melanoma susceptibility locus and somatic mutation inTET2

Publisher: Oxford University Press (OUP)

Date: 30-06-2014

DOI: 10.1093/CARCIN/BGU140

A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility

Publisher: Cambridge University Press (CUP)

Date: 20-01-2017

DOI: 10.1017/THG.2016.100

Abstract: Genome-wide association studies (GWAS) have revolutionized the field of gene mapping. As the GWAS field matures, it is becoming clear that for many complex traits, a proportion of the missing heritability is attributable to common variants of in idually small effect. Detecting these small effects in idually can be difficult, and statistical power would be increased if relevant variants could be grouped together for testing. Here, we propose a VEGAS2Pathway approach that aggregates association strength of in idual markers into pre-specified biological pathways. It accounts for gene size and linkage disequilibrium between markers using simulations from the multivariate normal distribution. Pathway size is taken into account via a res ling approach. Importantly, since the approach only requires summary data, the method can easily be applied in all GWASs, including meta-analysis, singleton-based, family-based, and DNA-pooling-based designs. This approach is implemented in a user-friendly web page vegas2.qimrberghofer.edu.au and a command line tool. The web implementation uses gene-sets from the gene ontology (GO), curated gene-sets from MSigDB (containing canonical pathways and gene-sets from BIOCARTA, REACTOME, KEGG databases), PANTHER, and pathway commons databases, enabling analysis of a wide range of complex traits. We applied this method on a colorectal cancer GWAS meta-analysis data set (10,934 cases, 12,328 controls) from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). We report statistically significant enrichment of association signal for the ‘BMP signaling’ and ‘muscle cell differentiation’ pathways, suggesting a possible role for these pathways onto the risk of colorectal cancer.

Genetic factors predisposing to homosexuality may increase mating success in heterosexuals

Publisher: Elsevier BV

Date: 11-2008

DOI: 10.1016/J.EVOLHUMBEHAV.2008.07.002

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Publisher: Springer Science and Business Media LLC

Date: 20-01-2020

DOI: 10.1038/S41588-019-0556-Y

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Publisher: Elsevier BV

Date: 10-2022

DOI: 10.1016/J.XGEN.2022.100192

Optimal Selection of Markers from DNA Pooling Experiments

Publisher: Springer Science and Business Media LLC

Date: 13-12-2009

DOI: 10.1007/S10519-009-9313-9

WALLABY Pilot Survey

Publisher: Oxford University Press (OUP)

Date: 28-11-2023

DOI: 10.1093/MNRAS/STAC3480

Abstract: We examine the H i gas kinematics of galaxy pairs in two clusters and a group using Australian Square Kilometre Array Pathfinder (ASKAP) WALLABY pilot survey observations. We compare the H i properties of galaxy pair candidates in the Hydra I and Norma clusters, and the NGC 4636 group, with those of non-paired control galaxies selected in the same fields. We perform H i profile decomposition of the s le galaxies using a tool, baygaud, which allows us to deblend a line-of-sight velocity profile with an optimal number of Gaussian components. We construct H i superprofiles of the s le galaxies via stacking of their line profiles after aligning the central velocities. We fit a double Gaussian model to the superprofiles and classify them as kinematically narrow and broad components with respect to their velocity dispersions. Additionally, we investigate the gravitational instability of H i gas discs of the s le galaxies using Toomre Q parameters and H i morphological disturbances. We investigate the effect of the cluster environment on the H i properties of galaxy pairs by iding the cluster environment into three subcluster regions (i.e. outskirts, infalling, and central regions). We find that the denser cluster environment (i.e. infalling and central regions) is likely to impact the H i gas properties of galaxies in a way of decreasing the litude of the kinematically narrow H i gas ($M_{\\rm {narrow}}^{\\rm {H\\, \\small {\\rm I}}}$/$M_{\\rm {total}}^{\\rm {H\\, \\small {\\rm I}}}$), and increasing the Toomre Q values of the infalling and central galaxies. This tendency is likely to be more enhanced for galaxy pairs in the cluster environment.

The causal relationship between gastro-esophageal reflux disease and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study

Publisher: Cold Spring Harbor Laboratory

Date: 09-2022

DOI: 10.1101/2022.08.31.22279411

Abstract: Gastro-esophageal reflux disease (GERD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GERD causes IPF, or IPF causes GERD, or because of confounding by factors, such as smoking, associated with both GERD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GERD and IPF are causally related. A bidirectional two-s le MR was performed to estimate the causal effect of GERD on IPF risk, and of IPF on GERD risk, using genetic data from the largest GERD (78,707 cases and 288,734 controls) and IPF (4,125 cases and 20,464 controls) genome-wide association meta-analyses currently available. GERD increased the risk of IPF, with an odds ratio (OR) of 1.6 (95% Confidence Interval, CI: 1.04-2.49 p=0.032). There was no evidence of a causal effect of IPF on the risk of GERD, with an OR of 0.99 (95%CI: 0.97-1.02 p=0.615). We found that GERD increases the risk of IPF, but found no evidence that IPF increases the risk of GERD. GERD should be considered in future studies of IPF risk, and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GERD on IPF should also be investigated.

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: analysis in Two Large Datasets

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 02-2018

DOI: 10.1167/IOVS.17-22708

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia: phenotypes, risk factors and genotypes

Publisher: Ferrata Storti Foundation (Haematologica)

Date: 31-03-2022

DOI: 10.3324/HAEMATOL.2021.280016

Abstract: Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1,464 children aged 1.0–17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP n=19) study were performed in 1,166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: erse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1,464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31–10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4% P .001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with erse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.

GAIA: An easy-to-use web-based application for interaction analysis of case-control data

Publisher: Springer Science and Business Media LLC

Date: 05-04-2006

DOI: 10.1186/1471-2350-7-34

Abstract: The advent of cheap, large scale genotyping has led to widespread adoption of genetic association mapping as the tool of choice in the search for loci underlying susceptibility to common complex disease. Whilst simple single locus analysis is relatively trivial to conduct, this is not true of more complex analysis such as those involving interactions between loci. The importance of testing for interactions between loci in association analysis has been highlighted in a number of recent high profile publications. Genetic Association Interaction Analysis (GAIA) is a web-based application for testing for statistical interactions between loci. It is based upon the widely used case-control study design for genetic association analysis and is designed so that non-specialists may routinely apply tests for interaction. GAIA allows simple testing of both additive and additive plus dominance interaction models and includes permutation testing to appropriately correct for multiple testing. The application will find use both in candidate gene based studies and in genome-wide association studies. For large scale studies GAIA includes a screening approach which prioritizes loci (based on the significance of main effects at one or both loci) for further interaction analysis. GAIA is available at www.bbu.cf.ac.uk/html/research/biostats.htm

Supplementary Information from Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 31-03-2023

DOI: 10.1158/0008-5472.22433402.V1

Abstract: Figures S1–S11, Tables S1–S6, Supplementary Materials and Methods, Supplementary Notes, and Supplementary References

Rationale and protocol for the 7- and 8-year longitudinal assessments of eye health in a cohort of young adults in the Raine Study

Publisher: BMJ

Date: 03-2020

DOI: 10.1136/BMJOPEN-2019-033440

Abstract: Eye diseases and visual impairment more commonly affect elderly adults, thus, the majority of ophthalmic cohort studies have focused on older adults. Cohort studies on the ocular health of younger adults, on the other hand, have been few. The Raine Study is a longitudinal study that has been following a cohort since their birth in 1989–1991. As part of the 20-year follow-up of the Raine Study, participants underwent a comprehensive eye examination. As part of the 27- and 28-year follow-ups, eye assessments are being conducted and the data collected will be compared with those of the 20-year follow-up. This will provide an estimate of population incidence and updated prevalence of ocular conditions such as myopia and keratoconus, as well as longitudinal change in ocular parameters in young Australian adults. Additionally, the data will allow exploration of the environmental, health and genetic factors underlying inter-subject differential long-term ocular changes. Participants are being contacted via telephone, email and/or social media and invited to participate in the eye examination. At the 27-year follow-up, participants completed a follow-up eye screening, which assessed visual acuity, autorefraction, ocular biometry and ocular sun exposure. Currently, at the 28-year follow-up, a comprehensive eye examination is being conducted which, in addition to all the eye tests performed at the 27-year follow-up visit, includes tonometry, optical coherence tomography, funduscopy and anterior segment topography, among others. Outcome measures include the incidence of refractive error and pterygium, an updated prevalence of these conditions, and the 8-year change in ocular parameters. The Raine Study is registered in the Australian New Zealand Clinical Trials Registry. The Gen2 20-year, 27-year and 28-year follow-ups are approved by the Human Research Ethics Committee of the University of Western Australia. Findings resulting from the study will be published in health or medical journals and presented at conferences. ACTRN12617001599369 Active, not recruiting.

A bias-reducing pathway enrichment analysis of genome-wide association data confirmed association of the MHC region with schizophrenia

Publisher: BMJ

Date: 20-12-2012

DOI: 10.1136/JMEDGENET-2011-100397

Abstract: After the recent successes of genome-wide association studies (GWAS), one key challenge is to identify genetic variants that might have a significant joint effect on complex diseases but have failed to be identified in idually due to weak to moderate marginal effect. One popular and effective approach is gene set based analysis, which investigates the joint effect of multiple functionally related genes (eg, pathways). However, a typical gene set analysis method is biased towards long genes, a problem that is especially severe in psychiatric diseases. A novel approach was proposed, namely generalised additive model (GAM) for GWAS (gamGWAS), for gene set enrichment analysis of GWAS data, specifically adjusting the gene length bias or the number of single-nucleotide polymorphisms per gene. GAM is applied to estimate the probability of a gene to be selected as significant given its gene length, followed by weighted res ling and computation of empirical p values for the rank of pathways. We demonstrated gamGWAS in two schizophrenia GWAS datasets from the International Schizophrenia Consortium and the Genetic Association Information Network. The gamGWAS results not only confirmed previous findings, but also highlighted several immune related pathways. Comparison with other methods indicated that gamGWAS could effectively reduce the correlation between pathway p values and its median gene length. gamGWAS can effectively relieve the long gene bias and generate reliable results for GWAS data analysis. It does not require genotype data or permutation of s le labels in the original GWAS data thus, it is computationally efficient.

Meta‐analysis of Genome‐Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Publisher: Wiley

Date: 28-01-2015

DOI: 10.1002/GEPI.21886

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Publisher: Springer Science and Business Media LLC

Date: 06-01-2013

DOI: 10.1038/NG.2506

PARP1 polymorphisms play opposing roles in melanoma occurrence and survival

Publisher: Wiley

Date: 06-11-2015

DOI: 10.1002/IJC.29280

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level

Publisher: BMJ

Date: 26-07-2022

DOI: 10.1136/GUTJNL-2021-326698

Abstract: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. We combined data from previous GWAS with new cohorts, increasing the s le size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-2011

DOI: 10.1097/OGX.0B013E318210CEA1

Higher polygenic risk for melanoma is associated with improved survival

Publisher: Cold Spring Harbor Laboratory

Date: 12-03-2022

DOI: 10.1101/2022.03.07.22272003

Abstract: Although there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA 5,762 patients with melanoma 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P ×10 −8 ) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08×10 −8 ) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77—3.21, P=1.07×10 −8 ) on chromosome 7. While neither SNP replicated (P .05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83—0.94, P=6.93×10 −5 I 2 =88%). The association with the PRS was not replicated (P 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results. We found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Publisher: BMJ

Date: 02-08-2016

DOI: 10.1136/GUTJNL-2016-311622

A genomewide association study of nicotine and alcohol dependence in Australian and dutch populations

Publisher: No publisher found

Date: 2010

DOI: 10.1375/TWIN.13.1.10 10.1375/TWIN.13.1.10 [PII]

Erratum: Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images (PLoS Genet (2021) 17:5 (e1009497) DOI: 10.1371/journal.pgen.1009497)

Publisher: Public Library of Science (PLoS)

Date: 18-10-2021

DOI: 10.1371/JOURNAL.PGEN.1009858

Evaluating a Causal Relationship between Complement Factor I Protein Level and Advanced Age-Related Macular Degeneration Using Mendelian Randomization

Publisher: Elsevier BV

Date: 06-2022

DOI: 10.1016/J.XOPS.2022.100146

Rare variants in optic disc area gene CARD10 enriched in primary open-angle glaucoma

Publisher: Wiley

Date: 03-10-2016

DOI: 10.1002/MGG3.248

Using Mendelian randomization to evaluate the causal relationship between serum C-reactive protein levels and age-related macular degeneration

Publisher: Springer Science and Business Media LLC

Date: 03-01-2020

DOI: 10.1007/S10654-019-00598-Z

Abstract: Serum C-reactive protein (CRP), an important inflammatory marker, has been associated with age-related macular degeneration (AMD) in observational studies however, the findings are inconsistent. It remains unclear whether the association between circulating CRP levels and AMD is causal. We used two-s le Mendelian randomization (MR) to evaluate the potential causal relationship between serum CRP levels and AMD risk. We derived genetic instruments for serum CRP levels in 418,642 participants of European ancestry from UK Biobank, and then conducted a genome-wide association study for 12,711 advanced AMD cases and 14,590 controls of European descent from the International AMD Genomics Consortium. Genetic variants which predicted elevated serum CRP levels were associated with advanced AMD (odds ratio [OR] for per standard deviation increase in serum CRP levels: 1.31, 95% confidence interval [CI]: 1.19-1.44, P = 5.2 × 10

The relationship between open angle glaucoma, optic disc morphology and Alzheimer’s Disease: a Mendelian randomization study

Publisher: Cold Spring Harbor Laboratory

Date: 02-09-2020

DOI: 10.1101/2020.08.30.20184846

Abstract: Alzheimer’s disease (AD) and open angle glaucoma (OAG) are common age-related neurodegenerative disorders with shared pathological features, leading to the hypothesis that glaucoma may represent a type of “ocular Alzheimer’s disease”. However, no causal relationship has yet been established. To test for a causal relationship, bi-directional two-s le Mendelian randomization analyses were performed using summary data from the largest available genome-wide association studies of AD and OAG. The effect on AD risk from exposure to genetically predicted OAG was measured using 24 single nucleotide polymorphisms (SNPs). In the reverse direction, the effect on glaucoma risk from exposure to genetically predicted AD was measured using 25 SNPs. Additionally, the relationship between AD and measurements of optic disc morphology (vertical cup:disc ratio (VCDR), optic cup area, optic disc area) and intraocular pressure (IOP) were investigated. People with congenitally larger optic discs, a phenotype not regarded to be related to glaucoma, had a lower risk of AD (OR=0.80 per mm 2 increase in disc area 95%CI=0.66,0.97 P =0.02) and people with genetically predicted AD had smaller optic disc sizes (−0.03 standard deviation change in mm 2 optic disc area per doubling odds of AD, 95%CI=-0.05,0.00 P -value=0.03). However, there was little evidence that exposure to genetically predicted OAG affected AD risk (OR=1.00 per doubling odds of OAG, 95%CI=0.98,1.03 P =0.83). Nor did genetically predicted IOP, VCDR or optic cup area influence AD risk. In the reverse direction, there was little evidence that genetically predicted AD had a causal effect on risk of OAG, IOP, VCDR or optic cup area. Genetic analyses show that congenital optic disc area influences AD risk but provide little support for a causal relationship between OAG and AD, suggesting that previous observed associations between OAG and AD may be due to reverse causation, confounding or other forms of bias. Glaucoma refers to a heterogenous group of neurodegenerative conditions characterised by progressive optic nerve head cupping and visual field loss. Primary open-angle glaucoma (POAG) is the commonest age-related glaucoma, accounting for 2/3 of all glaucoma cases. Elevated intraocular pressure (defined as IOP mmHg), age, myopia (negative refractive error), and family history are the main risk factors for POAG. Indeed, POAG is usually diagnosed on the basis of elevated IOP or diurnal spikes in IOP combined with progressive optic nerve head cupping and visual field loss. Furthermore, normal neuroretinal rim width (Figure 1) follows the ISNT rule (inferior superior nasal temporal) and so vertical optic cup:disc ratio (VCDR) is used clinically to distinguish pathological glaucomatous cupping from physiological cupping. The caveat is that congenitally larger optic discs tend to have larger physiological optic cups, and so optic cup area needs to be adjusted for optic disc area (Figure 1). While glaucoma is characterised by progressive increases in optic cup size, optic disc area does not change over a lifetime. IOP is the only modifiable risk factor for glaucoma and surgical, laser and medical interventions which lower IOP have been proven to slow down the progression of glaucomatous optic disc cupping and visual field loss. In contrast, elevated IOP without glaucomatous optic disc cupping or visual field loss is defined as ocular hypertension, not glaucoma. Measurements of IOP by applanation tonometry can be influenced by central corneal thickness, resistance, and hysteresis, and need to be corrected for these factors, e.g. by using the Ocular Response Analyzer. Nevertheless, the probability of converting from untreated ocular hypertension to POAG is ~2-3% per year. Some people develop progressive optic nerve head cupping and visual field loss despite IOP mmHg): so-called normal tension glaucoma (NTG). POAG and NTG are widely considered to represent a continuum in open angle glaucoma (OAG), and they are strongly correlated genetically (Figure 9). Nonetheless, risk factors other than IOP appear to be more important to the pathogenesis of NTG. For ex le, migraine, vasospasm, systemic hypotension and primary vascular dysregulation have all been associated with NTG (Figure 1). Many have also been linked to Alzheimer’s dementia. Many GWAS do not distinguish between POAG and NTG yet, this may be important to studies conducted in different populations since the prevalence of NTG varies widely depending on ethnicity. For ex le, ~30% of open angle glaucoma cases of European-descent have normal IOP, whereas % of open angle glaucoma cases in Japan have normal IOP. Furthermore, several GWAS have identified new risk loci for glaucoma from related phenotypes: IOP, corneal thickness, resistance and hysteresis, VCDR, and optic cup area (Figure 1). These phenotypes make powerful quantitative traits in GWAS and they are highly heritable across populations, but they are not sufficient in idually to meet the diagnostic definition of glaucoma. The importance is that some of these phenotypes, e.g. optic disc cupping, are not specific to glaucoma. Indeed, the differential diagnosis for optic disc cupping includes compressive lesions (e.g. pituitary macroadenoma), ischaemic, demyelinating, inflammatory, infiltrative, infectious, congenital and inherited disorders of the optic nerve. Therefore, signs of neurodegeneration in the eye, like optic disc cupping, can arise from a variety of aetiologies and not just glaucoma (Figure 1). Several epidemiological studies from the US, France, Germany, Australia, South Korea, Taiwan, and Japan have reported that open angle glaucoma (OAG) is more prevalent among people with Alzheimer’s disease (AD) or that AD is more prevalent among people with OAG. However, other studies have reported no association. We searched PubMed for studies published between database inception and 28 January 2020 that had investigated the relationship between Alzheimer’s disease and glaucoma using the search terms (“Alzheimer” or “Alzheimer’s” and glaucoma”). Papers in English and other languages were included, if there was an English abstract for assessment. We found the putative relationship between AD and glaucoma was the subject of several reviews and two meta-analyses. The first meta-analysis of 8 observational studies (6870 AD cases) concluded people with OAG have an increased risk of AD (RR=1.52 95% CI: 1.41-1.63 I 2 =97%, p .001). A positive association was found when analyses were restricted to Asia (RR=2.03 95%CI: 1.02-4.07) but not when they were restricted to America (RR=0.91 95%CI: 0.89-0.94). The second systematic review of 10 studies found that people with AD (RR=0.92 95% 95%CI:0.89-0.94 I 2 =89%, p .001) or dementia (RR=0.94 95%CI: 0.92-0.96 I 2 = 89.4%, p .001) had a lower risk of OAG. The studies cited in both reviews differed in case definition, ascertainment and population ethnicity, and were highly heterogenous in study design: results varied from large positive associations in small studies to negative or null estimates in cohort and record-linkage studies. Mechanistically, many authors have suggested that OAG is linked to intracranial pressure (ICP). It is reported that ICP is lower in people with OAG than healthy controls and ICP is lower in people with normal tension glaucoma (NTG) than people with OAG associated with elevated intraocular pressure (IOP). Turnover of cerebrospinal fluid (CSF) halves from birth to old age and is significantly reduced in people with AD and normal pressure hydrocephalus (NPH). In addition, people with NPH who receive ventriculoperitoneal shunts have increased risk of NTG. Hence, some authors have hypothesised that raised translaminar pressure gradient (the difference between IOP and ICP across the laminar cribrosa of the optic nerve head) may be responsible for the pathogenesis of glaucoma because this hypothesis would explain why it is both possible for some people to develop progressive optic nerve head cupping and visual field loss despite IOPs in the normal range, while raised IOP alone is insufficient to cause glaucoma in others (i.e. glaucoma is caused by low ICP). As low ICP is associated with AD, low ICP may be the mechanistic link between AD and OAG (Figure 2). An alternative hypothesis is that the production, circulation and absorption of intraocular fluid shares similar mechanisms to that of cerebrospinal fluid, and the failure of these mechanisms leads to the build-up of neurotoxins in OAG and AD. This hypothesis might explain why Aβ proteins and tau are detected in the retina of people affected by OAG and AD. In support of this hypothesis, there is substantial overlap in gene expression in the ciliary body compared with the choroid plexus, e.g. ion and water channels and transporters, and the renin-angiotensin system. There may also be a role for the glymphatic system, which provides a mechanism for the clearance of soluble waste products, e.g. Aβ protein in ocular fluid or CSF. The influx and efflux of CSF into the glymphatic system occurs via periarterial and perivenous spaces respectively, which finally drain into dural and cervical lymphatic vessels. The optic nerve is surrounded by CSF and is thought to have its own specialised glymphatic network. Here, the lamina cribrosa provides an additional barrier to fluid transport from inside the eye to the optic nerve in a manner that is dependent on translaminar pressure gradient. In models of glaucoma, defects in the lamina cribrosa are associated with the redirection of potentially harmful solutes, e.g. Aβ protein, from the intra-axonal compartment and glymphatic system of the optic nerve to its extracellular spaces. This leads to the build-up of potentially harmful solutes within the optic nerve and the degeneration of retinal ganglion cell axons. Though not well understood, it is possible that similar abnormalities in the glymphatic system of the brain might exist in AD leading to the accumulation of neurotoxins. There is also evidence that trans-synaptic neurodegeneration in the eye, e.g. from glaucoma, causes secondary neurodegeneration in functionally connected subcortical and cortical structures in the brain. Likewise, neurodegenerative processes in the brain, e.g. from dementia, can cause secondary neurodegeneration of the optic nerve. Tau pathology in AD is known to spread over time and could conceivably cause secondary neurodegeneration in the eye. Furthermore, amyloid microangiopathy can affect retinal and choroidal vasculature as well as cerebral blood flow in AD. Although amyloid microangiopathy has not been investigated in glaucoma, vascular dysfunction and genes involved in vascular endothelial morphology and genesis are consistently implicated in glaucoma. Hence, the neurodegenerative processes and vascular abnormalities common to both disorders might explain why they are both associated with visual field defects and the degeneration of retinal ganglion cells (RGCs). Studies using optical coherence tomography (OCT) imaging of the fundus have shown that thinning of the retinal nerve fibre layer (RNFL: the layer composed of RGC axons) and ganglion cell-inner plexiform layer (GC-IPL: composed of RGC bodies and dendrites) associate with future cognitive decline and dementia diagnosis. People with known glaucoma diagnoses were excluded from these analyses. However, the optic nerve is composed of RGC axons, which means that thinning of the RNFL and/or GC-IPL are signs of optic neuropathy from any cause, not just OAG. Hence, signs of neurodegeneration have been detected in the eye using OCT that are associated with future cognitive decline, but previous studies have not been designed to show whether these changes represent early OAG or whether they result from other unrelated neurogenerative processes affecting RGCs that are causally related to AD. Prior to this study, it was not clear whether there was a causal relationship between OAG and AD, whether their shared pathological features were merely non-specific signs of neurodegeneration, or whether some people were coincidentally affected by both disorders because of their high prevalence in older adults. Using the largest available population cohorts to maximize our statistical power (International Genomics of Alzheimer’s Project (IGAP), Alzheimer’s disease working group of the Psychiatric Genomics Consortium (PGC-ALZ), Alzheimer’s Disease Sequencing Project (ADSP), National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD) consortium and UK Biobank) we compared the results of observational epidemiological studies with causal estimates from Mendelian Randomization (MR) analyses to make causal inferences about the biological relationship between AD and OAG. In contrast to previous observational reports of an association between OAG and AD, we found weak evidence of a causal relationship between AD and OAG in either direction. Nor did we find strong evidence of a causal relationship between intraocular pressure (IOP), vertical cup:disc ratio (VCDR), and optic cup area with AD. Our data did, however, suggest that larger congenital optic disc size has a protective effect on AD risk. The genetic evidence in this study does not provide support for a causal relationship between AD and OAG or any related glaucoma phenotype, suggesting that the observed associations in previous studies were due to reverse causation, confounding and other types of bias. One possible source is collider bias, which occurs when two variables, e.g. AD and raised IOP, can independently cause a third collider variable, e.g. optic disc cupping and/or other signs of RGC degeneration: signs that are generally used to diagnose OAG. Collider bias is also an issue in studies of phenotypes related to glaucoma that are also used to define case-control status in the same cohort, e.g. IOP. In other words, conditioning on phenotypes which are also used to ascertain case-control status will bias the analyses. An additional source of bias may be caused by methods of ascertainment. GWAS generally define OAG based on a threshold for optic disc cupping +/-raised IOP, but non-progressive optic disc cupping is not glaucoma. Moreover, other possible causes of optic disc cupping, e.g. compressive or congenital (Panel), would not be excluded by a single anterior segment examination, but would require further investigation, e.g. MRI head scan, and serial measurements over time. Evidence that larger optic disc area is protective against AD or that people born with smaller optic discs have a greater risk of AD in future might support the idea of “cognitive reserve”, i.e. people with larger optic nerves and other correlated neuronal structures may be more resilient to age-related neurodegenerative processes. The links between specific genetic variants, e.g. APOE , optic disc size and educational attainment with AD suggest there may be several biological pathways that are causally related to AD (Figure 10). In summary, clinicians and scientists should be aware there is little evidence for a causal relationship between AD and OAG. OAG is widely considered to be an IOP-driven disease indeed, IOP mmHg is often used to diagnose POAG. However, this definition of glaucoma can lead to bias. Neurodegenerative changes affecting the eye can arise from multiple aetiologies and it is possible that IOP, AD and other unknown factors are independent risk factors that cause a similar pattern of RGC degeneration. Without strong evidence of a causal relationship, we predict little benefit in repurposing drugs developed for AD in clinical trials for OAG, except where they target common downstream pathways of neurodegeneration.

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Publisher: American Association for Cancer Research (AACR)

Date: 30-11-2015

DOI: 10.1158/1078-0432.CCR-15-0632

Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res 21(23) 5264–76. ©2015 AACR.

Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration

Publisher: Springer Science and Business Media LLC

Date: 10-04-2020

DOI: 10.1038/S10038-020-0750-X

Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Publisher: Springer Science and Business Media LLC

Date: 29-06-2023

DOI: 10.1038/S41588-023-01428-5

Abstract: Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total s le size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total s le size over 2.8 million 296 loci replicated at P 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus.

Germline variants are associated with increased primary melanoma tumor thickness at diagnosis

Publisher: Oxford University Press (OUP)

Date: 17-10-2020

DOI: 10.1093/HMG/DDAA222

Abstract: Germline genetic variants have been identified, which predispose in iduals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 in iduals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated in iduals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 in iduals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P & 5 × 10−8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.

Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Publisher: Wiley

Date: 02-04-2018

DOI: 10.1002/CAM4.1445

Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation ( r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy ( P = 6.0 × 10 −3 ) and concordance in effect direction ( P = 2.0 × 10 −3 ) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level ( P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.

Identification of a genetic variant associated with treatment outcome in ovarian cancer: the potential role of cholesterol metabolism as a determinant of response to chemotherapy

Publisher: Springer Science and Business Media LLC

Date: 2012

DOI: 10.1186/1897-4287-10-S2-A36

Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Publisher: Springer Science and Business Media LLC

Date: 13-05-2016

DOI: 10.1038/SREP25853

Abstract: Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7–15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E–08) and 2.3% (P = 6.9E–21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry s les (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4 P = 6.3E–04).

Naïve and memory B cells exhibit distinct biochemical responses following BCR engagement.

Publisher: Wiley

Date: 17-05-2016

DOI: 10.1038/ICB.2016.41

Abstract: Immunological memory is characterized by the rapid reactivation of memory B cells that produce large quantities of high-affinity antigen-specific antibodies. This contrasts the response of naïve B cells, and the primary immune response, which is much slower and of lower affinity. Memory responses are critical for protection against infectious diseases and form the basis of most currently available vaccines. Although we have known about the phenomenon of long-lived memory for centuries, the biochemical differences underlying these erse responses of naïve and memory B cells is incompletely resolved. Here we investigated the nature of B-cell receptor (BCR) signaling in human splenic naïve, IgM(+) memory and isotype-switched memory B cells following multivalent BCR crosslinking. We observed comparable rapid and transient phosphorylation kinetics for proximal (phosphotyrosine and spleen tyrosine kinase) and propagation (B-cell linker, phospholipase Cγ2) signaling components in these different B-cell subsets. However, the magnitude of activation of downstream components of the BCR signaling pathway were greater in memory compared with naïve cells. Although no differences were observed in the magnitude of Ca(2+) mobilization between subsets, IgM(+) memory B cells exhibited a more rapid Ca(2+) mobilization and a greater depletion of the Ca(2+) endoplasmic reticulum stores, while IgG(+) memory B cells had a prolonged Ca(2+) uptake. Collectively, our findings show that intrinsic signaling features of B-cell subsets contribute to the robust response of human memory B cells over naïve B cells. This has implications for our understanding of memory B-cell responses and provides a framework to modulate these responses in the setting of vaccination and immunopathologies, such as immunodeficiency and autoimmunity.

When do myopia genes have their effect? Comparison of genetic risks between children and adults

Publisher: Wiley

Date: 09-09-2016

DOI: 10.1002/GEPI.21999

Abstract: Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 in iduals aged 25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10-25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated and in adults 20 loci were associated. Association with GRS increased with age β = 0.0016 per risk allele (P = 2 × 10

A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies

Publisher: Wiley

Date: 22-11-2010

DOI: 10.1002/GEPI.20541

Potential influence of socioeconomic status on genetic correlations between alcohol consumption measures and mental health

Publisher: Cambridge University Press (CUP)

Date: 15-03-2019

DOI: 10.1017/S0033291719000357

Abstract: Background. Frequency and quantity of alcohol consumption are metrics commonly used to measure alcohol consumption behaviors. Epidemiological studies indicate that these alcohol consumption measures are differentially associated with (mental) health outcomes and socioeconomic status (SES). The current study aims to elucidate to what extent genetic risk factors are shared between frequency and quantity of alcohol consumption, and how these alcohol consumption measures are genetically associated with four broad phenotypic categories: (i) SES (ii) substance use disorders (iii) other psychiatric disorders and (iv) psychological ersonality traits. Methods. Genome-Wide Association analyses were conducted to test genetic associations with alcohol consumption frequency ( N = 438 308) and alcohol consumption quantity ( N = 307 098 regular alcohol drinkers) within UK Biobank. For the other phenotypes, we used genome-wide association studies summary statistics. Genetic correlations ( r g ) between the alcohol measures and other phenotypes were estimated using LD score regression. Results. We found a substantial genetic correlation between the frequency and quantity of alcohol consumption ( r g = 0.52). Nevertheless, both measures consistently showed opposite genetic correlations with SES traits, and many substance use, psychiatric, and psychological ersonality traits. High alcohol consumption frequency was genetically associated with high SES and low risk of substance use disorders and other psychiatric disorders, whereas the opposite applies for high alcohol consumption quantity. Conclusions. Although the frequency and quantity of alcohol consumption show substantial genetic overlap, they consistently show opposite patterns of genetic associations with SES-related phenotypes. Future studies should carefully consider the potential influence of SES on the shared genetic etiology between alcohol and adverse (mental) health outcomes.

LocusTrack: Integrated visualization of GWAS results and genomic annotation

Publisher: Springer Science and Business Media LLC

Date: 03-02-2015

DOI: 10.1186/S13029-015-0032-8

Author Correction: Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases (Nature Communications, (2019), 10, 1, (4219), 10.1038/s41467-019-11968-2)

Publisher: Springer Science and Business Media LLC

Date: 04-12-2019

DOI: 10.1038/S41467-019-13526-2

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A large cross-ancestry meta-analysis of genome-wide association studies identifies 69 novel risk loci for primary open-angle glaucoma and includes a genetic link with Alzheimer's disease

Publisher: Cold Spring Harbor Laboratory

Date: 03-02-2020

DOI: 10.1101/2020.01.30.927822

Abstract: We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.

Risk Factors Associated With First and Second Primary Melanomas in a High-Incidence Population

Publisher: American Medical Association (AMA)

Date: 2023

DOI: 10.1001/JAMADERMATOL.2022.4975

Abstract: An increasing number of people develop more than 1 primary melanoma, yet to date, no population-based prospective cohort studies have reported on risk factors for developing first vs second primary melanomas. To compare the clinical characteristics of first and second melanomas and then to estimate the relative risks of developing 1 vs multiple melanomas associated with demographic, phenotypic, sun exposure, and genetic factors. This population-based prospective cohort study included men and women aged 40 to 69 years recruited in 2011 and followed up until December 2018 in Queensland, Australia. Data analysis was performed from February to July 2022. Self-reported information about demographic, phenotypic, and sun exposure measures captured using a survey completed at baseline, and polygenic risk score for melanoma. Incident first or second primary melanoma diagnosis, and histologic and clinical characteristics thereof. The Wei-Lin-Weissfeld model for recurrent events was used to estimate the association of each factor with the risks of first and second primary melanoma. A total of 38 845 patients (mean [SD] age at baseline, 56.1 [8.2] years 17 775 men and 21 070 women) were included in the study. During a median follow-up period of 7.4 years, 1212 (3.1%) participants had a single primary melanoma diagnosis, and 245 (0.6%) had a second primary melanoma diagnosis. Second melanomas were more likely than first melanomas to be in situ for invasive tumors, second melanomas were more likely to be thin (ie, ≤1 mm) than first melanomas. Having many moles at age 21 years (self-reported using visual scoring tool) was more strongly associated with second (hazard ratio [HR], 6.36 95% CI, 3.77-10.75) than first primary melanoma (HR, 3.46 95% CI, 2.72-4.40) ( P value for difference between the HRs = .01). A high genetic predisposition (ie, polygenic risk score in tertile 3) was also more strongly associated with second (HR, 3.28 95% CI, 2.06-5.23) than first melanoma (HR, 2.06 95% CI, 1.71-2.49 P = .03). Second melanomas were more strongly associated with a history of multiple skin cancer excisions (HR, 2.63 95% CI, 1.80-3.83) than first melanomas (HR, 1.86 95% CI, 1.61-2.16 P = .05). For all other phenotypic characteristics and sun exposure measures, similarly elevated associations with first vs second melanomas were observed. Findings of this cohort study suggest that within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanomas.

Rare chromosomal deletions and duplications increase risk of schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 30-07-2008

DOI: 10.1038/NATURE07239

Retinal microvessels reflect familial vulnerability to psychotic symptoms: A comparison of twins discordant for psychotic symptoms and controls

Publisher: Elsevier BV

Date: 05-2015

DOI: 10.1016/J.SCHRES.2015.01.045

Height and overall cancer risk and mortality: Evidence from a Mendelian randomisation study on 310,000 UK Biobank participants /692/308/174 /692/499 article

Publisher: Springer Science and Business Media LLC

Date: 27-03-2018

DOI: 10.1038/S41416-018-0063-4

Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

Publisher: Cold Spring Harbor Laboratory

Date: 09-09-2018

DOI: 10.1101/412098

Abstract: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. This study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from “daily or almost daily” to “never”, 438,308 in iduals AC-Quantity: total units of alcohol per week, 307,098 in iduals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits. Positive genetic correlation was observed between MD and AD (rg MD-AD =+0.47, P =6.6×10 -10 ). AC-Quantity showed positive genetic correlation with both AD (rg AD-AC-Quantity =+0.75, P =1.8×10 -14 ) and MD (rg MD-AC-Quantity =+0.14, P =2.9×10 -7 ), while there was negative correlation of AC-Frequency with MD (rg MD-AC-Frequency =-0.17, P =1.5×10 -10 ) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P =1.29×10 -6 ) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD. Results support a causal role for MD on AD based on genetic datasets including thousands of in iduals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts. National Institute of Mental Health and National Institute on Drug Abuse. We searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms “alcohol” AND “depression” AND “Mendelian Randomization”. No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase ( ADH ) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased s le sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-s le Mendelian randomization to investigate causal relationships between alcohol dependence and major depression. Twin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large s le sizes to be informative. In this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of in iduals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence. Given the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization

Publisher: Springer Science and Business Media LLC

Date: 15-11-2018

DOI: 10.1038/S41598-018-34713-Z

Abstract: Consumption of coffee, tea and alcohol might be shaped by in idual differences in bitter taste perception but inconsistent observational findings provide little insight regarding causality. We conducted Mendelian randomization analyses using genetic variants associated with the perception of bitter substances (rs1726866 for propylthiouracil [PROP], rs10772420 for quinine and rs2597979 for caffeine) to evaluate the intake of coffee, tea and alcohol among up to 438,870 UK Biobank participants. A standard deviation (SD) higher in genetically predicted bitterness of caffeine was associated with increased coffee intake (0.146 [95%CI: 0.103, 0.189] cups/day), whereas a SD higher in those of PROP and quinine was associated with decreased coffee intake (−0.021 [−0.031, −0.011] and −0.081 [−0.108, −0.054] cups/day respectively). Higher caffeine perception was also associated with increased risk of being a heavy ( cups/day) coffee drinker (OR 1.207 [1.126, 1.294]). Opposite pattern of associations was observed for tea possibly due to the inverse relationship between both beverages. Alcohol intake was only negatively associated with PROP perception (−0.141 [−1.88, −0.94] times/month per SD increase in PROP bitterness). Our results reveal that bitter perception is causally associated with intake of coffee, tea and alcohol, suggesting a role of bitter taste in the development of bitter beverage consumption.

VEGAS2: Software for more flexible gene-based testing

Publisher: Cambridge University Press (CUP)

Date: 18-12-2015

DOI: 10.1017/THG.2014.79

Abstract: Gene-based tests such as ve rsatile g ene-based a ssociation s tudy (VEGAS) are commonly used following per-single nucleotide polymorphism (SNP) GWAS (genome-wide association studies) analysis. Two limitations of VEGAS were that the HapMap2 reference set was used to model the correlation between SNPs and only autosomal genes were considered. HapMap2 has now been superseded by the 1,000 Genomes reference set, and whereas early GWASs frequently ignored the X chromosome, it is now commonly included. Here we have developed VEGAS2, an extension that uses 1,000 Genomes data to model SNP correlations across the autosomes and chromosome X. VEGAS2 allows greater flexibility when defining gene boundaries. VEGAS2 offers both a user-friendly, web-based front end and a command line Linux version. The online version of VEGAS2 can be accessed through vegas2.qimrberghofer.edu.au/ . The command line version can be downloaded from vegas2.qimrberghofer.edu.au/zVEGAS2offline.tgz . The command line version is developed in Perl, R and shell scripting languages source code is available for further development.

Associations of sleep apnoea with glaucoma and age-related macular degeneration

Publisher: Springer Science and Business Media LLC

Date: 11-05-2021

DOI: 10.1186/S12916-021-01973-Y

Abstract: Sleep apnoea, a common sleep-disordered breathing condition, is characterised by upper airway collapse during sleep resulting in transient hypoxia, hypoperfusion of the optic nerve, and spike in intracranial pressure. Previous studies have reported conflicting findings on the association of sleep apnoea with glaucoma, and there are limited reports on the link between sleep apnoea and age-related macular degeneration (AMD). Middle-aged and older participants from the longitudinal United Kingdom (UK) Biobank ( n = 502,505) and the Canadian Longitudinal Study on Aging (CLSA n = 24,073) were included in this analysis. Participants in the UK Biobank and the CLSA were followed for 8 and 3 years, respectively. Participants with diagnosed glaucoma or AMD at baseline were excluded from the analysis. In the UK Biobank, sleep apnoea and incident cases of glaucoma and AMD were identified through hospital inpatient admission, primary care records, and self-reported data. Multivariable Cox proportional hazards models were used to explore associations of sleep apnoea with incidence of glaucoma or AMD. During the 8-year follow-up in the UK Biobank, glaucoma incidence rates per 1000 person-years were 2.46 and 1.59 for participants with and without sleep apnoea, and the AMD incidence rates per 1000 person-years were 2.27 and 1.42 for participants with and without sleep apnoea, respectively. Multivariable adjusted hazard ratios of glaucoma and AMD risk for sleep apnoea were 1.33 (95% confidence interval [CI] 1.10–1.60, P = 0.003) and 1.39 (95% CI 1.15–1.68, P 0.001) relative to participants without sleep apnoea. In the CLSA cohort, disease information was collected through in-person interview questionnaires. During the 3-year follow-up, glaucoma incidence rates per 1000 person-years for those with and without sleep apnoea were 9.31 and 6.97, and the AMD incidence rates per 1000 person-years were 8.44 and 6.67, respectively. In the CLSA, similar associations were identified, with glaucoma and AMD odds ratios of 1.43 (95% CI 1.13–1.79) and 1.39 (95% CI 1.08–1.77), respectively, in participants with sleep apnoea compared to those without sleep apnoea (both P 0.001). In two large-scale prospective cohort studies, sleep apnoea is associated with a higher risk of both glaucoma and AMD. These findings indicate that patients with sleep apnoea might benefit from regular ophthalmologic examinations.

Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.AJHG.2013.06.016

Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett's Esophagus, and Gastroesophageal Reflux

Publisher: Oxford University Press (OUP)

Date: 29-10-2013

DOI: 10.1093/JNCI/DJT303

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution

Publisher: Springer Science and Business Media LLC

Date: 18-02-2019

DOI: 10.1038/S41588-018-0334-2

The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study

Publisher: Oxford University Press (OUP)

Date: 19-11-2020

DOI: 10.1093/IJE/DYAA178

Abstract: Age-related macular degeneration (AMD) is a leading cause of vision loss. Whereas lipids have been studied extensively to understand their effects on cardiovascular diseases, their relationship with AMD remains unclear. Two-s le Mendelian randomization (MR) analyses were performed to systematically evaluate the causal relationships between eight serum lipid biomarkers, consisting of apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), total cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), direct low-density lipoprotein cholesterol (LDL-C), lipoprotein A [Lp(a)], triglycerides (TG) and non-HDL cholesterol (non-HDL-C), and the risk of different AMD stages and subtypes. We derived 64–407 genetic instruments for eight serum lipid biomarkers in 419 649 participants of European descent from the UK Biobank cohort. We conducted genome-wide association studies (GWAS) for 12 711 advanced AMD cases [8544 choroidal neovascularization (CNV) and 2656 geographic atrophy (GA) specific AMD subtypes] and 5336 intermediate AMD cases with 14 590 controls of European descent from the International AMD Genomics Consortium. Higher genetically predicted HDL-C and ApoA1 levels increased the risk of all AMD subtypes. LDL-C, ApoB, CHOL and non-HDL-C levels were associated with decreased risk of intermediate and GA AMD but not with CNV. Genetically predicted TG levels were associated with decreased risk of different AMD subtypes. Sensitivity analyses revealed no evidence for directional pleiotropy effects. In our multivariable MR analyses, adjusting for the effects of correlated lipid biomarkers yielded similar results. These results suggest the role of lipid metabolism in drusen formation and particularly in AMD development at the early and intermediate stages. Mechanistic studies are warranted to investigate the utility of lipid pathways for therapeutic treatment in preventing AMD.

Genome-Wide Meta-analysis Identifies Risk Loci and Improves Disease Prediction of Age-Related Macular Degeneration

Publisher: Elsevier BV

Date: 08-2023

DOI: 10.1016/J.OPHTHA.2023.08.023

Association of High Polygenic Risk With Visual Field Worsening Despite Treatment in Early Primary Open-Angle Glaucoma.

Publisher: American Medical Association (AMA)

Date: 2022

DOI: 10.1001/JAMAOPHTHALMOL.2022.4688

Abstract: Irreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of in iduals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk in iduals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma. To assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease. This cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022. The association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields. A total of 1777 eyes from 896 in iduals had sufficient data for structural progression analyses and 1563 eyes from 808 in iduals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 in iduals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. In iduals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5 95% CI, 1.13-1.97 P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52 95% CI, 0.28-0.96 P = .04). In this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify in iduals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.

Vitamin D receptor gene polymorphisms have negligible effect on human height

Publisher: No publisher found

Date: 2008

DOI: 10.1375/TWIN.11.5.488 10.1375/TWIN.11.5.488 [PII]

Targeted fishes are larger and more abundant in 'no-take' areas in a subtropical marine park

Publisher: Elsevier BV

Date: 11-2018

DOI: 10.1016/J.ECSS.2018.07.003

Examining Evidence for a Causal Association between Telomere Length and Nevus Count

Publisher: Elsevier BV

Date: 05-2022

DOI: 10.1016/J.JID.2021.09.021

Genetics of schizophrenia and bipolar affective disorder: Strategies to identify candidate genes

Publisher: Cold Spring Harbor Laboratory

Date: 2003

DOI: 10.1101/SQB.2003.68.383

Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting

Publisher: Springer Science and Business Media LLC

Date: 05-09-2022

DOI: 10.1186/S12967-022-03613-2

Abstract: The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA 5,762 patients with melanoma 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P 5 × 10–8) results were investigated in the Leeds Melanoma Cohort (LMC 1,947 patients with melanoma 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts. Two loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, HR = 2.09, 95%CI = 1.61–2.71, P = 2.08 × 10–8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR = 2.38, 95%CI = 1.77–3.21, P = 1.07 × 10–8) on chromosome 7. While neither SNP replicated in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets. After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR = 0.88, 95% CI = 0.83–0.94, P = 6.93 × 10–5 I2 = 88%). However, this was only driven by the high UV setting cohort (MIA HR = 0.84, 95% CI = 0.78–0.90). We found two loci potentially associated with MSS. Increased genetic susceptibility to develop CM is associated with improved MSS in a high UV setting.

From GWAS to genome sequencing: complementary approaches to identify melanoma predisposition genes

Publisher: Springer Science and Business Media LLC

Date: 12-04-2012

DOI: 10.1186/1897-4287-10-S2-A46

Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/S1470-2045(16)30240-6

Common Genetic Variants near the Brittle Cornea Syndrome Locus ZNF469 Influence the Blinding Disease Risk Factor Central Corneal Thickness

Publisher: Public Library of Science (PLoS)

Date: 13-05-2010

DOI: 10.1371/JOURNAL.PGEN.1000947

Neuregulin 1 and age of onset in the major psychoses

Publisher: Springer Science and Business Media LLC

Date: 28-01-2009

DOI: 10.1007/S00702-008-0182-9

Abstract: Genetic vulnerability to psychiatric illness extends across major psychiatric illness. Neuregulin 1 (NRG1) is a large gene on chromosome 8p, that has been identified as a susceptibility factor in bipolar disorder and schizophrenia. In particular, a core at risk haplotype has received considerable attention for a putative role in the pathophysiology of the major psychoses (schizophrenia and bipolar disorder). This core haplotype can be represented by three markers 478B14-848, 420M9-1395, and SNP8NRG221533. We genotyped 312 families with bipolar probands, and 120 families with schizophrenia probands. Association of the core haplotype was tested for with age-at-onset and with three phenotypes: major psychosis, schizophrenia, and bipolar disorder. Neither age of onset (P = 0.893) nor the major psychosis phenotype (P = 0.374) was associated with the core haplotype in the overall s le. Ours was the first study to investigate the NRG1 core haplotype with age of onset of major psychoses, and despite our preliminary negative findings, this area deserves further investigation.

Convergent evidence that oligodendrocyte lineage transcription factor 2 ( OLIG2 ) and interacting genes influence susceptibility to schizo

Publisher: Proceedings of the National Academy of Sciences

Date: 15-08-2006

DOI: 10.1073/PNAS.0603029103

Abstract: Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 ( OLIG2 ) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control s le ( n = ≈1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP , NRG1 , and ERBB4 . We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1 . To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP ( P 10 −7 ) and ERBB4 ( P = 0.002, corrected P = 0.038) but not NRG1 . In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other’s expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Publisher: Springer Science and Business Media LLC

Date: 22-09-2014

DOI: 10.1038/NCOMMS5883

Abstract: Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 in iduals of European ancestry and 6,784 in iduals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Global Biobank Meta-Analysis Initiative: Powering genetic discovery across human diseases

Publisher: Cold Spring Harbor Laboratory

Date: 21-11-2021

DOI: 10.1101/2021.11.19.21266436

Abstract: Biobanks are being established across the world to understand the genetic, environmental, and epidemiological basis of human diseases with the goal of better prevention and treatments. Genome-wide association studies (GWAS) have been very successful at mapping genomic loci for a wide range of human diseases and traits, but in general, lack appropriate representation of erse ancestries - with most biobanks and preceding GWAS studies composed of in iduals of European ancestries. Here, we introduce the Global Biobank Meta-analysis Initiative (GBMI) -- a collaborative network of 19 biobanks from 4 continents representing more than 2.1 million consented in iduals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWAS generated using harmonized genotypes and phenotypes from member biobanks. GBMI brings together results from GWAS analysis across 6 main ancestry groups: approximately 33,000 of African ancestry either from Africa or from admixed-ancestry diaspora (AFR), 18,000 admixed American (AMR), 31,000 Central and South Asian (CSA), 341,000 East Asian (EAS), 1.4 million European (EUR), and 1,600 Middle Eastern (MID) in iduals. In this flagship project, we generated GWASs from across 14 exemplar diseases and endpoints, including both common and less prevalent diseases that were previously understudied. Using the genetic association results, we validate that GWASs conducted in biobanks worldwide can be successfully integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics between biobanks. We demonstrate the value of this collaborative effort to improve GWAS power for diseases, increase representation, benefit understudied diseases, and improve risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of the studied traits.

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Publisher: Springer Science and Business Media LLC

Date: 03-2023

DOI: 10.1038/S41588-023-01323-Z

Predicting the Future of Genetic Risk Profiling of Glaucoma

Publisher: American Medical Association (AMA)

Date: 02-2021

DOI: 10.1001/JAMAOPHTHALMOL.2020.5404

Cost-effectiveness of polygenic risk profiling for primary open-angle glaucoma in the United Kingdom and Australia

Publisher: Cold Spring Harbor Laboratory

Date: 19-02-2021

DOI: 10.1101/2021.02.18.21251906

Abstract: Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. Early diagnosis and intervention is proven to slow disease progression and reduce disease burden. Currently, population-based screening for POAG is not generally recommended due to cost. In this study, we evaluate the cost-effectiveness of polygenic risk profiling as a screening tool for POAG. We used a Markov cohort model to evaluate the cost-effectiveness of implementing polygenic risk profiling as a new POAG-screening approach in the UK and Australia. Six health states were included in this model: death, early, mild, moderate, severe, and healthy in iduals. The evaluation was conducted from the healthcare payer’s perspective. We used the best available published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. The study followed the CHEERS checklist. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided per person and a ‘Blindness ICER’. We did one-way and two-way deterministic and probabilistic sensitivity analyses to reflect the uncertainty around predicting ICERs. Our proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of £24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of £10,095 (95%CI: £5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively. We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK. Although the level of willingness to pay for Australian Government is uncertain, and the ICER range for the UK is broad, we showed a clear target strategy for early detection and prevention of advanced POAG in these developed countries. the Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence.

Cholesterol‐lowering genetic variants are not associated with the risk of skin cancer

Publisher: Wiley

Date: 16-02-2023

DOI: 10.1111/JDV.18886

A comparison of compliance in the estimation of body fluid status using daily fluid balance charting and body weight changes during continuous renal replacement therapy

Publisher: Elsevier BV

Date: 03-2019

DOI: 10.1016/J.AUCC.2017.12.090

European and Polynesian admixture in the Norfolk Island population

Publisher: Springer Science and Business Media LLC

Date: 09-12-2010

DOI: 10.1038/HDY.2009.175

Abstract: The Norfolk Island population in the South Pacific is primarily the product of recent admixture between a small number of British male and Polynesian female founders. We identified and genotyped 128 Ancestry Informative Markers (AIMs) spread across the autosomes, X/Y chromosomes and mitochondrial DNA genome, to explore and quantify the current levels of genetic admixture in the Norfolk Islanders. On the basis of autosomal AIMs, the population shows mean European and Polynesian ancestry proportions of 88 and 12%, respectively. However, there is a substantial variation between in iduals ranging from total European ancestry to near total Polynesian origin. There is a strong correlation between in idual genetic estimates of Polynesian ancestry and those derived from the extensive pedigree and genealogical records of Islanders. Also in line with historical accounts, there is a substantial asymmetry in the maternal and paternal origins of the Islanders with almost all Y-chromosomes of European origin whereas at least 25% of mtDNAs appear to have a Polynesian origin. Accurate knowledge of ancestry will be important in future attempts to use the Island population in admixture mapping approaches to find the genes that underlie differences in the risk to some diseases between Europeans and Polynesians.

Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis

Publisher: BMJ

Date: 29-06-2022

DOI: 10.1136/GUTJNL-2020-323906

Abstract: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. We applied multitrait GWAS models combining GERD (78 707 cases 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

Combined analysis of keratinocyte cancers identifies novel genome-wide loci

Publisher: Oxford University Press (OUP)

Date: 07-06-2019

DOI: 10.1093/HMG/DDZ121

Abstract: The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. In idual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

Investigating Genetic Heterogeneity in Major Depression Through Item-level Genetic Analyses of the PHQ-9

Publisher: Cold Spring Harbor Laboratory

Date: 23-01-2019

DOI: 10.1101/528067

Abstract: Major Depressive Disorder (MDD) is a clinically heterogeneous disorder. Previous large-scale genetic studies of MDD have explored genetic risk factors of MDD case-control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity. In this study, we present the results of symptom-level genetic analyses and compare SNP-based heritability ( h 2 SNP ) and genetic correlations across major depression symptoms. We further investigate genetic correlations with a range of psychiatric disorders and other associated traits. Methods: We have analysed data from the UK biobank and included 148,752 subjects of white British ancestry with genotype data who completed nine items of a self-rated measure of depression: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD score regression analysis was used to calculate SNP-based heritability ( h 2 SNP ) and genetic correlations (r g ) across symptoms and to investigate genetic correlations with 25 external phenotypes. Confirmatory factor analyses were applied to test whether one, two, or three-factor models best fit the pattern of genetic correlations across the nine symptoms. We identified 9 novel genome-wide significant genomic loci, with no overlap in loci across depression symptoms. h 2 SNP ranged from 3% (suicidal ideation) to 11% (fatigue). Genetic correlations range from 0.54 to 0.96 (all p 1.39×10 −3 ) with 30 of 36 correlations being significantly smaller than 1. A 3-factor model provided the best fit to the genetic correlation matrix, with factors representing “psychological”, “neurovegetative”, and “psychomotor / concentration” symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms. Patterns of h 2 SNP and genetic correlations differed across the nine symptoms of depression. Our findings suggest that the large phenotypic heterogeneity observed for MDD is recapitulated at a genetic level. Future studies should investigate how genetic heterogeneity in MDD influences the efficacy of clinical interventions.

Myocilin Gene Gln368Ter Variant Penetrance and Association with Glaucoma in Population-Based and Registry-Based Studies

Publisher: American Medical Association (AMA)

Date: 2019

DOI: 10.1001/JAMAOPHTHALMOL.2018.4477

Association of Novel Loci With Keratoconus Susceptibility in a Multitrait Genome-Wide Association Study of the UK Biobank Database and Canadian Longitudinal Study on Aging

Publisher: American Medical Association (AMA)

Date: 06-2022

DOI: 10.1001/JAMAOPHTHALMOL.2022.0891

Uncovering Novel Genetic Loci and Biological Pathways Associated with Age-Related Cataracts through GWAS Meta-Analysis

Publisher: Research Square Platform LLC

Date: 19-04-2023

DOI: 10.21203/RS.3.RS-2755149/V1

Abstract: Background Age-related cataract is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation (UVR), and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Further research into the genetic basis of cataracts could provide valuable insights into the disease's etiology and lead to a better understanding of biological mechanisms that are associated with its development. Methods This study presents the largest genome-wide association study of cataracts to date, using data from 127,985 cases and 837,371 controls. We performed gene enrichment analysis to identify genes and biological pathways associated with cataracts. We integrated our results with gene expression reference datasets to identify genetic variants modifying risk for cataracts through changes in the expression of specific genes. We further explored drug-gene interactions to better understand the potential impact of pharmacological interventions on cataract development. Finally, we explored whether a causal relationship underlies the known comorbidity between type 1 diabetes and cataracts using a mendelian randomization framework, and the association between UV exposure and cataract risk in adults using a polygenic risk scoring approach. Findings Our study identified 85 independent genome-wide significant loci, 37 of which are novel. Gene-based association tests identified 126 genes associated with cataracts, hinting at a potential relationship between negative regulation of lipid biosynthesis and the development of cataracts. Four of the genes identified GNL3 , JAG1 , METTL21A , and CREB1 are involved in drug-gene interactions. Moreover, Mendelian Randomisation analysis identified a putative causal relationship between genetic predisposition to type 1 diabetes and an increased risk of cataracts. Lastly, we found evidence indicating that early-life exposure to UVR may have an impact on the later development of cataracts. Interpretation Our findings advance our understanding of the genetic basis of cataract and provide new insights into its etiology. We identified multiple genes and biological pathways associated with the condition, including associations with four genes from which drug repurposing could be proposed. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults and drug-genes interactions that has the potential of informing novel therapies.

Supplementary Information from Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 31-03-2023

DOI: 10.1158/0008-5472.22433402

Abstract: Figures S1–S11, Tables S1–S6, Supplementary Materials and Methods, Supplementary Notes, and Supplementary References

Cardiovascular Disease Predicts Structural and Functional Progression in Early Glaucoma

Publisher: Elsevier BV

Date: 2021

DOI: 10.1016/J.OPHTHA.2020.06.067

Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma

Publisher: Cold Spring Harbor Laboratory

Date: 14-07-2021

DOI: 10.1101/2021.07.14.452417

Abstract: To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared to those from healthy in iduals. We performed single-cell RNA-sequencing of a total of 330,569 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 2,235 significant loci across all cell types, 58 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 54 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

Familiality of Postpartum Depression in Unipolar Disorder: Results of a Family Study

Publisher: American Psychiatric Association Publishing

Date: 09-2006

DOI: 10.1176/AJP.2006.163.9.1549

Abstract: The authors previously reported strong evidence for familial aggregation of postpartum (puerperal) psychotic episodes in women with bipolar disorder. The authors here examine whether vulnerability to postpartum triggering of depressive episodes aggregates in families and assess how this aggregation varies with the definition of postpartum onset. Postpartum depression occurrence was studied in the female members of 120 sibling pairs recruited at a site within an international multicenter study of sibling pairs with recurrent unipolar depression. Employing a range of definitions of postpartum onset, the authors examined concordance for postpartum episode status between sisters. Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months). Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery. The evidence for familiality maximized with a postpartum onset definition of 6-8 weeks. These results implicate familial factors in susceptibility to the triggering of narrowly defined postpartum depressive episodes in women with recurrent major depression. They suggest that a postnatal onset definition of within 6-8 weeks of delivery may be optimal in studies of the triggering of depressive illness by childbirth.

150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility

Publisher: Elsevier BV

Date: 07-2023

DOI: 10.1016/J.XGEN.2023.100326

Genetic Classification of Populations Using Supervised Learning

Publisher: Public Library of Science (PLoS)

Date: 12-05-2011

DOI: 10.1371/JOURNAL.PONE.0014802

Most pooling variation in array-based DNA pooling is attributable to array error rather than pool construction error

Publisher: Springer Science and Business Media LLC

Date: 31-01-2007

DOI: 10.1038/SJ.EJHG.5201768

Abstract: Genome-wide association (GWA) approaches are important in complex disease gene mapping studies but are often prohibitively expensive. Array-based DNA pooling has been shown to offer substantial cost savings compared with in idual genotyping. This reduced cost potentially brings well-powered GWA studies well within the reach of most laboratories. The main factor, which affects the efficiency of pooling compared with in idual genotyping is the magnitude of the pooling error variance. By examining variation between and within pools it is shown that most of the error associated with pooling is attributable to array variation not pooling construction variation (assuming the pools are not small and the pools are accurately constructed). With Affymetrix HindIII 50K arrays used here the array-specific variance is seven times the pooling construction variance. This has important implications for optimal study design for array-based pooling. Given carefully constructed pools, resources should be allocated to increasing the number of arrays per s le rather than to constructing multiple pools.

The Genetics of Myopia

Publisher: Springer Singapore

Date: 10-10-2019

DOI: 10.1007/978-981-13-8491-2_5

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

Publisher: Cold Spring Harbor Laboratory

Date: 17-12-2021

DOI: 10.1101/2021.12.16.21267891

Abstract: Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) with previously multi-ancestry studies. 18 novel significant loci, three of which were ancestry-specific, and five sex-specific were identified. We performed gene-enrichment and transcriptome-wide association studies (TWAS), implicating vascular and cancer genes. A fifth of these genes are primary ciliary genes. Extensive statistical analysis of genes in the SIX6 and CDKN2B-AS1 loci (implicated in POAG, cardiovascular diseases and cancers) found interaction between SIX6 and causal variants in chr9p21.3, with expression effect on CDKN2A/B . We infer that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our results further support the contribution of vascular, cancer, and primary cilia genes in POAG pathogenesis.

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma

Publisher: Oxford University Press (OUP)

Date: 31-08-2018

DOI: 10.1093/HMG/DDY282

The effect of screening on melanoma incidence and biopsy rates

Publisher: Oxford University Press (OUP)

Date: 10-2022

DOI: 10.1111/BJD.21649

Abstract: Cutaneous melanomas are common cancers in white-skinned populations, and early detection is promoted as a means of reducing morbidity and mortality. There is concern that increased skin screening is leading to overdiagnosis of indolent melanomas with low risk of lethality. The extent of melanoma overdiagnosis associated with screening is unknown. To estimate possible overdiagnosis by comparing subsequent melanoma incidence and biopsy rates among people subjected to skin screening those who were not. We recruited 43 762 residents of Queensland, Australia, aged 40–69 years, with no prior history of melanoma, selected at random from a population register in 2010. At baseline, participants completed a comprehensive melanoma risk factor survey and were asked if their skin had been examined by a doctor in the 3 years prior to baseline. We calculated incidence and relative risk of histologically confirmed melanoma (invasive and in situ) in years 2–7 of follow-up, obtained through linkage to the cancer registry. In secondary analyses, we measured biopsy rates in years 2–6 of follow-up. We used propensity score analysis to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). In total, 28 155 participants underwent skin screening prior to baseline. We observed 967 first-incident melanomas (381 invasive) during 197 191 person-years of follow-up. Those screened had higher rates of melanoma (aHR 1·29, 95% CI 1·02–1·63) and subsequent skin biopses (aHR 1·85, 95% CI 1·69–2·04) than unscreened participants. The higher risk associated with skin screening was evident for in situ melanoma (aHR 1·45, 95% CI 1·09–1·92) but not invasive melanoma (aHR 1·05, 95% CI 0·72–1·54). In secondary analyses, where screening was defined as having a skin biopsy in the first year after baseline, we observed significantly increased risks of melanoma (aHR 1·53, 95% CI 1·23–1·89) and subsequent biopsies (aHR 2·64, 95% CI 2·46–2·84) relative to those who did not have a biopsy. People who undergo skin screening subsequently experience higher rates of biopsies and melanoma (especially in situ melanoma), even after adjusting for all known risk factors, consistent with overdiagnosis. What is already known about this topic? Cutaneous melanomas are common cancers in white-skinned populations for which early detection is promoted as a means of reducing morbidity and mortality.There is concern that increased surveillance is leading to the overdiagnosis of indolent melanomas that are not destined to be lethal.The extent of melanoma overdiagnosis associated with surveillance is not known. What does this study add? People subjected to skin examinations by a doctor or who undergo skin biopsies subsequently have higher numbers of biopsies and higher rates of melanoma than people not subjected to either, even after adjusting for all known risk factors.These findings suggest that heightened surveillance leads to a proportion of melanomas being diagnosed that otherwise may not have come to clinical attention.

Evaluating the association between keratoconus and the corneal thickness genes in an independent Australian population.

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 17-12-2013

DOI: 10.1167/IOVS.13-12982

Abstract: A recent genome-wide association study (GWAS) identified six loci associated with central corneal thickness that also conferred associated risk of keratoconus (KC). We aimed to assess whether genetic associations existed for these loci with KC or corneal curvature in an independent cohort of European ancestry. In total, 157 patients with KC were recruited from public and private clinics in Melbourne, Australia, and 673 in iduals without KC were identified through the Genes in Myopia study from Australia. The following six single-nucleotide polymorphisms (SNPs) that showed a statistically significant association with KC in a recent GWAS study were selected for genotyping in our cohort: rs4894535 (FNDC3B), rs1324183 (MPDZ-NF1B), rs1536482 (RXRA-COL5A1), rs7044529 (COL5A), rs2721051 (FOXO1), and rs9938149 (BANP-ZNF469). The SNPs were assessed for their association with KC or corneal curvature using logistic or linear regression methods, with age and sex included as covariates. Bonferroni corrections were applied to account for multiple testing. Genotyping data were available for five of the SNPs. Statistically significant associations with KC were found for the SNPs rs1324183 (P = 0.001 odds ratio [OR], 1.68) and rs9938149 (P = 0.010 OR, 1.47). Meta-analysis of previous studies yielded genome-wide significant evidence of an association for rs1324183, firmly establishing it as a KC risk variant. None of the SNPs were significantly associated with corneal curvature. The SNPs rs1324183 in the MPDZ-NF1B gene and rs9938149 (between BANP and ZNF4659) were associated with KC in this independent cohort, but their association was via a non-corneal curvature route.

Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study

Publisher: Oxford University Press (OUP)

Date: 06-06-2017

DOI: 10.1093/IJE/DYX068

A common intronic variant of PARP1 confers melanoma risk and mediates melanocyte growth via regulation of MITF

Publisher: Springer Science and Business Media LLC

Date: 31-07-2017

DOI: 10.1038/NG.3927

Abstract: Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ∼100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (-/GGGCCC r

Automated AI labelling of optic nerve head enables new insights into cross-ancestry glaucoma risk and genetic discovery in over 280,000 images from the Uk biobank and canadian longitudinal study on aging

Publisher: Cold Spring Harbor Laboratory

Date: 05-11-2020

DOI: 10.1101/2020.11.03.367623

Abstract: Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.

Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers

Publisher: Cold Spring Harbor Laboratory

Date: 09-08-2019

DOI: 10.1101/723825

Abstract: We analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS s le sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Publisher: Cold Spring Harbor Laboratory

Date: 20-03-2022

DOI: 10.1101/2022.03.16.22272457

Abstract: Meta-analysis is pervasively used to combine multiple genome-wide association studies (GWAS) into a more powerful whole. To resolve causal variants, meta-analysis studies typically apply summary statistics-based fine-mapping methods as they are applied to single-cohort studies. However, it is unclear whether heterogeneous characteristics of each cohort ( e . g ., ancestry, s le size, phenotyping, genotyping, or imputation) affect fine-mapping calibration and recall. Here, we first demonstrate that meta-analysis fine-mapping is substantially miscalibrated in simulations when different genotyping arrays or imputation panels are included. To mitigate these issues, we propose a summary statistics-based QC method, SLALOM, that identifies suspicious loci for meta-analysis fine-mapping by detecting outliers in association statistics based on ancestry-matched local LD structure. Having validated SLALOM performance in simulations and the GWAS Catalog, we applied it to 14 disease endpoints from the Global Biobank Meta-analysis Initiative and found that 67% of loci showed suspicious patterns that call into question fine-mapping accuracy. These predicted suspicious loci were significantly depleted for having likely causal variants, such as nonsynonymous variants, as a lead variant (2.7x Fisher’s exact P = 7.3 × 10 −4 ). Compared to fine-mapping results in in idual biobanks, we found limited evidence of fine-mapping improvement in the GBMI meta-analyses. Although a full solution requires complete synchronization across cohorts, our approach identifies likely spurious results in meta-analysis fine-mapping. We urge extreme caution when interpreting fine-mapping results from meta-analysis.

Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Publisher: Springer Science and Business Media LLC

Date: 30-03-2020

DOI: 10.1038/S41588-020-0599-0

Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Publisher: Hindawi Limited

Date: 09-06-2017

DOI: 10.1002/HUMU.23247

Abstract: Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10

Genetic Associations Between Smoking- and Glaucoma-Related Traits.

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 14-02-2023

DOI: 10.1167/TVST.12.2.20

Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Publisher: Springer Science and Business Media LLC

Date: 08-01-2019

DOI: 10.1038/S41467-018-07819-1

Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.

WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness

Publisher: Oxford University Press (OUP)

Date: 05-06-2015

DOI: 10.1093/HMG/DDV211

Abstract: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a s le of 1029 in iduals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent s les from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a s le of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Publisher: Springer Science and Business Media LLC

Date: 03-08-2015

DOI: 10.1038/NG.3373

Study profile: the Genetics of Glaucoma Study.

Publisher: BMJ

Date: 08-2023

DOI: 10.1136/BMJOPEN-2022-068811

Abstract: Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment. More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media c aign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA s le and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules. 4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%). GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in in iduals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an in idual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Publisher: Ferrata Storti Foundation (Haematologica)

Date: 11-02-2022

DOI: 10.3324/HAEMATOL.2020.268565

Abstract: Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28–4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

Genetic Risk of Cardiovascular Disease Is Associated with Macular Ganglion Cell-Inner Plexiform Layer Thinning in an Early Glaucoma Cohort.

Publisher: Elsevier BV

Date: 03-2021

DOI: 10.1016/J.XOPS.2021.100108

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Publisher: Cold Spring Harbor Laboratory

Date: 20-08-2021

DOI: 10.1101/2021.08.19.457044

Abstract: Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy in iduals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 in iduals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma†

Publisher: Oxford University Press (OUP)

Date: 17-09-2011

DOI: 10.1093/HMG/DDR415

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

Publisher: Springer Science and Business Media LLC

Date: 05-2011

DOI: 10.1038/NG.824

Abstract: We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 in iduals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010 rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68 rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.

Longitudinal Data Analysis in Pedigree Studies

Publisher: Wiley

Date: 2003

DOI: 10.1002/GEPI.10280

Abstract: Longitudinal family studies provide a valuable resource for investigating genetic and environmental factors that influence long-term averages and changes over time in a complex trait. This paper summarizes 13 contributions to Genetic Analysis Workshop 13, which include a wide range of methods for genetic analysis of longitudinal data in families. The methods can be grouped into two basic approaches: 1) two-step modeling, in which repeated observations are first reduced to one summary statistic per subject (e.g., a mean or slope), after which this statistic is used in a standard genetic analysis, or 2) joint modeling, in which genetic and longitudinal model parameters are estimated simultaneously in a single analysis. In applications to Framingham Heart Study data, contributors collectively reported evidence for genes that affected trait mean on chromosomes 1, 2, 3, 5, 8, 9, 10, 13, and 17, but most did not find genes affecting slope. Applications to simulated data suggested that even for a gene that only affected slope, use of a mean-type statistic could provide greater power than a slope-type statistic for detecting that gene. We report on the results of a small experiment that sheds some light on this apparently paradoxical finding, and indicate how one might form a more powerful test for finding a slope-affecting gene. Several areas for future research are discussed.

Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia

Publisher: Springer Science and Business Media LLC

Date: 04-10-2011

DOI: 10.1038/MP.2011.129

Abstract: In a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 Mb interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A combination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

Publisher: Springer Science and Business Media LLC

Date: 13-11-2011

DOI: 10.1038/NATURE10630

The Role of KRAS rs61764370 in Invasive Epithelial Ovarian Cancer: Implications for Clinical Testing

Publisher: American Association for Cancer Research (AACR)

Date: 06-2011

DOI: 10.1158/1078-0432.CCR-10-3405

Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res 17(11) 3742–50. ©2011 AACR.

Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Publisher: Elsevier BV

Date: 2022

DOI: 10.1016/J.AJHG.2022.11.014

A Novel Approach for Pathway Analysis of GWAS Data Highlights Role of BMP Signaling and Muscle Cell Differentiation in Colorectal Cancer Susceptibility (vol 20, pg 1, 2017)

Publisher: Cambridge University Press (CUP)

Date: 23-02-2017

DOI: 10.1017/THG.2017.6

Abstract: The publishers regret to announce that the affiliation for the above paper was incorrectly inserted. The correct affiliation is below: Aniket Mishra 1 , Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colorectal Cancer Family Registry (CCFR), and Stuart MacGregor 1 1 Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

WALLABY early science – III. An H i study of the spiral galaxy NGC 1566

Publisher: Oxford University Press (OUP)

Date: 27-05-2019

DOI: 10.1093/MNRAS/STZ1448

Abstract: This paper reports on the atomic hydrogen gas (H i) observations of the spiral galaxy NGC 1566 using the newly commissioned Australian Square Kilometre Array Pathfinder radio telescope. We measure an integrated H i flux density of $180.2$ Jy km s−1 emanating from this galaxy, which translates to an H i mass of $1.94\\times 10^{10}\\, \\mathrm{ M}_{\\odot }$ at an assumed distance of $21.3$ Mpc. Our observations show that NGC 1566 has an asymmetric and mildly warped H i disc. The H i-to-stellar mass fraction (M$_{\\rm{H\\,{{\\small I}}}}$/M∗) of NGC 1566 is 0.29, which is high in comparison with galaxies that have the same stellar mass ($10^{10.8}$ M⊙). We also derive the rotation curve of this galaxy to a radius of $50$ kpc and fit different mass models to it. The NFW, Burkert, and pseudo-isothermal dark matter halo profiles fit the observed rotation curve reasonably well and recover dark matter fractions of 0.62, 0.58, and 0.66, respectively. Down to the column density sensitivity of our observations ($N_{\\rm{H\\,{{\\small I}}}}\\, =\\, 3.7\\times 10^{19}$ cm−2), we detect no H i clouds connected to, or in the nearby vicinity of, the H i disc of NGC 1566 nor nearby interacting systems. We conclude that, based on a simple analytic model, ram pressure interactions with the IGM can affect the H i disc of NGC 1566 and is possibly the reason for the asymmetries seen in the H i morphology of NGC 1566.

Time spent outdoors in childhood is associated with reduced risk of myopia as an adult

Publisher: Springer Science and Business Media LLC

Date: 18-03-2021

DOI: 10.1038/S41598-021-85825-Y

Abstract: Myopia (near-sightedness) is an important public health issue. Spending more time outdoors can prevent myopia but the long-term association between this exposure and myopia has not been well characterised. We investigated the relationship between time spent outdoors in childhood, adolescence and young adulthood and risk of myopia in young adulthood. The Kidskin Young Adult Myopia Study (KYAMS) was a follow-up of the Kidskin Study, a sun exposure-intervention study of 1776 children aged 6–12 years. Myopia status was assessed in 303 (17.6%) KYAMS participants (aged 25–30 years) and several subjective and objective measures of time spent outdoors were collected in childhood (8–12 years) and adulthood. Index measures of total, childhood and recent time spent outdoors were developed using confirmatory factor analysis. Logistic regression was used to assess the association between a 0.1-unit change in the time outdoor indices and risk of myopia after adjusting for sex, education, outdoor occupation, parental myopia, parental education, ancestry and Kidskin Study intervention group. Spending more time outdoors during childhood was associated with reduced risk of myopia in young adulthood (multivariable odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69, 0.98). Spending more time outdoors in later adolescence and young adulthood was associated with reduced risk of late-onset myopia (≥ 15 years of age, multivariable OR 0.79, 95% CI 0.64, 0.98). Spending more time outdoors in both childhood and adolescence was associated with less myopia in young adulthood.

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.YGYNO.2013.07.107

Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 10-08-2018

DOI: 10.1167/IOVS.18-24082

A Genomewide Association Study of Nicotine and Alcohol Dependence in Australian and Dutch Populations

Publisher: Cambridge University Press (CUP)

Date: 02-2010

DOI: 10.1375/TWIN.13.1.10

Whole exome sequencing implicates eye development, the unfolded protein response and plasma membrane homeostasis in primary open-angle glaucoma

Publisher: Public Library of Science (PLoS)

Date: 06-03-2017

DOI: 10.1371/JOURNAL.PONE.0172427

Overlapping genetic architecture between Parkinson disease and melanoma

Publisher: Springer Science and Business Media LLC

Date: 16-12-2020

DOI: 10.1007/S00401-019-02110-Z

Contribution of mutations in known mendelian glaucoma genes to advanced early-onset primary open-angle glaucoma

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 10-03-2017

DOI: 10.1167/IOVS.16-21049

Abstract: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of in iduals with advanced early-onset POAG. The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10-16). Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma

Publisher: Oxford University Press (OUP)

Date: 14-02-2018

DOI: 10.1093/HMG/DDY053

Coffee consumption and risk of breast cancer: A Mendelian randomization study.

Publisher: Public Library of Science (PLoS)

Date: 19-01-2021

DOI: 10.1371/JOURNAL.PONE.0236904

Abstract: Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. We conducted a two-s le Mendelian randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80–1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR = 0.90, 95% CI: 0.79–1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75–1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer OR: 1.00, 95% CI: 0.80–1.25), weighted median (OR: 0.97, 95% CI: 0.89–1.05) and weighted mode (OR: 1.00, CI: 0.93–1.07). The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.

The role of GABRA2 in alcohol dependence, smoking, and illicit drug use in an Australian population sample

Publisher: Wiley

Date: 17-09-2008

DOI: 10.1111/J.1530-0277.2008.00768.X

Analysis of pooled DNA samples on high density arrays without prior knowledge of differential hybridization rates

Publisher: Oxford University Press (OUP)

Date: 13-04-2006

DOI: 10.1093/NAR/GKL136

Vitamin D receptor gene polymorphisms have negligible effect on human height.

Publisher: Cambridge University Press (CUP)

Date: 10-2008

DOI: 10.1375/TWIN.11.5.488

Abstract: Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult in iduals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a s le of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian s les from Australia ( N = 3906) and the Netherlands ( N = 1689) for polymorphisms in VDR. The Australian s les were twin families with height measures from 3 time points throughout adolescence. The Dutch s les were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height — this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.

Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma

Publisher: Springer Science and Business Media LLC

Date: 11-01-2016

DOI: 10.1038/NG.3482

Physical Activity Is Associated With Macular Thickness: A Multi-Cohort Observational Study

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 03-03-2023

DOI: 10.1167/IOVS.64.3.11

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Publisher: MDPI AG

Date: 19-05-2020

DOI: 10.3390/CANCERS12051285

Abstract: Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1% p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1% p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.

Genome-wide association study identifiesWNT7Bas a novel locus for central corneal thickness in Latinos

Publisher: Oxford University Press (OUP)

Date: 20-09-2016

DOI: 10.1093/HMG/DDW319

Genetic association at the 9p21 glaucoma locus contributes to sex bias in normal-tension glaucoma

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 28-06-2016

DOI: 10.1167/IOVS.16-19401

Abstract: Many genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at the 9p21 glaucoma locus (CDKN2B/CDKN2B-AS1) to be significantly associated with primary open-angle glaucoma (POAG), with association being stronger in normal tension glaucoma (NTG) and advanced glaucoma. We aimed to determine whether any observed differences in genetic association at the 9p21 locus are influenced by sex. Sex was assessed as a risk factor for POAG for 2241 glaucoma participants from the Australian and New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, and the Flinders Medical Centre. A total of 3176 controls were drawn from the Blue Mountains Eye Study and South Australia: 1523 advanced POAG and 718 nonadvanced POAG cases were genotyped along with 3176 controls. We selected 13 SNPs at the 9p21 locus, and association results were subanalyszd by sex for high-tension glaucoma (HTG) and NTG. Odds ratios (ORs) between sexes were compared. A sex bias was present within advanced NTG cases (57.1% female versus 42.9% male, P = 0.0026). In all POAG cases, the strongest associated SNP at 9p21 was rs1063192 (OR, 1.43 P = 4 × 10-18). This association was stronger in females (OR, 1.5 P = 5 × 10-13) than in males (OR, 1.35 P = 7 × 10-7), with a statistically significant difference in female to male OR comparison (P = 1.0 × 10-2). An NTG to HTG subanalysis yielded statistically significant results only in females (OR, 1.63 P = 1.5 × 10-4) but not in males (OR, 1.15 P = 2.8 × 10-1), with a statistically significant difference in female to male OR comparison (P = 1.4 × 10-4). This study demonstrated that female sex is a risk factor for developing advanced NTG. The stronger genetic signals at the 9p21 locus among females may contribute at least in part to the observed sex bias for NTG.

Symptom-level genetic modelling identifies novel risk loci and unravels the shared genetic architecture of anxiety and depression

Publisher: Cold Spring Harbor Laboratory

Date: 14-04-2020

DOI: 10.1101/2020.04.08.20057653

Abstract: Depression and anxiety are highly prevalent and comorbid psychiatric traits that cause considerable burden worldwide. Previous studies have revealed substantial genetic overlap between depression, anxiety, and a closely related personality trait – neuroticism. Here, we use factor analysis and genomic structural equation modelling (Genomic SEM) to investigate the genetic factor structure underlying 28 items assessing depression, anxiety and neuroticism. Symptoms of depression and anxiety loaded on two distinct, although genetically correlated factors, while neuroticism items were partitioned between them. We leveraged this factor structure to conduct multivariate genome-wide association analyses on latent factors of anxiety symptoms and depressive symptoms, using data from over 400,000 in iduals in the UK Biobank. We identified 89 independent variants for the depressive factor (61 genomic loci, 29 novel) and 102 independent variants for the anxiety factor (73 loci, 71 novels). Of these variants, 72% and 78%, respectively, replicated in an independent 23andMe cohort of ∼1.9 million in iduals with self-reported diagnosis of depression (634,037 cases) and anxiety (624,615 cases). A pairwise GWAS analysis revealed substantial genetic overlap between anxiety and depression but also showed trait-specific genetic influences e.g. genomic regions specific to depressive symptoms were associated with hypertriglyceridemia, while regions specific to anxiety symptoms were linked to blood pressure phenotypes. The substantial genetic overlap between the two traits was further evidenced by a lack of trait-specificity in polygenic prediction of depressive and anxiety symptoms. Our results provide novel insight into the genetic architecture of depression and anxiety and comorbidity between them.

Operation of the Schizophrenia Susceptibility Gene, Neuregulin 1, Across Traditional Diagnostic Boundaries to Increase Risk for Bipolar Disorder

Publisher: American Medical Association (AMA)

Date: 06-2005

DOI: 10.1001/ARCHPSYC.62.6.642

Abstract: Family and twin data suggest that, in addition to susceptibility genes specific for bipolar disorder or schizophrenia, genes exist that contribute to susceptibility across the traditional kraepelinian ide. Several studies have provided evidence that variation at the neuregulin 1 (NRG1) gene on chromosome 8p12 influences susceptibility to schizophrenia. The most consistent finding has been that one particular haplotype (the "core" haplotype) is overrepresented in cases compared with control subjects. To investigate the possible role of NRG1 in bipolar disorder. Genetic case-control association analysis. Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. Five hundred twenty-nine patients with DSM-IV bipolar I disorder and 1011 controls from the United Kingdom (100% white). We genotyped the markers constituting the NRG1 core haplotype in cases and controls and reanalyzed our existing data from 573 DSM-IV schizophrenia cases with this larger set of controls. We found a significant difference in haplotype distribution between bipolar cases and controls globally (P = .003) and specifically for the core haplotype. Frequencies were 10.2% for bipolar cases and 7.8% for controls (effect size, as measured by odds ratio [OR], 1.37 95% confidence interval [CI], 1.03-1.80 P = .04). The effect size in our bipolar s le was similar to that in our schizophrenia s le (OR, 1.22 95% CI, 0.92-1.61). In the bipolar cases with predominantly mood-incongruent psychotic features (n = 193), the effect was greater (OR, 1.71 95% CI, 1.29-2.59 P = .009), as was the case in the subset of schizophrenia cases (n = 27) who had experienced mania (OR, 1.64 95% CI, 0.54-5.01). Our findings suggest that neuregulin 1 plays a role in influencing susceptibility to bipolar disorder and schizophrenia and that it may exert a specific effect in the subset of functional psychosis that has manic and mood-incongruent psychotic features.

Association Between In Vivo Alcohol Metabolism and Genetic Variation in Pathways that Metabolize the Carbon Skeleton of Ethanol and NADH Reoxidation in the Alcohol Challenge Twin Study

Publisher: Wiley

Date: 11-05-2012

DOI: 10.1111/J.1530-0277.2012.01829.X

Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis

Publisher: Springer Science and Business Media LLC

Date: 12-12-2011

DOI: 10.1038/NG.731

Genetic variants for smoking behaviour and risk of skin cancer

Publisher: Springer Science and Business Media LLC

Date: 06-10-2023

DOI: 10.1038/S41598-023-44144-0

Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

Publisher: Springer Science and Business Media LLC

Date: 15-07-2021

DOI: 10.1007/S00439-021-02312-0

No Association Between Schizophrenia and Polymorphisms in COMT in Two Large Samples

Publisher: American Psychiatric Association Publishing

Date: 09-2005

DOI: 10.1176/APPI.AJP.162.9.1736

Abstract: A valine/methionine polymorphism in the catechol O-methyltransferase (COMT) gene has been proposed to influence susceptibility to schizophrenia, as has a COMT haplotype in Ashkenazi Jewish and Irish subjects. The authors examined these hypotheses. They reviewed data from more than 2,800 in iduals, including almost 1,200 with schizophrenia, from case-control and family-based European association s les. The authors found no support for the hypothesis that a valine/methionine polymorphism in the COMT gene influences susceptibility to schizophrenia or the hypothesis that a COMT haplotype influences susceptibility to schizophrenia in Ashkenazi Jewish and Irish subjects. The data suggest that the valine allele of COMT does not increase susceptibility to schizophrenia in Europeans and that the Ashkenazi or Irish haplotype does not increase susceptibility. Ethnic variation in the linkage disequilibrium structure at COMT means that the haplotype data may not generalize across populations. However, the authors' examination of the hypothesis that the valine allele confers susceptibility, with a particularly strong effect in Europeans, reveals that no such caveat applies.

Cost-effectiveness of polygenic risk profiling for primary open-angle glaucoma in the United Kingdom and Australia

Publisher: Springer Science and Business Media LLC

Date: 13-12-2022

DOI: 10.1038/S41433-022-02346-2

Variation at the DAOA/G30 Locus Influences Susceptibility to Major Mood Episodes but Not Psychosis in Schizophrenia and Bipolar Disorder

Publisher: American Medical Association (AMA)

Date: 04-2006

DOI: 10.1001/ARCHPSYC.63.4.366

Abstract: Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. To obtain a stringent replication of association in large s les of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the in iduals, and comparisons were made between affected and unaffected in iduals. We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which in iduals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories.

Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Publisher: Springer Science and Business Media LLC

Date: 06-04-2016

DOI: 10.1038/NCOMMS11008

Abstract: Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry in iduals, we identify six novel loci ( FAM150B-ACP1 , LINC00340 , FBN1 , DIS3L-MAP2K1 , ARID2-SNAT1 and SLC14A2 ) associated with refractive error. In Asian populations, three genome-wide significant loci AREG , GABRR1 and PDE10A also exhibit strong interactions with education ( P .5 × 10 −5 ), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Aging

Publisher: Elsevier BV

Date: 09-2017

DOI: 10.1016/J.JID.2017.04.026

Abstract: Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait at genome-wide significance (P = 4.1 × 10

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Publisher: Springer Science and Business Media LLC

Date: 11-01-2021

DOI: 10.1038/S41467-020-20368-W

Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Publisher: Springer Science and Business Media LLC

Date: 24-11-2017

DOI: 10.1038/S41467-017-00837-5

Abstract: Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1 , that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically erse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.

Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Publisher: Springer Science and Business Media LLC

Date: 28-05-2018

DOI: 10.1038/S41588-018-0127-7

Association Between Population Density and Genetic Risk for Schizophrenia

Publisher: American Medical Association (AMA)

Date: 09-2018

DOI: 10.1001/JAMAPSYCHIATRY.2018.1581

Effects of GABRA2 variation on physiological, psychomotor and subjective responses in the alcohol challenge twin study

Publisher: Cambridge University Press (CUP)

Date: 04-2008

DOI: 10.1375/TWIN.11.2.174

Abstract: Multiple reports have identified variation in the GABRA2 gene as contributing to the genetic susceptibility to alcohol dependence. However, both the mechanism behind this association, and the range of alcohol-related phenotypes affected by variation in this gene, are currently undefined. Other data suggest that the risk of alcohol dependence is increased by relative insensitivity to alcohol's intoxicating effects. We have therefore tested whether GABRA2 variation is associated with variation in the subjective and objective effects of a standard dose of alcohol in humans. Data on responses to alcohol from the Alcohol Challenge Twin Study (Martin et al., 1985) have been tested against allelic and haplotype information obtained by typing 41 single-nucleotide polymorphisms in or close to the GABRA2 gene. Nominally significant allelic associations ( p .05, without correction for multiple testing) were found for body sway, motor coordination, pursuit rotor and arithmetical computation tasks, and for the personality dimension of Neuroticism. Because of the large number of phenotypes tested, these possibly significant findings will need to be confirmed in further studies.

Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder

Publisher: Royal College of Psychiatrists

Date: 2006

DOI: 10.1192/BJP.BP.105.009969

Abstract: Brain-derived neurotrophic factor (BDNF) influences neuronal survival, proliferation and plasticity Three family-based studies have shown association of the common Valine (Val) allele of the Val66Met polymorphism of the BDNF gene with susceptibility to bipolar disorder. To replicate this finding. We genotyped the Val66Met polymorphism in our UK White bipolar case-control s le ( n =3062). We found no overall evidence of allele or genotype association. However, we found association with disease status in the subset of 131 in iduals that had experienced rapid cycling at some time ( P =0.004). We found a similar association on re-analysis of our previously reported family-based association s le ( P .03, one-tailed test). Variation at the Val66Met polymorphism of BDNF does not play a major role in influencing susceptibility to bipolar disorder as a whole, but is associated with susceptibility to the rapid-cycling subset of the disorder.

Meta-analysis fine-mapping is often miscalibrated at single-variant resolution

Publisher: Elsevier BV

Date: 12-2022

DOI: 10.1016/J.XGEN.2022.100210

Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.JID.2018.05.023

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Publisher: Springer Science and Business Media LLC

Date: 19-03-2020

DOI: 10.1038/S42003-020-0802-Y

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 in iduals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11 / FBLN2 rs2630445, RBP3 rs11204213) others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Multi-Trait Genetic Analysis Identifies Autoimmune Loci Associated with Cutaneous Melanoma

Publisher: Elsevier BV

Date: 06-2022

DOI: 10.1016/J.JID.2021.08.449

Abstract: Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multitrait analysis of GWAS (MTAG). We used bivariate linkage disequilibrium-score regression score regression to identify traits that are genetically correlated with clinically confirmed cutaneous melanoma and then used publicly available GWAS for these traits in a multitrait analysis of GWAS. Multitrait analysis of GWAS allows GWAS to be combined while accounting for s le overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci, 19 of them were not previously reported in the input cutaneous melanoma GWAS meta-analysis. Of these loci, 55 were replicated (P < 0.05/74, Bonferroni-corrected P-value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the, to our knowledge, previously unreported cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

Association between putative functional variants in the PSMB9 gene and risk of melanoma – re‐analysis of published melanoma genome‐wide association studies

Publisher: Wiley

Date: 27-03-2013

DOI: 10.1111/PCMR.12069

Continental‐scale acoustic telemetry and network analysis reveal new insights into stock structure

Publisher: Wiley

Date: 05-05-2021

DOI: 10.1111/FAF.12565

Abstract: Delineation of population structure (i.e. stocks) is crucial to successfully manage exploited species and to address conservation concerns for threatened species. Fish migration and associated movements are key mechanisms through which discrete populations mix and are thus important determinants of population structure. Detailed information on fish migration and movements is becoming more accessible through advances in telemetry and analysis methods however such information is not yet used systematically in stock structure assessment. Here, we described how detections of acoustically tagged fish across a continental‐scale array of underwater acoustic receivers were used to assess stock structure and connectivity in seven teleost and seven shark species and compared to findings from genetic and conventional tagging. Network analysis revealed previously unknown population connections in some species, and in others bolstered support for existing stock discrimination by identifying nodes and routes important for connectivity. Species with less variability in their movements required smaller s le sizes (45–50 in iduals) to reveal useful stock structure information. Our study shows the power of continental‐scale acoustic telemetry networks to detect movements among fishery jurisdictions. We highlight methodological issues that need to be considered in the design of acoustic telemetry studies for investigating stock structure and the interpretation of the resulting data. The advent of broad‐scale acoustic telemetry networks across the globe provides new avenues to understand how movement informs population structure and can lead to improved management.

A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma

Publisher: Springer Science and Business Media LLC

Date: 10-12-2022

DOI: 10.1038/S41467-022-35345-8

Abstract: Basal cell carcinoma and squamous cell carcinoma are the most common skin cancers, and have genetic overlap with melanoma, pigmentation traits, autoimmune diseases, and blood biochemistry biomarkers. In this multi-trait genetic analysis of over 300,000 participants from Europe, Australia and the United States, we reveal 78 risk loci for basal cell carcinoma (19 previously unknown and replicated) and 69 for squamous cell carcinoma (15 previously unknown and replicated). The previously unknown risk loci are implicated in cancer development and progression (e.g. CDKL1 ), pigmentation (e.g. TPCN2 ), cardiometabolic (e.g. FADS2 ), and immune-regulatory pathways for innate immunity (e.g. IFIH1 ), and HIV-1 viral load modulation (e.g. CCR5 ). We also report an optimised polygenic risk score for effective risk stratification for keratinocyte cancer in the Canadian Longitudinal Study of Aging (794 cases and 18139 controls), which could facilitate skin cancer surveillance e.g. in high risk subpopulations such as transplantees.

Common sequence variants on 20q11.22 confer melanoma susceptibility

Publisher: Springer Science and Business Media LLC

Date: 18-05-2008

DOI: 10.1038/NG.163

Association between endometriosis and the interleukin 1A (IL1A) locus

Publisher: Oxford University Press (OUP)

Date: 21-10-2015

DOI: 10.1093/HUMREP/DEU267

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.XHGG.2021.100041

Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned

Publisher: Springer Science and Business Media LLC

Date: 02-11-2010

DOI: 10.1038/MP.2010.109

Genetically determined risk of keratinocyte carcinoma and risk of other cancers

Publisher: Oxford University Press (OUP)

Date: 28-12-2021

DOI: 10.1093/IJE/DYAA265

Abstract: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. In the first approach (one-s le), we calculated the polygenic risk scores (PRS) for KC using in idual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-s le) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. Using the one-s le approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13–1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-s le approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03–1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

Association of Genetic Variation with Keratoconus

Publisher: American Medical Association (AMA)

Date: 02-2020

DOI: 10.1001/JAMAOPHTHALMOL.2019.5293

A randomized trial of catheters of different lengths to achieve right atrium versus superior vena cava placement for continuous renal replacement therapy

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1053/J.AJKD.2012.01.021

Cell-type specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Publisher: Cold Spring Harbor Laboratory

Date: 08-12-2017

DOI: 10.1101/231423

Abstract: Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for % of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior to LD-pruning and 4,997 eGenes (FDR .05), which are higher numbers than in any GTEx tissue type with a similar s le size. Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were not observed to be eGenes in two types of GTEx skin tissues or TCGA melanoma s les. The melanocyte dataset also identified cell-type specific trans- eQTLs with a pigmentation-associated SNP for four genes, likely through its cis -regulation of IRF4 , encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as melanoma-associated variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for six known GWAS loci including unique genes identified by the melanocyte dataset. Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes ( ZFP90, HEBP1, MSC, CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.

A common variant near TGFBR3 is associated with primary open angle glaucoma

Publisher: Oxford University Press (OUP)

Date: 10-04-2015

DOI: 10.1093/HMG/DDV128

Correction to: Overlapping genetic architecture between Parkinson disease and melanoma (Acta Neuropathologica, (2020), 139, 2, (347-364), 10.1007/s00401-019-02110-z)

Publisher: Springer Science and Business Media LLC

Date: 14-03-2020

DOI: 10.1007/S00401-020-02143-9

Does genetic risk modify the effect of skin screening on melanoma detection rates?

Publisher: Oxford University Press (OUP)

Date: 08-09-2023

DOI: 10.1093/BJD/LJAD333

Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Publisher: Springer Science and Business Media LLC

Date: 04-11-2014

DOI: 10.1007/S00439-014-1500-Y

Assessing the Genetic Predisposition of Education on Myopia: A Mendelian Randomization Study

Publisher: Wiley

Date: 26-10-2016

DOI: 10.1002/GEPI.21936

Polyunsaturated Fatty Acid Levels and the Risk of Keratinocyte Cancer: A Mendelian Randomization Analysis

Publisher: American Association for Cancer Research (AACR)

Date: 04-12-2021

DOI: 10.1158/1055-9965.EPI-20-1765

Abstract: Keratinocyte cancer is the commonest cancer, imposing a high economic burden on the health care system. Observational studies have shown mixed associations between polyunsaturated fatty acids (PUFA) and keratinocyte cancer, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We explored whether genetically predicted PUFA levels are associated with BCC and SCC risks. We conducted a two-s le Mendelian randomization study using PUFA level genome-wide association studies (GWAS) from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n & 8,000), and the meta-analysis GWASs from UKB, 23andMe, and Qskin for BCC (n = 651,138) and SCC (n = 635,331) risk. One SD increase in genetically predicted levels of linoleic acid [OR = 0.94, 95% confidence interval (CI) = 0.91–0.97, P = 1.4 × 10–4] and alpha-linolenic acid (OR = 0.91, 95% CI = 0.86–0.96, P = 5.1 × 10–4) was associated with a reduced BCC risk, while arachidonic acid (OR = 1.04, 95% CI = 1.02–1.06, P = 3.2 × 10–4) and eicosapentaenoic acid (OR = 1.10, 95% CI = 1.04–1.16, P = 1.5 × 10–3) were associated with an increased BCC risk. Higher genetically predicted levels of linoleic acid and alpha-linolenic acid were associated with a reduced BCC risk, but arachidonic acid and eicosapentaenoic acid were associated with a higher BCC risk. PUFA-related diet and supplementation could influence BCC etiology.

Is there a causal relationship between vitamin D and melanoma risk? A Mendelian randomization study

Publisher: Oxford University Press (OUP)

Date: 11-09-2019

DOI: 10.1111/BJD.18238

Abstract: Several preclinical studies have identified the antiproliferative effects of 25-hydroxyvitamin D [25(OH)D vitamin D]. Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR. To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach. We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration - rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 - were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data. A 20 nmol L The results suggest that vitamin D levels may not be causally associated with the risk of melanoma. What's already known about this topic? Antitumour activity of vitamin D has been identified in preclinical studies. Observational studies link vitamin D deficiency with an increased risk of a range of cancers. There is a growing public interest for vitamin D supplementation. Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk. Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk. What does this study add? Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.

Use of phenotypic covariates in association analysis by sequential addition of cases

Publisher: Springer Science and Business Media LLC

Date: 15-03-2006

DOI: 10.1038/SJ.EJHG.5201604

Abstract: Optimal use of phenotype information is important in complex disease gene mapping. We describe a method, sequential addition, for the analysis of case-control data by taking into account of a quantitative trait that is measured in cases but not in controls. The method also provides an estimate of the best phenotype definition for future studies. We demonstrate proof of principle, using an ex le of incorporation of age-at-onset data into a study of a small s le for association between APOE and late-onset Alzheimer's disease. The sequential addition method finds evidence of association when conventional case-control methods fail. We also illustrate the use of the method for taking account of a dimensional measure of psychosis in a study of the schizophrenia susceptibility gene, dysbindin, in bipolar disorder.

Pleiotropic analysis of cancer risk loci on esophageal adenocarcinoma risk

Publisher: American Association for Cancer Research (AACR)

Date: 11-2015

DOI: 10.1158/1055-9965.EPI-15-0596

Abstract: Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 24(11) 1801–3. ©2015 AACR.

Gene Discovery Using Twins

Publisher: Cambridge University Press (CUP)

Date: 04-2020

DOI: 10.1017/THG.2020.38

Abstract: One of Nick’s key early achievements at QIMR was to establish a twin study on melanoma risk factors. The Brisbane Twin Nevus Study (BTNS) had an initial focus on nevus (mole) count in adolescents but, reflecting Nick’s broad interests, expanded in scope enormously over the decades. In the skin cancer arena, BTNS was essential to genetic discoveries in melanoma, eye color and pigmentation. Later studies amassed data on thousands of phenotypes, ranging from molecular phenotypes such as gene expression to studies where gene mapping findings in adolescents turned out to have translational potential in late-onset diseases. Nick’s twin data have formed the basis for an enormous range of discoveries, with Nick and his colleagues continuing to capitalize on these data.

WALLABY early science - V. ASKAP H I imaging of the Lyon Group of Galaxies 351

Publisher: Oxford University Press (OUP)

Date: 06-2019

DOI: 10.1093/MNRAS/STZ2501

Abstract: We present an H i study of the galaxy group LGG 351 using Widefield ASKAP L-band Legacy All-sky Blind Survey (WALLABY) early science data observed with the Australian Square Kilometre Array Pathfinder (ASKAP). LGG 351 resides behind the M 83 group at a velocity range (cz) of ∼3500–4800 km s−1 within the rich Hydra-Centaurus overdensity region. We detect 40 sources with the discovery of a tidally interacting galaxy pair and two new H i sources that are not presented in previous optical catalogues. 23 out of 40 sources have new redshifts derived from the new H i data. This study is the largest WALLABY sub-s le to date and also allows us to further validate the performance of ASKAP and the data reduction pipeline askapsoft. Extended H i emission is seen in six galaxies indicating interaction within the group, although no H i debris is found. We also detect H i in a known ultra-faint dwarf galaxy (dw 1328−29), which demonstrates that it is not a satellite of the M 83 group as previously thought. In conjunction with multiwavelength data, we find that our galaxies follow the atomic gas fraction and baryonic Tully–Fisher scaling relations derived from the GALEX Arecibo SDSS Survey. In addition, majority of our galaxies fall within the star formation main sequence indicating inefficiency of gas removal processes in this loose galaxy group.

Longitudinal variance-components analysis of the Framingham Heart Study data

Publisher: Springer Science and Business Media LLC

Date: 2003

DOI: 10.1186/1471-2156-4-S1-S22

Identifying Relationships among Genomic Disease Regions: Predicting Genes at Pathogenic SNP Associations and Rare Deletions

Publisher: Public Library of Science (PLoS)

Date: 26-06-2009

DOI: 10.1371/JOURNAL.PGEN.1000534

A genome-wide analysis of 'Bounty' descendants implicates several novel variants in migraine susceptibility

Publisher: Springer Science and Business Media LLC

Date: 08-06-2012

DOI: 10.1007/S10048-012-0325-X

Data from Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 31-03-2023

DOI: 10.1158/0008-5472.C.6514361

Abstract: Abstract Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median i n /i = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources ( i n /i = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas ( i n /i = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., i BRCA1/2 /i variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis. Significance: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations. /

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Publisher: Springer Science and Business Media LLC

Date: 07-2009

DOI: 10.1038/NATURE08185

Genome-wide association analysis of lifetime cannabis use (N=184,765) identifies new risk loci, genetic overlap with mental health, and a causal influence of schizophrenia on cannabis use

Publisher: Cold Spring Harbor Laboratory

Date: 08-01-2018

DOI: 10.1101/234294

Abstract: Cannabis use is a heritable trait [1] that has been associated with adverse mental health outcomes. To identify risk variants and improve our knowledge of the genetic etiology of cannabis use, we performed the largest genome-wide association study (GWAS) meta-analysis for lifetime cannabis use (N=184,765) to date. We identified 4 independent loci containing genome-wide significant SNP associations. Gene-based tests revealed 29 genome-wide significant genes located in these 4 loci and 8 additional regions. All SNPs combined explained 10% of the variance in lifetime cannabis use. The most significantly associated gene, CADM2 , has previously been associated with substance use and risk-taking phenotypes [2–4]. We used S-PrediXcan to explore gene expression levels and found 11 unique eGenes. LD-score regression uncovered genetic correlations with smoking, alcohol use and mental health outcomes, including schizophrenia and bipolar disorder. Mendelian randomisation analysis provided evidence for a causal positive influence of schizophrenia risk on lifetime cannabis use.

WALLABY Early Science – IV. ASKAP H i imaging of the nearby galaxy IC 5201

Publisher: Oxford University Press (OUP)

Date: 26-07-2019

DOI: 10.1093/MNRAS/STZ2063

Abstract: We present a Wide-field ASKAP L-Band Legacy All-sky Blind surveY (WALLABY) study of the nearby (vsys = 915 km s−1) spiral galaxy IC 5201 using the Australian Square Kilometre Array Pathfinder (ASKAP). IC 5201 is a blue, barred spiral galaxy that follows the known scaling relations between stellar mass, SFR, H i mass, and diameter. We create a four-beam mosaicked H i image cube from 175 h of observations made with a 12-antenna sub-array. The root mean square noise level of the cube is 1.7 mJy beam−1 per channel, equivalent to a column density of $N_{\\rm H\\, \\small {I}}$ = 1.4 × 1020 cm−2 over 25 km s−1. We report nine extragalactic H i detections – five new H i detections including the first velocity measurements for two galaxies. These sources are IC 5201, three dwarf satellite galaxies, two galaxies, and a tidal feature belonging to the NGC 7232/3 triplet and two potential infalling galaxies to the triplet. There is evidence of a previous tidal interaction between IC 5201 and the irregular satellite AM 2220−460. A close fly-by is likely responsible for the asymmetric optical morphology of IC 5201 and warping its disc, resulting in the irregular morphology of AM 2220−460. We quantify the H i kinematics of IC 5201, presenting its rotation curve as well as showing that the warp starts at 14 kpc along the major axis, increasing as a function of radius with a maximum difference in position angle of 20°. There is no evidence of stripped H i, triggered or quenched star formation in the system as measured using DECam optical and GALEX UV photometry.

Attitudes towards glaucoma genetic risk assessment in unaffected individuals

Publisher: Cold Spring Harbor Laboratory

Date: 22-10-2021

DOI: 10.1101/2021.10.19.21264544

Abstract: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an in idual’s risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected in iduals towards PRS testing for glaucoma, and sought to identify factors associated with interest in testing. We surveyed 418 unaffected in iduals including those with a first-degree relative with glaucoma (n=193), those who had a recent eye examination (n=117), and general members of the community (n=108). Overall, 71.3% indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (OR 14.58, 95%CI (1.15-185.50), p=0.039), those concerned about developing glaucoma (OR 4.37, 95%CI (2.32-8.25), p .001), those with an intention to take appropriate measures regarding eye health (OR 2.39, 95%CI (1.16-4.95), p=0.019), and those preferring to know if considered to be at-risk or not (OR 4.52, 95%CI (2.32-8.83), p .001). These findings represent a valuable assessment of general public interest in glaucoma polygenic risk testing, which will be integral to the implementation and uptake of novel PRS based tests into clinical practice.

Assessment of melanoma candidate genes in a meta‐analysis of 16 534 melanoma cases

Publisher: Wiley

Date: 26-05-2019

DOI: 10.1111/JDV.15662

Hormonal responses differ when playing violent video games against an ingroup and outgroup

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.EVOLHUMBEHAV.2009.07.002

A Polygenic Risk Score Predicts Intraocular Pressure Readings Outside Office Hours and Early Morning Spikes as Measured by Home Tonometry

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.OGLA.2020.12.002

WALLABY early science - I. The NGC 7162 galaxy group

Publisher: Oxford University Press (OUP)

Date: 29-10-2019

DOI: 10.1093/MNRAS/STY2930

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Publisher: Elsevier BV

Date: 09-2019

DOI: 10.1016/J.AJHG.2019.08.001

Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1)

Publisher: Elsevier BV

Date: 04-2005

DOI: 10.1016/J.BIOPSYCH.2005.01.018

Abstract: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control s le. Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar s le (726 Caucasian UK DSM-IV bipolar I patients 1407 ethnically matched controls). No significant differences were found in the distribution of the 3-locus haplotype in the full s le. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia s le. This finding was not significant after correction for multiple testing. Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset s le is small and the hypothesis requires testing in independent, adequately powered s les.

IMI 2021 yearly digest

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 28-04-2021

DOI: 10.1167/IOVS.62.5.7

Association of polymorphisms in MACRO domain containing 2 with thyroid-associated orbitopathy

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 15-06-2016

DOI: 10.1167/IOVS.15-18797

Abstract: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in in iduals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in in idual DNA s les from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. In the GWAS of pooled DNA s les, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6 rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on in idual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5 odds ratio [OR] = 1.77 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.

ALMA/ACA CO Survey of the IC 1459 and NGC 4636 Groups: Environmental Effects on the Molecular Gas of Group Galaxies

Publisher: American Astronomical Society

Date: 09-2022

DOI: 10.3847/1538-4365/AC7EBA

Abstract: We present new results of a 12 CO( J = 1–0) imaging survey using the Atacama Compact Array (ACA) for 31 H i detected galaxies in the IC 1459 and NGC 4636 groups. This is the first CO imaging survey for loose galaxy groups. We obtained well-resolved CO data (∼0.7–1.5 kpc) for a total of 16 galaxies in two environments. By comparing our ACA CO data with the H i and UV data, we probe the impacts of the group environment on the cold gas components (CO and H i gas) and star formation activity. We find that CO and/or H i morphologies are disturbed in our group members, some of which show highly asymmetric CO distributions (e.g., IC 5264, NGC 7421, and NGC 7418). In comparison with isolated galaxies in the xCOLD GASS s le, our group galaxies tend to have low star formation rates and low H 2 gas fractions. Our findings suggest that the group environment can change the distribution of cold gas components, including the molecular gas and star formation properties of galaxies. This is supporting evidence that preprocessing in the group-like environment can play an important role in galaxy evolution.

WALLABY pre-pilot survey

Publisher: Cambridge University Press (CUP)

Date: 2023

DOI: 10.1017/PASA.2023.11

Abstract: We present the highest resolution and sensitivity $\\sim$ $1.4\\,$ GHz continuum observations of the Eridanus supergroup obtained as a part of the Widefield Australian Square Kilometer Array Pathfinder (ASKAP) L -band Legacy All-sky Blind surveY (WALLABY) pre-pilot observations using the ASKAP. We detect 9461 sources at 1.37 GHz down to a flux density limit of $\\sim$ $0.1$ mJy at $6.1''\\times 7.9''$ resolution with a median root mean square of 0.05 mJy beam $^{-1}$ . We find that the flux scale is accurate to within 5 % (compared to NVSS at 1.4 GHz). We then determine the global properties of eight Eridanus supergroup members, which are detected in both radio continuum and neutral hydrogen (HI) emission, and find that the radio-derived star formation rates (SFRs) agree well with previous literature. Using our global and resolved radio continuum properties of the nearby Eridanus galaxies, we measure and extend the infrared-radio correlation (IRRC) to lower stellar masses and inferred SFRs than before. We find the resolved IRRC to be useful for: (1) discriminating between active galactic nuclei and star-forming galaxies (2) identifying background radio sources and (3) tracing the effects of group environment pre-processing in NGC 1385. We find evidence for tidal interactions and ram-pressure stripping in the HI, resolved spectral index and IRRC morphologies of NGC 1385. There appears to be a spatial coincidence (in projection) of double-lobed radio jets with the central HI hole of NGC 1367. The destruction of polycyclic aromatic hydrocarbons by merger-induced shocks may be driving the observed WISE W3 deficit observed in NGC 1359. Our results suggest that resolved radio continuum and IRRC studies are excellent tracers of the physical processes that drive galaxy evolution and will be possible on larger s le of sources with upcoming ASKAP radio continuum surveys.

WALLABY Pilot Survey

Publisher: Cambridge University Press (CUP)

Date: 2022

DOI: 10.1017/PASA.2022.43

Abstract: We present the Widefield ASKAP L-band Legacy All-sky Blind surveY (WALLABY) Pilot Phase I H i kinematic models. This first data release consists of H i observations of three fields in the direction of the Hydra and Norma clusters, and the NGC 4636 galaxy group. In this paper, we describe how we generate and publicly release flat-disk tilted-ring kinematic models for 109/592 unique H i detections in these fields. The modelling method adopted here—which we call the WALLABY Kinematic Analysis Proto-Pipeline (WKAPP) and for which the corresponding scripts are also publicly available—consists of combining results from the homogeneous application of the FAT and 3DBarolo algorithms to the subset of 209 detections with sufficient resolution and $S/N$ in order to generate optimised model parameters and uncertainties. The 109 models presented here tend to be gas rich detections resolved by at least 3–4 synthesised beams across their major axes, but there is no obvious environmental bias in the modelling. The data release described here is the first step towards the derivation of similar products for thousands of spatially resolved WALLABY detections via a dedicated kinematic pipeline. Such a large publicly available and homogeneously analysed dataset will be a powerful legacy product that that will enable a wide range of scientific studies.

Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Publisher: Oxford University Press (OUP)

Date: 17-03-2023

DOI: 10.1093/JNCI/DJAD043

Abstract: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci. We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci. We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci. Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger s le sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

Publisher: Impact Journals, LLC

Date: 31-01-2016

DOI: 10.18632/ONCOTARGET.7047

Data from Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 31-03-2023

DOI: 10.1158/0008-5472.C.6514361.V1

Abstract: Abstract Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median i n /i = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources ( i n /i = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas ( i n /i = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., i BRCA1/2 /i variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis. Significance: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations. /

A regional citrate anticoagulation protocol for pre-dilutional CVVHDf: The 'Modified Alabama Protocol'

Publisher: Elsevier BV

Date: 08-2008

DOI: 10.1016/J.AUCC.2008.04.002

Rapid inexpensive genome-wide association using pooled whole blood

Publisher: Cold Spring Harbor Laboratory

Date: 03-10-2009

DOI: 10.1101/GR.094680.109

Abstract: Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large data sets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls, respectively, is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration, and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analyzed by GWAS, and will enable developing nations to participate in GWAS.

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Publisher: Springer Science and Business Media LLC

Date: 14-11-2018

DOI: 10.1038/S41467-018-06649-5

Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

Mendelian randomization study for genetically predicted polyunsaturated fatty acids levels on overall cancer risk and mortality

Publisher: American Association for Cancer Research (AACR)

Date: 06-2019

DOI: 10.1158/1055-9965.EPI-18-0940

Abstract: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes. We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA. None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for ex le, arachidonic acid (AA) overall cancer risk (OR, 1.02 95% CI, 1.00–1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92 95% CI, 0.86–0.98 P = 0.02) however, this was nonsignificant after multiple testing correction. From in idual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05 95% CI, 1.03–1.07), with similar results for the other correlated PUFAs. Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer. Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the in idual cancer findings.

Increasing water-use efficiency in rice fields threatens an endangered waterbird

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.AGEE.2021.107638

Family-Based Genome-Wide Association Study of South Indian Pedigrees SupportsWNT7Bas a Central Corneal Thickness Locus

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 18-05-2018

DOI: 10.1167/IOVS.17-23536

A versatile gene-based test for genome-wide association studies

Publisher: Elsevier BV

Date: 07-2010

DOI: 10.1016/J.AJHG.2010.06.009

A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort

Publisher: Oxford University Press (OUP)

Date: 11-02-2014

DOI: 10.1093/HMG/DDU050

Genome partitioning of genetic variation for height from 11,214 sibling pairs

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1086/522934

Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

Publisher: Elsevier BV

Date: 02-2021

DOI: 10.1016/J.JID.2020.06.017

Linkage Analysis in a Large Family from Pakistan with Depression and a High Incidence of Consanguineous Marriages

Publisher: S. Karger AG

Date: 2008

DOI: 10.1159/000135265

Abstract: i Objectives: /i A genome wide scan for linkage was performed in a five generation family with a high incidence of depression and high average coefficient of inbreeding ascertained in a rural area of Pakistan. The effect of inbreeding on linkage analysis in an extended pedigree is discussed. i Methods: /i 372 microsatellite markers were used in a genome wide linkage study. Inbreeding coefficients were measured by two methods using both genealogical and genotype data. i Results: /i Of 111 family members with phenotypic information, 82 were diagnosed with recurrent major depression. Linkage analysis using the program Superlink online generated LOD scores of less than one at all loci. A model free analysis with SimWalk did not result in any significant linkage score. The mean inbreeding coefficient was 0.038 estimated from genealogical data and 0.02 estimated from the genotype data. These results did not differ significantly. The effects of inbreeding included a reduction in the polymorphism information content of markers and an overestimate of marker allele frequencies. i Conclusion: /i The analysis of very large families is computationally demanding. Problems encountered in this analysis, including loss of power due to reduced polymorphism information content and sensitivity of the LOD score method to estimates of allele frequencies, severely limited the chance of detecting linkage.

ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer

Publisher: Oxford University Press (OUP)

Date: 23-06-2014

DOI: 10.1093/JNCI/DJU149

Coffee consumption and risk of breast cancer: a Mendelian Randomization study

Publisher: Cold Spring Harbor Laboratory

Date: 17-07-2020

DOI: 10.1101/2020.07.17.208421

Abstract: Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. We conducted a two-s le Mendelian randomization randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR=0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07). The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak inverse association.

Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

Publisher: Springer Science and Business Media LLC

Date: 24-05-2017

DOI: 10.1038/NCOMMS15539

Abstract: Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk ( P × 10 −8 ), implicating genes involved in sex steroid hormone pathways ( FN1 , CCDC170 , ESR1 , SYNE1 and FSHB ). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

No Strong Association between the Apolipoprotein E E4 Allele and Glaucoma

Publisher: Elsevier BV

Date: 09-2023

DOI: 10.1016/J.XOPS.2023.100287

Bias, precision and heritability of self-reported and clinically measured height in Australian twins

Publisher: Springer Science and Business Media LLC

Date: 25-08-2006

DOI: 10.1007/S00439-006-0240-Z

Abstract: Many studies of quantitative and disease traits in human genetics rely upon self-reported measures. Such measures are based on questionnaires or interviews and are often cheaper and more readily available than alternatives. However, the precision and potential bias cannot usually be assessed. Here we report a detailed quantitative genetic analysis of stature. We characterise the degree of measurement error by utilising a large s le of Australian twin pairs (857 MZ, 815 DZ) with both clinical and self-reported measures of height. Self-report height measurements are shown to be more variable than clinical measures. This has led to lowered estimates of heritability in many previous studies of stature. In our twin s le the heritability estimate for clinical height exceeded 90%. Repeated measures analysis shows that 2-3 times as many self-report measures are required to recover heritability estimates similar to those obtained from clinical measures. Bivariate genetic repeated measures analysis of self-report and clinical height measures showed an additive genetic correlation >0.98. We show that the accuracy of self-report height is upwardly biased in older in iduals and in in iduals of short stature. By comparing clinical and self-report measures we also showed that there was a genetic component to females systematically reporting their height incorrectly this phenomenon appeared to not be present in males. The results from the measurement error analysis were subsequently used to assess the effects of error on the power to detect linkage in a genome scan. Moderate reduction in error (through the use of accurate clinical or multiple self-report measures) increased the effective s le size by 22% elimination of measurement error led to increases in effective s le size of 41%.

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Publisher: Oxford University Press (OUP)

Date: 30-01-2015

DOI: 10.1093/HMG/DDV027

Abstract: Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8)], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9) for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Publisher: Cold Spring Harbor Laboratory

Date: 07-08-2017

DOI: 10.1101/173112

Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs at a genome-wide level of significance in KITLG , DOCK8 , and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A , CYP1B1 , PPARGC1B , HDAC4 , FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1 , reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

Author Correction: Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization

Publisher: Springer Science and Business Media LLC

Date: 11-03-2020

DOI: 10.1038/S41598-020-60488-3

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Melanoma Genetics: Recent Findings Take Us Beyond Well-Traveled Pathways

Publisher: Elsevier BV

Date: 07-2012

DOI: 10.1038/JID.2012.75

Abstract: Genetic linkage and candidate gene studies have identified a number of genes involved in melanoma susceptibility, such as MC1R and CDKN2A, via the endophenotypes of pigmentation and nevus proliferation. A series of genome-wide association studies (GWASs) in 2008 and 2009 showed that a handful of additional genes (e.g., ASIP, TYR, and PLA2G6) influencing these endophenotypes also affected melanoma risk. The most recent wave of melanoma GWASs has uncovered genes functioning independently of the known melanoma-associated phenotypes, highlighting the role of processes such as DNA repair and cell cycle control. We take this opportunity to summarize these new and exciting findings and integrate them into the current framework of our understanding of melanoma genetics.

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

Publisher: Springer Science and Business Media LLC

Date: 27-04-2020

DOI: 10.1038/S41588-020-0611-8

Erratum: Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

Publisher: Springer Science and Business Media LLC

Date: 29-05-2013

DOI: 10.1038/NG0613-712B

Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration

Publisher: Elsevier BV

Date: 07-2023

DOI: 10.1016/J.XCRM.2023.101085

Genome-wide multi-ethnic meta-analysis identifies 22 independent risk loci for normal tension glaucoma and predominantly overlaps with high tension glaucoma.

Publisher: Research Square Platform LLC

Date: 16-08-2023

DOI: 10.21203/RS.3.RS-3176408/V1

Abstract: Background Primary open-angle glaucoma (POAG) is often ided into two subtypes. High-tension glaucoma (HTG) is characterized by elevated intraocular pressure (IOP), while normal-tension glaucoma (NTG) is characterized by IOP consistently in the normal range. However, this notion is still controversial as some studies argue that different tension subtypes is part of the same pathogenic process while other studies claim that NTG represents a different etiological process where primary neurodegeneration has a higher impact. This study aimed to elucidate the shared and distinct genetic architecture for NTG and HTG. Method To identify risk loci specific to NTG, we conducted a large international multi-ethnic multi-trait meta-analysis of 7,942 NTG cases and 384,431 controls without any form of glaucoma, and a structural measurement of the integrity of the optic nerve, vertical cup-to-disc ratio (VCDR, N = 282,100), adjusted for IOP using the mtCOJO method. We also performed an assessment of the genetic overlap between NTG and HTG (N HTG cases = 5144, N controls = 47,997) using the GWAS pairwise method (GWAS-PW). Findings: This study identified 22 risk loci associated with NTG. Of these, 17 loci are novel for NTG, and two loci, BMP4 and TBKBP1 , have not previously been associated at the genome-wide significant level with glaucoma. The contribution of BMP4 in the development of NTG was further supported by integrating single-cell transcriptomic data from neuron-like cells, along with methylomic data from peripheral blood. Examination of each locus across the genome using the GWAS-PW method indicated that risk loci are shared across NTG and HTG. The magnitude of the effect of the genome-wide significant loci tends to be lower in NTG compared to their effects on HTG, particularly for IOP-related loci. Additionally, we identified 42 drug-gene interactions with four genes ( ABCA1, CDKN2A, CDKN2B and ITGB3 ) that were prioritized through our gene-based analysis. Interpretation: This work expands our understanding of the genetics of NTG and highlights a strong genetic overlap between HTG and NTG. Despite the genetic overlap, we have shown that IOP-related loci tend to have a smaller effect size in NTG when compared with HTG whereas neurodegenerative loci independent of IOP have similar effect sizes on NTG and HTG. These results indicate that while there is a significant overlap in risk loci between NTG and HTG, a precise estimation of their effect sizes on NTG using larger studies could help develop genetic risk prediction models to identify in iduals at a higher risk of developing NTG. We have also identified some potential targets for neuroprotective treatment through the interaction of four genes and multiple drugs. By harnessing multi-omics data, we substantiated the involvement of gene expression and DNA methylation of BMP4 in the etiology of NTG.

A Genome Scan for Quantitative Trait Loci in a Wild Population of Red Deer (Cervus elaphus)

Publisher: Oxford University Press (OUP)

Date: 12-2002

DOI: 10.1093/GENETICS/162.4.1863

Abstract: Recent empirical evidence indicates that although fitness and fitness components tend to have low heritability in natural populations, they may nonetheless have relatively large components of additive genetic variance. The molecular basis of additive genetic variation has been investigated in model organisms but never in the wild. In this article we describe an attempt to map quantitative trait loci (QTL) for birth weight (a trait positively associated with overall fitness) in an unmanipulated, wild population of red deer (Cervus elaphus). Two approaches were used: interval mapping by linear regression within half-sib families and a variance components analysis of a six-generation pedigree of & animals. Evidence for segregating QTL was found on three linkage groups, one of which was significant at the genome-wide suggestive linkage threshold. To our knowledge this is the first time that a QTL for any trait has been mapped in a wild mammal population. It is hoped that this study will stimulate further investigations of the genetic architecture of fitness traits in the wild.

Effect of increased body mass index on risk of diagnosis or death from cancer

Publisher: Springer Science and Business Media LLC

Date: 08-02-2019

DOI: 10.1038/S41416-019-0386-9

Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner's perspective

Publisher: Wiley

Date: 02-05-2019

DOI: 10.1002/GEPI.22207

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank Optical Coherence Tomography images

Publisher: Cold Spring Harbor Laboratory

Date: 26-07-2020

DOI: 10.1101/2020.07.20.20157180

Abstract: Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is often used to diagnose and manage multiple ophthalmic diseases including glaucoma. We present the first large-scale quantitative genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has previously been associated with glaucoma, and Mendelian randomisation confirms that inner retinal thickness, despite being a valid biomarker for the disease, is not on the same genetic causal pathway as glaucoma. Image analysis methods were used to extract overall retinal thickness at the fovea, representative of hypoplasia, with which three out of the 46 SNPs were associated. These SNPs have been previously linked with pigmentation, confirmed by their association with hair colour in the UK Biobank dataset. We additionally associate these three loci with visual acuity. In contrast to the already known Mendelian causes of severe foveal hypoplasia, our results suggest a previously unknown spectrum of foveal hypoplasia in the population, in part genetically determined, that has consequences on visual function.

Genome-wide association analysis of 95 549 individuals identifies novel loci and genes influencing optic disc morphology

Publisher: Oxford University Press (OUP)

Date: 06-09-2019

DOI: 10.1093/HMG/DDZ193

Abstract: Optic nerve head morphology is affected by several retinal diseases. We measured the vertical optic disc diameter (DD) of the UK Biobank (UKBB) cohort (N = 67 040) and performed the largest genome-wide association study (GWAS) of DD to date. We identified 81 loci (66 novel) for vertical DD. We then replicated the novel loci in International Glaucoma Genetic Consortium (IGGC, N = 22 504) and European Prospective Investigation into Cancer–Norfolk (N = 6005) in general the concordance in effect sizes was very high (correlation in effect size estimates 0.90): 44 of the 66 novel loci were significant at P & 0.05, with 19 remaining significant after Bonferroni correction. We identified another 26 novel loci in the meta-analysis of UKBB and IGGC data. Gene-based analyses identified an additional 57 genes. Human ocular tissue gene expression analysis showed that most of the identified genes are enriched in optic nerve head tissue. Some of the identified loci exhibited pleiotropic effects with vertical cup-to-disc ratio, intraocular pressure, glaucoma and myopia. These results can enhance our understanding of the genetics of optic disc morphology and shed light on the genetic findings for other ophthalmic disorders such as glaucoma and other optic nerve diseases.

Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 24-05-2013

DOI: 10.1167/IOVS.13-11952

WALLABY pilot survey

Publisher: Cambridge University Press (CUP)

Date: 2023

DOI: 10.1017/PASA.2023.28

Abstract: We investigate the ersity in the sizes and average surface densities of the neutral atomic hydrogen (H i ) gas discs in $\\sim$ 280 nearby galaxies detected by the Widefield ASKAP L-band Legacy All-sky Blind Survey (WALLABY). We combine the uniformly observed, interferometric H i data from pilot observations of the Hydra cluster and NGC 4636 group fields with photometry measured from ultraviolet, optical, and near-infrared imaging surveys to investigate the interplay between stellar structure, star formation, and H i structural parameters. We quantify the H i structure by the size of the H i relative to the optical disc and the average H i surface density measured using effective and isodensity radii. For galaxies resolved by $ $ $1.3$ beams, we find that galaxies with higher stellar masses and stellar surface densities tend to have less extended H i discs and lower H i surface densities: the isodensity H i structural parameters show a weak negative dependence on stellar mass and stellar mass surface density. These trends strengthen when we limit our s le to galaxies resolved by $ $ 2 beams. We find that galaxies with higher H i surface densities and more extended H i discs tend to be more star forming: the isodensity H i structural parameters have stronger correlations with star formation. Normalising the H i disc size by the optical effective radius (instead of the isophotal radius) produces positive correlations with stellar masses and stellar surface densities and removes the correlations with star formation. This is due to the effective and isodensity H i radii increasing with mass at similar rates while, in the optical, the effective radius increases slower than the isophotal radius. Our results are in qualitative agreement with previous studies and demonstrate that with WALLABY we can begin to bridge the gap between small galaxy s les with high spatial resolution H i data and large, statistical studies using spatially unresolved, single-dish data.

Associations Between Depression and Anxiety Symptoms and Retinal Vessel Caliber in Adolescents and Young Adults

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2014

DOI: 10.1097/PSY.0000000000000117

Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

Publisher: Public Library of Science (PLoS)

Date: 03-05-2012

DOI: 10.1371/JOURNAL.PGEN.1002611

Author Correction: GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability.

Publisher: Springer Science and Business Media LLC

Date: 05-06-2019

DOI: 10.1038/S41593-019-0402-7

Abstract: Several occurrences of the word 'schizophrenia' have been re-worded as 'liability to schizophrenia' or 'schizophrenia risk', including in the title, which should have been "GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability," as well as in Supplementary Figures 1-10 and Supplementary Tables 7-10, to more accurately reflect the findings of the work.

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity

Publisher: Elsevier BV

Date: 07-2020

DOI: 10.1016/J.OPHTHA.2019.12.025

Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study

Publisher: Oxford University Press (OUP)

Date: 14-09-2018

DOI: 10.1093/HMG/DDY307

Abstract: There is considerable debate regarding the role that 25-hydroxyvitamin D [25(OH)D] concentrations play in cancer risk or mortality, with earlier studies drawing mixed conclusions. Using data from the UK Biobank (UKB), we evaluate whether genetically predicted 25(OH)D concentrations are associated with overall cancer susceptibility and cancer mortality using five 25(OH)D genetic markers. Data comprised 438 870 white British UKB participants aged 37-73, including 46 155 cancer cases and 6998 cancer-specific deaths. Participants with keratinocyte cancers and/or benign tumors were excluded from the analysis. Odds ratios were calculated per 20 nmol/L increase in genetically predicted 25(OH)D for cancer risk and cancer mortality. For in idual cancer risks, estimates were meta-analyzed with publicly available data using a fixed-effect inverse-variance-weighted model. We demonstrated that genetically low plasma 25(OH)D concentrations were not associated with increased cancer risk nor cancer mortality. Stratification by sex or cancer types did not reveal any meaningful differences albeit wider confidence intervals. Fixed-effect meta-analysis of our in idual cancer risk estimates with those derived from publicly available cancer consortia data and previous studies further reinforced our null Mendelian randomization findings on prostate, lung, colorectal and breast cancers with tight confidence intervals for ovarian and pancreatic cancers, our estimates were less precise despite being not statistically significant. Taken altogether, our results provide no genetic evidence for an association between vitamin D and overall cancer outcomes, with tight confidence intervals to exclude all but very small effect sizes.

WALLABY Pilot Survey

Publisher: Oxford University Press (OUP)

Date: 28-02-2023

DOI: 10.1093/MNRAS/STAD602

Abstract: Galaxy morphology in atomic hydrogen (H i) and in the ultraviolet (UV) are closely linked. This has motivated their combined use to quantify morphology over the full H i disc for both H i and UV imaging. We apply galaxy morphometrics: concentration, asymmetry, gini, M20 and multimode-intensity-deviation statistics to the first moment-0 maps of the WALLABY Survey of galaxies in the hydra cluster centre. Taking advantage of this new H i survey, we apply the same morphometrics over the full H i extent on archival GALEX FUV and NUV data to explore how well H i truncated, extended ultraviolet disc (XUV) and other morphological phenomena can be captured using pipeline WALLABY data products. Extended H i and UV discs can be identified relatively straightforward from their respective concentration. Combined with WALLABY H i, even the shallowest GALEX data are sufficient to identify XUV discs. Our second goal is to isolate galaxies undergoing ram-pressure stripping in the H i morphometric space. We employ four different machine learning techniques, a decision tree, a k-nearest neighbour, a support-vector machine, and a random forest. Up to 80 per cent precision and recall are possible with the random forest giving the most robust results.

Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function

Publisher: Public Library of Science (PLoS)

Date: 09-09-2010

DOI: 10.1371/JOURNAL.PGEN.1001097

Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality

Publisher: Springer Science and Business Media LLC

Date: 21-09-2021

DOI: 10.1007/S00439-020-02223-6

Abstract: Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (P

Determining Possible Shared Genetic Architecture Between Myopia and Primary Open-Angle Glaucoma.

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 19-07-2019

DOI: 10.1167/IOVS.18-26231

Genome-wide association identifies ATOH7 as a major gene determining human optic disc size

Publisher: Oxford University Press (OUP)

Date: 15-04-2010

DOI: 10.1093/HMG/DDQ144

Cold gas outflows from the Small Magellanic Cloud traced with ASKAP

Publisher: Springer Science and Business Media LLC

Date: 29-10-2018

DOI: 10.1038/S41550-018-0608-8

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease

Publisher: Springer Science and Business Media LLC

Date: 18-11-2016

DOI: 10.1186/S12864-016-3276-Z

eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Publisher: American Association for Cancer Research (AACR)

Date: 16-06-2022

DOI: 10.1158/1055-9965.EPI-22-0096

Abstract: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Multiplex melanoma families are enriched for polygenic risk

Publisher: Oxford University Press (OUP)

Date: 27-07-2020

DOI: 10.1093/HMG/DDAA156

Abstract: Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of in idually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10−5 and 6.3 × 10−45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

Genetic variation affects morphological retinal phenotypes extracted from UK Biobank optical coherence tomography images

Publisher: Public Library of Science (PLoS)

Date: 12-05-2021

DOI: 10.1371/JOURNAL.PGEN.1009497

Abstract: Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function.

A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families

Publisher: American Psychiatric Association Publishing

Date: 08-2011

DOI: 10.1176/APPI.AJP.2011.10091319

Evaluation of Association of HNF1B Variants with Diverse Cancers: Collaborative Analysis of Data from 19 Genome-Wide Association Studies

Publisher: Public Library of Science (PLoS)

Date: 28-05-2010

DOI: 10.1371/JOURNAL.PONE.0010858

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Publisher: Springer Science and Business Media LLC

Date: 14-05-2018

DOI: 10.1038/S41467-018-03646-6

Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, % of the CCT-loci are near or within Mendelian disorder genes. These included FBN1 , ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus ( r = −0.62, P = 5.30 × 10 −5 ) but not between CCT and primary open-angle glaucoma ( r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Attitudes Towards Polygenic Risk Testing in Individuals with Glaucoma

Publisher: Elsevier BV

Date: 07-2022

DOI: 10.1016/J.OGLA.2021.11.002

Abstract: Glaucoma is the leading cause of irreversible blindness worldwide however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying in idual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic however, little is known about the attitudes of patients toward such testing. Cross-sectional, questionnaire-based study. Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. One thousand one hundred sixty-nine in iduals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the in idual would recommend the test to family members or others. Our results show strong interest in the test, with 69.4% of in iduals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70 95% confidence interval [CI], 1.15-2.49 P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05 95% CI, 1.28-3.29 P = 0.003), and those who were worried about developing glaucoma (OR, 2.07 95% CI, 1.27-3.37 P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.

Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study

Publisher: Oxford University Press (OUP)

Date: 25-11-2017

DOI: 10.1093/IJE/DYX236

Identification of a Candidate Gene for Astigmatism

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 13-02-2013

DOI: 10.1167/IOVS.12-10463

Does polygenic risk influence associations between sun exposure and melanoma? A prospective cohort analysis

Publisher: Oxford University Press (OUP)

Date: 17-12-2019

DOI: 10.1111/BJD.18703

Abstract: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly s led from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with ergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with ergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020 183:205-206. Plain language summary available online.

Ultraviolet radiation exposure and melanoma: evidence for gene-environment interaction in a large prospective cohort

Publisher: Cold Spring Harbor Laboratory

Date: 14-06-2019

DOI: 10.1101/666123

Abstract: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on the relationship between sunlight and melanoma from prospective studies are scant, and the combination of ultraviolet exposure data collected before melanoma diagnosis and genetic information is rarer still. We aimed to quantify the association between ambient and personal UV exposure in relation to risk of incident melanoma (invasive invasive+ in situ ) in a large population-based prospective study of men and women (n=38,833) residing in a high ambient UV setting, and to examine potential gene-environment interactions. During a median follow-up time of 4.4 years, 782 (1.5%) participants developed cutaneous melanoma (316 invasive, 466 in situ ). Country of birth, age at migration and sunburns during all periods of life were significantly associated with melanoma risk. Histories of keratinocyte cancer and of other actinic lesions were both strongly associated with melanoma risk. An interaction with polygenic risk is possible among people at low risk, markers of cumulative sun exposure were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early life ambient exposure were associated with melanoma. Polygenic risk scores can assist in identifying in iduals for whom sunlight exposure is most relevant.

Legacy of mutiny on the Bounty: founder effect and admixture on Norfolk Island

Publisher: Springer Science and Business Media LLC

Date: 08-07-2009

DOI: 10.1038/EJHG.2009.111

WALLABY pilot survey: Public release of H i data for almost 600 galaxies from phase 1 of ASKAP pilot observations

Publisher: Cambridge University Press (CUP)

Date: 2022

DOI: 10.1017/PASA.2022.50

Abstract: We present WALLABY pilot data release 1, the first public release of H i pilot survey data from the Wide-field ASKAP L-band Legacy All-sky Blind Survey (WALLABY) on the Australian Square Kilometre Array Pathfinder. Phase 1 of the WALLABY pilot survey targeted three $60\\,\\mathrm{deg}^{2}$ regions on the sky in the direction of the Hydra and Norma galaxy clusters and the NGC 4636 galaxy group, covering the redshift range of $z \\lesssim 0.08$ . The source catalogue, images and spectra of nearly 600 extragalactic H i detections and kinematic models for 109 spatially resolved galaxies are available. As the pilot survey targeted regions containing nearby group and cluster environments, the median redshift of the s le of $z \\approx 0.014$ is relatively low compared to the full WALLABY survey. The median galaxy H i mass is $2.3 \\times 10^{9}\\,{\\rm M}_{{\\odot}}$ . The target noise level of $1.6\\,\\mathrm{mJy}$ per 30 ′′ beam and $18.5\\,\\mathrm{kHz}$ channel translates into a $5 \\sigma$ H i mass sensitivity for point sources of about $5.2 \\times 10^{8} \\, (D_{\\rm L} / \\mathrm{100\\,Mpc})^{2} \\, {\\rm M}_{{\\odot}}$ across 50 spectral channels ( ${\\approx} 200\\,\\mathrm{km \\, s}^{-1}$ ) and a $5 \\sigma$ H i column density sensitivity of about $8.6 \\times 10^{19} \\, (1 + z)^{4}\\,\\mathrm{cm}^{-2}$ across 5 channels ( ${\\approx} 20\\,\\mathrm{km \\, s}^{-1}$ ) for emission filling the 30 ′′ beam. As expected for a pilot survey, several technical issues and artefacts are still affecting the data quality. Most notably, there are systematic flux errors of up to several 10% caused by uncertainties about the exact size and shape of each of the primary beams as well as the presence of sidelobes due to the finite deconvolution threshold. In addition, artefacts such as residual continuum emission and bandpass ripples have affected some of the data. The pilot survey has been highly successful in uncovering such technical problems, most of which are expected to be addressed and rectified before the start of the full WALLABY survey.

Genomic Locus Modulating Corneal Thickness in the Mouse Identifies POU6F2 as a Potential Risk of Developing Glaucoma

Publisher: Cold Spring Harbor Laboratory

Date: 11-2017

DOI: 10.1101/212605

Abstract: Purpose: Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. Methods: The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to identify quantitative trait loci (QTLs) modulating this phenotype using the bioinformatics tools on GeneNetwork ( www.genenetwork.org ). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human primary open-angle glaucoma (POGA) genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG. Results: This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region ( Pou6f2 ) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene ( POU6F2 ), with the highest significance level of p = 10 −6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2 -null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Conclusions: Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2 , that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury. Glaucoma is a complex group of diseases with several known causal mutations and many known risk factors. One well-known risk factor for developing primary open angle glaucoma is the thickness of the central cornea. The present study leverages a unique blend of systems biology methods using BXD recombinant inbred mice and genome-wide association studies from humans to define a putative molecular link between a phenotypic risk factor (central corneal thickness) and glaucoma. We identified a transcription factor, POU6F2, that is found in the developing retinal ganglion cells and cornea. POU6F2 is also present in a subpopulation of retinal ganglion cells and in stem cells of the cornea. Functional studies reveal that POU6F2 is associated the central corneal thickness and with susceptibility of retinal ganglion cells to injury.

A multi-phenotype analysis reveals 19 novel susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma

Publisher: Cold Spring Harbor Laboratory

Date: 08-03-2022

DOI: 10.1101/2022.03.06.22271725

Abstract: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common forms of skin cancer. There is genetic overlap between skin cancers, pigmentation traits, and autoimmune diseases. We use linkage disequilibrium score regression to identify 20 traits (melanoma, pigmentation traits, autoimmune diseases, and blood biochemistry biomarkers) with a high genetic correlation ( r g 10%, P 0.05) with BCC (20,791 cases and 286,893 controls in the UK Biobank) and SCC (7,402 cases and 286,892 controls in the UK Biobank), and use a multi-trait genetic analysis to identify 78 and 69 independent genome-wide significant (P 5 × 10 -8 ) susceptibility loci for BCC and SCC respectively 19 BCC and 15 SCC loci are both novel and replicated (P 0.05) in a large independent cohort 23andMe, Inc (BCC: 251,963 cases and 2,271,667 controls, and SCC: 134,700 cases and 2,394,699 controls. Novel loci are implicated in BCC/SCC development and progression (e.g. CDKL1 ), pigmentation (e.g. DSTYK ), cardiometabolic pathways (e.g. FADS2 ), and immune-regulatory pathways including innate immunity against coronaviruses (e.g. IFIH1 ), and HIV-1 viral load modulation and disease progression (e.g. CCR5 ). We also report a powerful and optimised BCC polygenic risk score that enables effective risk stratification for keratinocyte cancer in a large prospective Canadian Longitudinal Study of Aging (794 cases and 18139 controls) e.g. percentage of participants reclassified MTAG PRS = 36.57%, 95% CI = 35.89-37.26% versus UKB PRS = 33.23%, 95% CI=32.56-33.91%).

Obesity and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: A Mendelian Randomization Study

Publisher: Oxford University Press (OUP)

Date: 30-09-2014

DOI: 10.1093/JNCI/DJU252

Retinal ganglion cell-specific genetic regulation in primary open-angle glaucoma

Publisher: Elsevier BV

Date: 06-2022

DOI: 10.1016/J.XGEN.2022.100142

Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration

Publisher: Springer Science and Business Media LLC

Date: 31-05-2016

DOI: 10.1038/SREP26885

Abstract: Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h 2 g = 0.42 ± 0.09) and AMD (h 2 g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h 2 g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (r g = 0.47 ± 0.25) which remained after removing known loci (r g = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (r g = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

Publisher: Elsevier BV

Date: 07-2019

DOI: 10.1016/J.AJHG.2019.05.002

A pilot survey for transients and variables with the Australian Square Kilometre Array Pathfinder

Publisher: Oxford University Press (OUP)

Date: 04-05-2018

DOI: 10.1093/MNRAS/STY1157

Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci

Publisher: Oxford University Press (OUP)

Date: 08-10-2014

DOI: 10.1093/HMG/DDU516

Genetic and environmental factors in conjunctival UV autofluorescence

Publisher: American Medical Association (AMA)

Date: 04-2015

DOI: 10.1001/JAMAOPHTHALMOL.2014.5627

Genetic studies of body mass index yield new insights for obesity biology

Publisher: Springer Science and Business Media LLC

Date: 11-02-2015

DOI: 10.1038/NATURE14177

Symptom-level modelling unravels the shared genetic architecture of anxiety and depression

Publisher: Springer Science and Business Media LLC

Date: 15-04-2021

DOI: 10.1038/S41562-021-01094-9

Publisher Correction: Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

Publisher: Springer Science and Business Media LLC

Date: 14-01-2019

DOI: 10.1038/S41467-018-08078-W

Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.

A single nucleotide polymorphism in CHAT influences response to acetylcholinesterase inhibitors in Alzheimer's disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-2006

DOI: 10.1097/01.FPC.0000189799.88596.04

Abstract: Alzheimer's disease (AD) is a devastating neurodegeneration with a characteristic deficit in cholinergic neurotransmission. Treatment with acetylcholinesterase (AChE) inhibitors aims to reverse this deficit and does ameliorate the decline in cognition in some AD patients, although response is variable. To examine whether sequence variation in the gene encoding choline acetyltransferase (CHAT), which encodes the major catalytic enzyme of the cholinergic pathway, predicts response to AChE inhibitors. Alzheimer's disease patients (121) were treated with cholinesterase inhibitors and the effect of treatment on cognition was measured using the Mini Mental State Examination (MMSE). Six polymorphisms in CHAT were analysed for association with change in MMSE score. After correction for multiple testing, we found one SNP, rs733722, in a promoter region of CHAT, is associated with response of AD patients to cholinesterase inhibitors (P = 0.03) and accounts for 6% of the variance in response to AChE inhibitors. Rs733722 represents a putative marker of response to AChE inhibitors in AD patients.

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Publisher: Springer Science and Business Media LLC

Date: 15-02-2018

DOI: 10.1038/S41598-018-20435-9

Abstract: Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis s le size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1 , LINC02052 and CRYGS , LMX1B , and LMO7 using single variant tests, one additional locus ( C9 ) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

Optimal Two-Stage Testing for Family-Based Genome-wide Association Studies

Publisher: Elsevier BV

Date: 03-2008

DOI: 10.1016/J.AJHG.2008.02.003

Quantitative Trait Locus Analysis of Longitudinal Quantitative Trait Data in Complex Pedigrees

Publisher: Oxford University Press (OUP)

Date: 11-2005

DOI: 10.1534/GENETICS.105.043828

Abstract: There is currently considerable interest in genetic analysis of quantitative traits such as blood pressure and body mass index. Despite the fact that these traits change throughout life they are commonly analyzed only at a single time point. The genetic basis of such traits can be better understood by collecting and effectively analyzing longitudinal data. Analyses of these data are complicated by the need to incorporate information from complex pedigree structures and genetic markers. We propose conducting longitudinal quantitative trait locus (QTL) analyses on such data sets by using a flexible random regression estimation technique. The relationship between genetic effects at different ages is efficiently modeled using covariance functions (CFs). Using simulated data we show that the change in genetic effects over time can be well characterized using CFs and that including parameters to model the change in effect with age can provide substantial increases in power to detect QTL compared with repeated measure or univariate techniques. The asymptotic distributions of the methods used are investigated and methods for overcoming the practical difficulties in fitting CFs are discussed. The CF-based techniques should allow efficient multivariate analyses of many data sets in human and natural population genetics.

Genetically determined cutaneous nevi and risk of cancer

Publisher: Wiley

Date: 20-11-2022

DOI: 10.1002/IJC.33874

Abstract: Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk‐marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using in idual‐level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29‐1.55 QSkin OR 1.58, 95% CI: 1.29‐1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33‐1.44 QSkin OR 1.20, 95% CI: 1.05‐1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28‐1.55 QSkin OR 1.44, 95% CI: 1.19‐1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases.

Investigating the genetic and causal relationship between initiation or use of alcohol, caffeine, cannabis and nicotine

Publisher: Elsevier BV

Date: 05-2020

DOI: 10.1016/J.DRUGALCDEP.2020.107966

Polyunsaturated fatty acids and risk of melanoma: A Mendelian randomisation analysis

Publisher: Wiley

Date: 05-03-2018

DOI: 10.1002/IJC.31334

Abstract: Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for ex le, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17

Accurate Imputation-Based Screening of Gln368Ter Myocilin Variant in Primary Open-Angle Glaucoma

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 03-08-2015

DOI: 10.1167/IOVS.15-17305

Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1016/J.THROMRES.2019.04.011

Abstract: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. In idual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. The incidence of VTE was 5.1%. Extremes of weight at diagnosis ( 95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.

Identification of a locus near ULK1 associated with progression-free survival in ovarian cancer

Publisher: American Association for Cancer Research (AACR)

Date: 23-06-2021

DOI: 10.1158/1055-9965.EPI-20-1817

Abstract: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin aclitaxel chemotherapy. We found seven SNPs at 12q24.33 associated with PFS (P & 5 × 10–8), the top SNP being rs10794418 (HR = 1.24 95% CI, 1.15–1.34 P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604

Germline variation in the insulin-like growth factor pathway and risk of Barrett’s esophagus and esophageal adenocarcinoma

Publisher: Oxford University Press (OUP)

Date: 10-12-2020

DOI: 10.1093/CARCIN/BGAA132

Abstract: Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor P = 0.0090, q = 0.0542). These gene-level signals remained significant at q & 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Author response: Stronger association of CDKN2B-AS1 variants in female normal-tension glaucoma patients in a Japanese population

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 22-11-2016

DOI: 10.1167/IOVS.16-20917

High Polygenic Risk Is Associated with Earlier Initiation and Escalation of Treatment in Early Primary Open-Angle Glaucoma

Publisher: Elsevier BV

Date: 08-2023

DOI: 10.1016/J.OPHTHA.2023.03.028

Discovery of genomic loci associated with sleep apnoea risk through multi-trait GWAS analysis with snoring

Publisher: Cold Spring Harbor Laboratory

Date: 30-09-2020

DOI: 10.1101/2020.09.29.20199893

Abstract: Sleep apnoea is characterised by periods of halted breathing during sleep. Despite its association with severe health conditions, the aetiology of sleep apnoea remains understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants. We performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (N Total =523,366), followed by a multi-trait analysis of GWAS (MTAG) to boost power, leveraging the high genetic correlation between sleep apnoea and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional & joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (N Total =1,477,352 N cases =175,522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. Our MTAG analysis uncovered 49 significant independent loci associated with sleep apnoea risk. Twenty-nine variants were replicated in the 23andMe cohort. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. Our study uncovered multiple genetic loci associated with sleep apnoea risk, thus increasing our understanding of the aetiology of this condition and its relationship with other complex traits.

Effects of human footprint and biophysical factors on the body-size structure of fished marine species

Publisher: Wiley

Date: 27-07-2022

DOI: 10.1111/COBI.13807

Abstract: Marine fisheries in coastal ecosystems in many areas of the world have historically removed large‐bodied in iduals, potentially impairing ecosystem functioning and the long‐term sustainability of fish populations. Reporting on size‐based indicators that link to food‐web structure can contribute to ecosystem‐based management, but the application of these indicators over large (cross‐ecosystem) geographical scales has been limited to either fisheries‐dependent catch data or er‐based methods restricted to shallow waters ( m) that can misrepresent the abundance of large‐bodied fished species. We obtained data on the body‐size structure of 82 recreationally or commercially targeted marine demersal teleosts from 2904 deployments of baited remote underwater stereo‐video (stereo‐BRUV). S ling was at up to 50 m depth and covered approximately 10,000 km of the continental shelf of Australia. Seascape relief, water depth, and human gravity (i.e., a proxy of human impacts) were the strongest predictors of the probability of occurrence of large fishes and the abundance of fishes above the minimum legal size of capture. No‐take marine reserves had a positive effect on the abundance of fishes above legal size, although the effect varied across species groups. In contrast, sublegal fishes were best predicted by gradients in sea surface temperature (mean and variance). In areas of low human impact, large fishes were about three times more likely to be encountered and fishes of legal size were approximately five times more abundant. For conspicuous species groups with contrasting habitat, environmental, and biogeographic affinities, abundance of legal‐size fishes typically declined as human impact increased. Our large‐scale quantitative analyses highlight the combined importance of seascape complexity, regions with low human footprint, and no‐take marine reserves in protecting large‐bodied fishes across a broad range of species and ecosystem configurations.

Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia

Publisher: American Medical Association (AMA)

Date: 06-2021

DOI: 10.1001/JAMAOPHTHALMOL.2021.0497

Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma

Publisher: Cold Spring Harbor Laboratory

Date: 19-05-2022

DOI: 10.1101/2022.05.14.22275022

Abstract: Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide however, the molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of POAG and IOP GWAS loci and of overlapping eQTLs and sQTLs in 49 GTEx tissues and retina prioritized causal genes for 60% of loci. These genes were enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues revealed that the colocalizing genes and genome-wide POAG and IOP associations were enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominated IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.

Genome-wide association meta-analysis identifies new endometriosis risk loci

Publisher: Springer Science and Business Media LLC

Date: 28-10-2012

DOI: 10.1038/NG.2445

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

Publisher: Springer Science and Business Media LLC

Date: 16-02-2010

DOI: 10.1038/MP.2010.7

Abstract: Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the 'enrichment' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery s le. Nominally significant pathways were tested in the validation s le, and five pathways were found to be significant (P=0.03-0.001) only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three s les (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Publisher: Springer Science and Business Media LLC

Date: 24-01-2018

DOI: 10.1038/S41598-018-19590-W

Abstract: Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood s ling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2 , a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 10 6 , empirical P = 1.4 × 10 −5 ), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10 −9 , empirical P = 1.3 × 10 −7 ). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population

Publisher: Wiley

Date: 28-04-2008

DOI: 10.1002/AJMG.B.30775

Abstract: We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic ersity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the in idual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping.

Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders.

Publisher: Elsevier BV

Date: 06-2023

DOI: 10.1016/J.EBIOM.2023.104615

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma

Publisher: Springer Science and Business Media LLC

Date: 12-09-2010

DOI: 10.1038/NG.661

Steady-state visual evoked potential based classification system for detecting migraine seizures

Publisher: IEEE

Date: 11-2013

DOI: 10.1109/NER.2013.6696179

A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42

Publisher: Springer Science and Business Media LLC

Date: 13-07-2004

DOI: 10.1038/SJ.MP.4001544

A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25

Publisher: Springer Science and Business Media LLC

Date: 12-09-2010

DOI: 10.1038/NG.664

Genetic variants near PDGFRA are associated with corneal curvature in Australians

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 11-10-2012

DOI: 10.1167/IOVS.12-10489

Genetic heterogeneity in self-reported depressive symptoms identified through genetic analyses of the PHQ-9.

Publisher: Cambridge University Press (CUP)

Date: 18-09-2019

DOI: 10.1017/S0033291719002526

Abstract: Depression is a clinically heterogeneous disorder. Previous large-scale genetic studies of depression have explored genetic risk factors of depression case–control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity. We analyse data from 148 752 subjects of white British ancestry in the UK Biobank who completed nine items of a self-rated measure of current depressive symptoms: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD Score Regression was used to calculate SNP-based heritability ( h 2 SNP ) and genetic correlations ( r g ) across symptoms and to investigate genetic correlations with 25 external phenotypes. Genomic structural equation modelling was used to test the genetic factor structure across the nine symptoms. We identified nine genome-wide significant genomic loci (8 novel), with no overlap in loci across symptoms. h 2 SNP ranged from 6% (concentration problems) to 9% (appetite changes). Genetic correlations ranged from 0.54 to 0.96 (all p 1.39 × 10 −3 ) with 30 of 36 correlations being significantly smaller than one. A two-factor model provided the best fit to the genetic covariance matrix, with factors representing ‘psychological’ and ‘somatic’ symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms. Patterns of SNP associations and genetic correlations differ across the nine symptoms, suggesting that current depressive symptoms are genetically heterogeneous. Our study highlights the value of symptom-level analyses in understanding the genetic architecture of a psychiatric trait. Future studies should investigate whether genetic heterogeneity is recapitulated in clinical symptoms of major depression.

Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank

Publisher: Elsevier BV

Date: 09-2021

DOI: 10.1016/J.OPHTHA.2021.03.007

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

Publisher: Public Library of Science (PLoS)

Date: 08-07-2010

DOI: 10.1371/JOURNAL.PGEN.1001016

Counting nevi on the outer arm provides an accurate and feasible alternative to total body nevus count

Publisher: Wiley

Date: 26-06-2023

DOI: 10.1111/JDV.19279

A coherent, representative, and bioregional marine reserve network shows consistent change in rocky reef fish assemblages

Publisher: Wiley

Date: 04-2021

DOI: 10.1002/ECS2.3447

Abstract: Worldwide, several countries have established coherent, representative, and large‐scale networks of marine reserves to conserve bio ersity. Very few have, however, published systematic assessments of the ecological responses to this network protection, hindering broad understanding of their generality, utility, and efficacy. We present data collected from systematic s ling of rocky reef fish assemblages at sites across a network of 27 no‐take marine reserve areas (NTMR) and 27 partially protected areas (PPA) nested within multiple marine parks (regional networks) across three Australian bioregions spanning km of coastline (7° latitude) to test the generality of ecological change across this network. We also s led 18 reference areas (outside of the marine parks) to provide an independent assessment of potential NTMR effects and also to assess whole marine park effects. Baited remote underwater video (BRUV) was used to s le fishes between depths of 20–40 m over austral winters in four years (2010, 2011, 2015, and 2016). Despite substantial bioregional differences in fish assemblages, large and consistent effects of NTMR protection were detected across all bioregions for a key commercially and recreationally harvested species, Chrysophrys auratus (pink snapper). There were substantial increases in relative abundance of C. auratus in NTMR compared with fished zones through time (effect sizes %). The wider assemblage of targeted fish (excluding C. auratus ) only showed relatively small effects of protection (~11%) with trends observed for site‐attached wrasses (labrids) and planktivores (e.g., commercially fished Scorpis lineolata ) that are recreationally and commercially harvested. Furthermore, the relative abundance of non‐target or by‐catch species generally did not differ among management zones across the bioregional network. These results highlight how NTMR can be used to assess the ecological effects of fishing and wider environmental management, and can be incorporated into ecosystem‐based management for reef species more generally. Importantly, the provision of robust evidence of the performance and generality of NTMR over large‐spatial scales (e.g., bioregions) provides greater confidence in the expected outcomes from marine reserve networks as a conservation management approach.

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability

Publisher: Springer Science and Business Media LLC

Date: 27-08-2201

DOI: 10.1038/S41593-018-0206-1

Highly cost-efficient genome-wide association studies using DNA pools and dense SNP arrays

Publisher: Oxford University Press (OUP)

Date: 05-02-2008

DOI: 10.1093/NAR/GKM1060

Uncovering the complex relationship between balding, testosterone and skin cancers in men

Publisher: Springer Science and Business Media LLC

Date: 03-10-2023

DOI: 10.1038/S41467-023-41231-8

Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans

Publisher: Elsevier BV

Date: 11-2009

DOI: 10.1016/J.AJHG.2009.10.009

GWAS findings for human iris patterns: Associations with variants in genes that influence normal neuronal pattern development

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.AJHG.2011.07.011

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Publisher: Oxford University Press (OUP)

Date: 10-01-2017

DOI: 10.1093/HMG/DDW399

Common Germline Risk Variants Impact Somatic Alterations and Clinical Features across Cancers

Publisher: American Association for Cancer Research (AACR)

Date: 26-10-2023

DOI: 10.1158/0008-5472.CAN-22-1492

Abstract: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations.

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Publisher: Springer Science and Business Media LLC

Date: 31-08-2014

DOI: 10.1038/NG.3087

Gastroesophageal reflux GWAS identifies risk loci that also associate with subsequent severe esophageal diseases

Publisher: Springer Science and Business Media LLC

Date: 16-09-2019

DOI: 10.1038/S41467-019-11968-2

Abstract: Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.

New insight into human sweet taste: a genome-wide association study of the perception and intake of sweet substances

Publisher: Elsevier BV

Date: 06-2019

DOI: 10.1093/AJCN/NQZ043

Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia

Publisher: Springer Science and Business Media LLC

Date: 10-02-2013

DOI: 10.1038/NG.2554

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Publisher: Springer Science and Business Media LLC

Date: 13-10-2013

DOI: 10.1038/NG.2796

Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA

Publisher: Elsevier BV

Date: 07-2021

DOI: 10.1016/J.AJHG.2021.05.005

Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma.

Publisher: American Medical Association (AMA)

Date: 09-2021

DOI: 10.1001/JAMAOPHTHALMOL.2021.2440

Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.CGH.2018.03.007

Covariate linkage analysis of GAW14 simulated data incorporating subclinical phenotype, sex, population, parent-of-origin, and interaction

Publisher: Springer Science and Business Media LLC

Date: 12-2005

DOI: 10.1186/1471-2156-6-S1-S45

Abstract: We evaluate a method for the incorporation of covariates into linkage analysis using the Genetic Analysis Workshop 14 simulated data. Focusing on a randomly chosen replicate (42) we investigated the effect of the 12 subclinical phenotypes, sex, population, and parent-of-origin on the linkage signal from a model-free linkage analysis of Kofendrerd Personality Disorder. We detected a linkage peak on chromosome 1, at about 175 cM, which varied depending upon in iduals' status for subclinical phenotype b. A linkage peak on chromosome 3 (310 cM) was found not to depend upon subclinical phenotype status. Further peaks were found on chromosomes 5 (12 cM), 9 (4 cM), and 10 (95 cM), depending on the status of subclinical phenotypes a, k, and c/d/g, respectively. Retrospective comparison of our results with the simulation model showed correct identification of disease loci D1-5 on chromosomes 1, 3, 5, 9 and 10, respectively.

Deep investigation of neutral gas origins (DINGO): H i stacking experiments with early science data

Publisher: Oxford University Press (OUP)

Date: 26-10-2022

DOI: 10.1093/MNRAS/STAC3065

Abstract: We present early science results from Deep Investigation of Neutral Gas Origins (DINGO), an $\\rm H$i survey using the Australian Square Kilometre Array Pathfinder (ASKAP). Using ASKAP subarrays available during its commissioning phase, DINGO early science data were taken over ∼60 deg2 of the Galaxy And Mass Assembly (GAMA) 23 h region with 35.5 h integration time. We make direct detections of six known and one new sources at z & 0.01. Using $\\rm H$ i spectral stacking, we investigate the $\\rm H$ i gas content of galaxies at 0.04 & z & 0.09 for different galaxy colours. The results show that galaxy morphology based on optical colour is strongly linked to $\\rm H$ i gas properties. To examine environmental impacts on the $\\rm H$i gas content of galaxies, three subs les are made based on the GAMA group catalogue. The average $\\rm H$i mass of group central galaxies is larger than those of satellite and isolated galaxies, but with a lower $\\rm H$i gas fraction. We derive a variety of $\\rm H$i scaling relations for physical properties of our s le, including stellar mass, stellar mass surface density, NUV − r colour, specific star formation rate, and halo mass. We find that the derived $\\rm H$i scaling relations are comparable to other published results, with consistent trends also observed to ∼0.5 dex lower limits in stellar mass and stellar surface density. The cosmic $\\rm H$i densities derived from our data are consistent with other published values at similar redshifts. DINGO early science highlights the power of $\\rm H$i spectral stacking techniques with ASKAP.

A retrospective review of fluid balance control in CRRT

Publisher: Elsevier BV

Date: 11-2017

DOI: 10.1016/J.AUCC.2016.05.004

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Publisher: Springer Science and Business Media LLC

Date: 03-07-2020

DOI: 10.1038/S41467-020-16483-3

Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that s le sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Continuous renal replacement treatment and the 'bleeding patient'

Publisher: BMJ

Date: 11-01-2011

DOI: 10.1136/BCR.01.2009.1523

Association of Myopia and Intraocular Pressure with Retinal Detachment in European Descent Participants of the UK Biobank Cohort: A Mendelian Randomization Study

Publisher: American Medical Association (AMA)

Date: 06-2020

DOI: 10.1001/JAMAOPHTHALMOL.2020.1231

Scaling of Activity Space in Marine Organisms across Latitudinal Gradients

Publisher: University of Chicago Press

Date: 04-2023

DOI: 10.1086/723405

Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes

Publisher: Cold Spring Harbor Laboratory

Date: 17-10-2018

DOI: 10.1101/GR.233304.117

Abstract: Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for % of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans -eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis -regulation of IRF4 . Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes ( ZFP90 , HEBP1 , MSC , CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.

No Association Between Vitamin D Status and Risk of Barrett's Esophagus or Esophageal Adenocarcinoma: A Mendelian Randomization Study

Publisher: Elsevier BV

Date: 10-2019

DOI: 10.1016/J.CGH.2019.01.041

Survival outcomes in patients with multiple primary melanomas

Publisher: Wiley

Date: 10-04-2015

DOI: 10.1111/JDV.13144

Abstract: A substantial number of melanoma patients will develop multiple primary melanomas (MPM). Currently, little is known about the impact of MPM on survival. We aimed to determine whether melanoma survival is worse for patients with MPM compared to those with a single invasive primary melanoma (SPM). A cohort study was conducted. Patients were sourced from an Australian population, with follow-up information collected retrospectively from registry data. Melanoma-specific survival analysis was performed to find associated variables after adjustment for known prognostic factors, using four different models, each selecting a different index melanoma lesion. 1068 stage I and II melanoma patients were followed up for a median of 24.4 years. MPM was found in 17.8% of the cohort (190 patients), more likely among males and older age groups. Other clinicopathological parameters were similar between the MPM and SPM (878 patients) cohorts. After adjustment for age, sex and Breslow thickness, MPM was a hazard for death from melanoma, across all models, reaching significance when considering the last invasive lesion as the index melanoma (HR = 2.76, P = 0.017). Patients with multiple invasive lesions seem more at risk of death from melanoma, independent of known prognostic factors.

sofia 2 – an automated, parallel H i source finding pipeline for the WALLABY survey

Publisher: Oxford University Press (OUP)

Date: 05-07-2021

DOI: 10.1093/MNRAS/STAB1881

Abstract: We present sofia 2, the fully automated 3D source finding pipeline for the WALLABY extragalactic H i survey with the Australian SKA Pathfinder (ASKAP). sofia 2 is a reimplementation of parts of the original sofia pipeline in the c programming language and makes use of OpenMP for multithreading of the most time-critical algorithms. In addition, we have developed a parallel framework called sofia-X that allows the processing of large data cubes to be split across multiple computing nodes. As a result of these efforts, sofia 2 is substantially faster and comes with a much reduced memory footprint compared to its predecessor, thus allowing the large WALLABY data volumes of hundreds of gigabytes of imaging data per epoch to be processed in real time. The source code has been made publicly available to the entire community under an open-source licence. Performance tests using mock galaxies injected into genuine ASKAP data suggest that in the absence of significant imaging artefacts sofia 2 is capable of achieving near-100 per cent completeness and reliability above an integrated signal-to-noise ratio (SNR) of about 5–6. We also demonstrate that sofia 2 generally recovers the location, integrated flux, and w20 line width of galaxies with high accuracy. Other parameters, including the peak flux density and w50 line width, are more strongly biased due to the influence of the noise on the measurement. In addition, very faint galaxies below an integrated SNR of about 10 may get broken up into multiple components, thus requiring a strategy to identify fragmented sources and ensure that they do not affect the integrity of any scientific analysis based on the sofia 2 output.

Discovery of genomic loci associated with sleep apnea risk through multi-trait GWAS analysis with snoring

Publisher: Oxford University Press (OUP)

Date: 16-12-2022

DOI: 10.1093/SLEEP/ZSAC308

Abstract: Despite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk. We performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352 Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. Our SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. Our study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.

Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration

Publisher: Cold Spring Harbor Laboratory

Date: 24-08-2022

DOI: 10.1101/2022.08.24.22279172

Abstract: Age-related macular degeneration (AMD) is a leading cause of blindness in the industrialised world and is projected to affect million people worldwide by 2040. Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study. We evaluated the effect of 4,591 exposure traits on early AMD using univariable MR. Statistically significant results were explored further using: validation in an advanced AMD cohort MR Bayesian model averaging (MR-BMA) and multivariable MR. Overall, 44 traits were found to be putatively causal for early AMD in univariable analysis. Serum proteins that were found to have significant relationships with AMD included S100-A5 (odds ratio [OR]=1.07, p-value=6.80E-06), cathepsin F (OR=1.10, p-value=7.16E-05) and serine palmitoyltransferase 2 (OR=0.86, p-value=1.00E-03). Univariable MR analysis also supported roles for complement and immune cell traits. Although numerous lipid traits were found to be significantly related to AMD, MR-BMA suggested a driving causal role for serum sphingomyelin (marginal inclusion probability [MIP]=0.76 model-averaged causal effect [MACE]=0.29). The results of this MR study support several putative causal factors for AMD and highlight avenues for future translational research. This project was funded by the Wellcome Trust (224643/Z/21/Z) the University of Manchester’s Wellcome Institutional Strategic Support Fund (Wellcome ISSF) grant (204796/Z/16/Z) the UK National Institute for Health Research (NIHR) Academic Clinical Fellow and Clinical Lecturer Programmes Retina UK and Fight for Sight (GR586) the Australian National Health and Medical Research Council (NHMRC) (1150144). A phenome-wide Mendelian randomisation analysis revealed a causal link between age-related macular degeneration and a number of lipid, complement, immune cell, and serum protein traits, highlighting potential treatment targets.

Is Genetic Risk for Sleep Apnea Causally Linked With Glaucoma Susceptibility?

Publisher: Association for Research in Vision and Ophthalmology (ARVO)

Date: 20-01-2022

DOI: 10.1167/IOVS.63.1.25

Chronic gastroesophageal reflux disease shares genetic background with esophageal adenocarcinoma and Barrett's esophagus

Publisher: Oxford University Press (OUP)

Date: 23-12-2016

DOI: 10.1093/HMG/DDV512

Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

Publisher: Wiley

Date: 05-10-2016

DOI: 10.1002/IJC.29863

Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Publisher: Springer Science and Business Media LLC

Date: 31-08-2014

DOI: 10.1038/NG.3079

The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study

Publisher: European Respiratory Society (ERS)

Date: 20-04-2023

DOI: 10.1183/13993003.01585-2022

Abstract: Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. A bidirectional two-s le MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04–2.49 p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997–1.000 p=0.245). We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated.

Meta-Analysis Combining New and Existing Data Sets Confirms that the TERT-CLPTM1L Locus Influences Melanoma Risk

Publisher: Elsevier BV

Date: 02-2012

DOI: 10.1038/JID.2011.322

Polygenic Risk Scores Stratify Keratinocyte Cancer Risk among Solid Organ Transplant Recipients with Chronic Immunosuppression in a High Ultraviolet Radiation Environment

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.JID.2021.03.034

Abstract: Solid organ transplant recipients (SOTRs) have elevated risks for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), especially in high UVR environments. We assessed whether polygenic risk scores can improve the prediction of BCC and SCC risks and multiplicity over and above the traditional risk factors in SOTRs in a high UV setting. We built polygenic risk scores for BCC (n = 594,881) and SCC (n = 581,431) using UK Biobank and 23andMe datasets, validated them in the Australian QSkin Sun and Health Study cohort (n > 6,300), and applied them in SOTRs in the skin tumor in allograft recipients cohort from Queensland, Australia, a high UV environment. About half of the SOTRs with a high genetic risk developed BCC (absolute risk = 45.45%, 95% confidence interval = 33.14-58.19%) and SCC (absolute risk = 44.12%, 95% confidence interval = 32.08-56.68%). For both cancers, SOTRs in the top quintile were at >3-fold increased risk relative to those in the bottom quintile. The respective polygenic risk scores improved risk predictions by 2% for BCC (area under the curve = 0.77 vs. 0.75, P = 0.0691) and SCC (area under the curve = 0.84 vs. 0.82, P = 0.0260), over and above the established risk factors, and 19.03% (for BCC) and 18.10% (for SCC) of the SOTRs were reclassified in a high/medium/low risk scenario. The polygenic risk scores also added predictive accuracy for tumor multiplicity (BCC R

Abstract 5493: Genome-wide study of carboplatin and paclitaxel disposition in ovarian cancer patients

Publisher: American Association for Cancer Research (AACR)

Date: 08-2015

DOI: 10.1158/1538-7445.AM2015-5493

Abstract: Germline genetic variation can affect chemotherapeutic drug disposition, toxicity and efficacy. Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize in idual treatment. Compared to the traditional candidate gene approach, a genome-wide association study (GWAS) is unbiased but usually requires a large s le size. Since most cytotoxics have a short half-life and are given cyclically, multiple blood s les are therefore required to adequately define drug disposition and systemic exposure. This limits patient s le sizes in pharmacokinetic studies. The aim of this study was to identify SNPs that are associated with carboplatin and paclitaxel pharmacokinetic parameters using a GWAS approach in two small patient cohorts. Methods: Two independent pharmacokinetic cohorts were recruited in Australia (N = 61, both carboplatin and paclitaxel) and the Netherlands (N = 35, paclitaxel only). A total of 719,665 SNPs were genotyped using Illumina Human OmniExpress arrays. Linear regression was used to test the association between each SNP and the trait of interest, both unadjusted and adjusted for corresponding covariates using PLINK. We performed separate analysis within each population and then ran meta-analysis combining results from different populations weighted by s le sizes using METAL. Results: Carboplatin and paclitaxel disposition is a relative stable phenotype. The genomic control parameters in the test statistics for the adjusted carboplatin and paclitaxel analysis were 1.03 and 1.02 respectively, suggesting that there was little concern for population substructure or other artefacts. We identified highly significant SNPs in ABCC2 associated with carboplatin clearance (asymptotic p = 5.2 × 10−6, empirical p = 1.4 × 10−5 from 107 permutations) which are highly plausible pharmacogenomic markers given the known role of ABCC2 in carboplatin efflux. We also identified a novel SNP associated with paclitaxel disposition with genome wide significance in chromosome 1 (rs17130142, asymptotic p = 2.0 × 10−9, empirical p = 1.3× 10−7), in an intergenic region, neighboring PKN2. Conclusion: Although these findings requires a validation in a larger study, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective even when performed in a relative small s le number and can be adopted in drug development and treatment programs. Citation Format: Bo Gao, Yi Lu, Annemieke J.M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Ingrid Boere, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Catherine Kennedy, Yoke-Eng Chiew, Sharon E. Johnatty, Philip Beale, Michelle Harrison, Craig Luccarini, Alison M. Dunning, Ron H.J. Mathijssen, Paul Harnett, Rosemary L. Balleine, Georgia Chenevix-Trench, Stuart MacGregor, Anna deFazio. Genome-wide study of carboplatin and paclitaxel disposition in ovarian cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research 2015 Apr 18-22 Philadelphia, PA. Philadelphia (PA): AACR Cancer Res 2015 (15 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2015-5493

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Publisher: Springer Science and Business Media LLC

Date: 24-02-2021

DOI: 10.1038/S41467-020-20851-4

Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638 , CLIC5, SLC2A12, YAP1, MXRA5 , and SMAD6 . Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Genetic risk of glaucoma is associated with vascular and retinal nerve fibre wedge defects

Publisher: Wiley

Date: 06-10-2023

DOI: 10.1111/AOS.15775

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder

Publisher: Elsevier BV

Date: 07-2003

DOI: 10.1086/376547

Abstract: Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for s le size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Genetic burden associated with varying degrees of disease severity in endometriosis

Publisher: Oxford University Press (OUP)

Date: 16-04-2015

DOI: 10.1093/MOLEHR/GAV021

Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: An integrated analysis

Publisher: Oxford University Press (OUP)

Date: 07-11-2009

DOI: 10.1093/HMG/DDN372

Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis

Publisher: Oxford University Press (OUP)

Date: 28-11-2012

DOI: 10.1093/HMG/DDS491

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Publisher: Impact Journals, LLC

Date: 15-06-2017

DOI: 10.18632/ONCOTARGET.18501

Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Publisher: Cold Spring Harbor Laboratory

Date: 07-09-2018

DOI: 10.1101/406967

Abstract: Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P ×10 −8 ), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p .28×10 3 ) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

Polymorphisms in genes of relevance for oestrogen and oxytocin pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma: A pooled analysis from the BEACON consortium

Publisher: Public Library of Science (PLoS)

Date: 25-09-2015

DOI: 10.1371/JOURNAL.PONE.0138738

Most common 'sporadic' cancers have a significant germline genetic component

Publisher: Oxford University Press (OUP)

Date: 18-06-2014

DOI: 10.1093/HMG/DDU312

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Publisher: Springer Science and Business Media LLC

Date: 27-11-2019

DOI: 10.1038/S42003-019-0634-9

Abstract: A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG) intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is h ered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Abstract 4487: An INDEL variant confers melanoma risk through PARP1 expression regulation

Publisher: American Association for Cancer Research (AACR)

Date: 15-07-2016

DOI: 10.1158/1538-7445.AM2016-4487

Abstract: Recent genome wide association studies identified several new loci for melanoma susceptibility including chr1q42.1 locus encompassing Poly [ADP-ribose] polymerase 1 (PARP1). As an effort to identify effecter genes and functional risk variants from this locus we performed expression quantitative trait loci (eQTL) analysis in 62 melanoma cell lines. Among the genes in 1Mb area eQTL was identified for PARP1 and subsequently validated by qPCR, where increased PARP1 levels are significantly correlated with the risk allele (p = 0.03, copy number adjusted). Further allele discrimination qPCR of PARP1 transcripts in 14 melanoma cell lines heterozygous and of neutral copy for the lead SNP indicated significantly higher proportion for the risk allele (p = .0001). Same allelic imbalance was also observed in 51 heterozygous melanomas with neutral copy numbers from The Cancer Genome Atlas (p = .028). To identify functional risk variants mediating these effects we annotated this locus using six melanoma relevant cell types available from ENCODE and Roadmap database. Based on recent fine mapping data suggesting single-SNP model for this locus we prioritized high LD variants for nomination. Among 65 SNPs of high LD with the lead SNP or imputed best SNP (r2& .6 using 1000 Genomes phase3), four exhibited strong evidence as potential transcriptional enhancers. Electro Mobility Shift Assays and luciferase assays on these four variants demonstrated that one of them, a six-base pair INDEL (-/GGGCCC) in the first intron, displayed strong allelic functionality. Consistent with the expression data melanoma-associated deletion allele results in higher luciferase activity while protective insertion allele binds a group of proteins with higher affinity. Subsequent comparative mass-spectrometry for these insertion-binding proteins identified a striking collection of Guanine-quadruplex binding proteins including RECQ1 as potential inhibitors of PARP1 expression. Consistent with this hypothesis over-expression of RECQL results in more pronounced allelic difference in luciferase activities indicating that RECQ1 contributes to allelic PARP1 expression. Further interrogation of RECQ1 and PARP1 expression correlation analysis suggested that RECQ1 levels are inversely correlated with PARP1 in melanomas carrying insertion alleles. These data demonstrate that increased PARP1 expression is correlated with melanoma risk and an INDEL variant mediates differential PARP1 expression possibly through secondary DNA structure binding proteins including RECQ1. Citation Format: Jiyeon Choi, Matthew Makowski, Tongwu Zhang, Matthew Law, Wendy Kim, Michael Kovacs, Hemang Parikh, Lauren Aoude, Michael Gartside, Jeffrey Trent, Michiel Vermeulen, Stuart Macgregor, Nicholas Hayward, Mai Xu, Kevin Brown. An INDEL variant confers melanoma risk through PARP1 expression regulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr 4487.

Re-weightingMC1R, ASIPandIRF4risk variants optimises polygenic risk scores for keratinocyte cancer stratification in solid organ transplant recipients

Publisher: Cold Spring Harbor Laboratory

Date: 18-02-2023

DOI: 10.1101/2023.02.17.23286114

Abstract: Solid organ transplant recipients (SOTRs) are at much higher risk of developing squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), compared to the general population. Previous studies have derived genetics-based predictors (polygenic risk scores, PRS) of SCC and BCC risk in SOTRs by assuming that genetic risk variants act in the same way in the general population as in SOTRs, but this assumption has not been fully tested. To investigate whether known genetic risk variants for SCC and BCC have different effect sizes in SOTRs versus in non-transplantees, and if a re-weighted PRS would improve risk prediction. We conducted genome-wide association studies for SCC and BCC separately in the non-transplant general population and in SOTRs, and compared the risks associated with selected common genetic variants for KC risk in SOTR vs non-transplant in iduals from the UK Biobank. For regions with an increased log odds ratio in SOTRs, PRSs including these weights were validated in the QSkin study, and applied to the Australian STAR SOTR cohort. Effect sizes for functional variants in MC1R (rs1805007), ASIP (rs6059655), and IRF4 (rs12203592) were much more strongly associated with the risk of KC in SOTRs than in non-transplantees. The proportional increase in the effect sizes ranged from 1.9-fold for rs6059655 and BCC risk (SOTRs log (OR)=0.49, 95%CI=0.00-0.98 vs log (OR)=0.26, 95%CI=0.24-0.30 in non-transplantees) to as high as 4.8-fold for rs1805007 and SCC risk (SOTR log (OR)=0.88, 95% CI=0.41-1.35 vs log (OR)=0.18, 95% CI=0.12-0.24 in non-transplantees). PRS with SOTR derived weights for these SNPs showed improved SCC/BCC risk stratification in the STAR Cohort, with the optimised PRS reclassifying 19% of SCC cases vs 8% using the standard PRS, and 18% of BCC cases vs 12% using the standard PRS. Effect sizes for SCC and BCC risk for genetic variants in the MC1R, ASIP and IRF4 genes are elevated in SOTRs, and correctly weighting these variants improves risk stratification based on polygenic risk.

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Publisher: Public Library of Science (PLoS)

Date: 25-01-2018

DOI: 10.1371/JOURNAL.PGEN.1007145

The APOE E4 Allele Is Associated with Faster Rates of Neuroretinal Thinning in a Prospective Cohort Study of Suspect and Early Glaucoma.

Publisher: Elsevier BV

Date: 06-2022

DOI: 10.1016/J.XOPS.2022.100159

Rare variant analyses across multiethnic cohorts identify novel genes for refractive error

Publisher: Springer Science and Business Media LLC

Date: 03-01-2023

DOI: 10.1038/S42003-022-04323-7

Abstract: Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. In iduals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies (GWAS), but a great part of the refractive error heritability is still missing. Some of this heritability may be explained by rare variants (minor allele frequency [MAF] ≤ 0.01.). We performed multiple gene-based association tests of mean Spherical Equivalent with rare variants in exome array data from the Consortium for Refractive Error and Myopia (CREAM). The dataset consisted of over 27,000 total subjects from five cohorts of Indo-European and Eastern Asian ethnicity. We identified 129 unique genes associated with refractive error, many of which were replicated in multiple cohorts. Our best novel candidates included the retina expressed PDCD6IP , the circadian rhythm gene PER3 , and P4HTM , which affects eye morphology. Future work will include functional studies and validation. Identification of genes contributing to refractive error and future understanding of their function may lead to better treatment and prevention of refractive errors, which themselves are important risk factors for various blinding conditions.

Evaluating the role of alcohol consumption in breast and ovarian cancer susceptibility using population-based cohort studies and two-sample Mendelian randomization analyses

Publisher: Wiley

Date: 13-10-2021

DOI: 10.1002/IJC.33308

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Publisher: Springer Science and Business Media LLC

Date: 03-2021

DOI: 10.1038/S42003-021-01784-0

Abstract: Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Association Between Body Mass Index and Primary Open Angle Glaucoma in Three Cohorts

Publisher: Elsevier BV

Date: 2023

DOI: 10.1016/J.AJO.2022.08.006

Abstract: To evaluate the relationship between body mass index (BMI) and glaucoma progression. Multicohort observational study. This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study. In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI [0.005, 0.069] P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β -0.048/SD 95% CI [-0.056, 0.96] P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98] P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD 95% CI [0.91, 0.98] P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD 95% CI [0.06, 0.15] P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β -0.007/SD 95% CI [-0.01, -0.001] P = .023). Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.

WALLABY Early Science – II. The NGC 7232 galaxy group

Publisher: Oxford University Press (OUP)

Date: 05-01-2019

DOI: 10.1093/MNRAS/STZ017

Abstract: We report on neutral hydrogen (H i) observations of the NGC 7232 group with the Australian Square Kilometre Array Pathfinder (ASKAP). These observations were conducted as part of the Wide-field ASKAP L-Band Legacy All-sky Blind surveY (WALLABY) Early Science program with an array of 12 ASKAP antennas equipped with Phased Array Feeds, which were used to form 36 beams to map a field of view of 30 deg2. Analysing a subregion of the central beams, we detect 17 H i sources. Eleven of these detections are identified as galaxies and have stellar counterparts, of which five are newly resolved H i galaxy sources. The other six detections appear to be tidal debris in the form of H i clouds that are associated with the central triplet, NGC 7232/3, comprising the spiral galaxies NGC 7232, NGC 7232B, and NGC 7233. One of these H i clouds has a mass of MH i ∼ 3 × 108 M⊙ and could be the progenitor of a long-lived tidal dwarf galaxy. The remaining H i clouds are likely transient tidal knots that are possibly part of a diffuse tidal bridge between NGC 7232/3 and another group member, the lenticular galaxy IC 5181.

Sweet Taste Perception is Associated with Body Mass Index at the Phenotypic and Genotypic Level

Publisher: Cambridge University Press (CUP)

Date: 05-08-2016

DOI: 10.1017/THG.2016.60

Abstract: Investigations on the relationship between sweet taste perception and body mass index (BMI) have been inconclusive. Here, we report a longitudinal analysis using a genetically informative s le of 1,576 adolescent Australian twins to explore the relationship between BMI and sweet taste. First, we estimated the phenotypic correlations between perception scores for four different sweet compounds (glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame) and BMI. Then, we computed the association between adolescent taste perception and BMI in early adulthood (reported 9 years later). Finally, we used twin modeling and polygenic risk prediction analysis to investigate the genetic overlap between BMI and sweet taste perception. Our findings revealed that BMI in early adulthood was significantly associated with each of the sweet perception scores, with the strongest correlation observed in aspartame with r = 0.09 ( p = .007). However, only limited evidence of association was observed between sweet taste perception and BMI that was measured at the same time (in adolescence), with the strongest evidence of association observed for glucose with a correlation coefficient of r = 0.06 ( p = .029) and for aspartame with r = 0.06 ( p = .035). We found a significant ( p .05) genetic correlation between glucose and NHDC perception and BMI. Our analyses suggest that sweet taste perception in adolescence can be a potential indicator of BMI in early adulthood. This association is further supported by evidence of genetic overlap between the traits, suggesting that some BMI genes may be acting through biological pathways of taste perception.

New genetic loci link adipose and insulin biology to body fat distribution

Publisher: Springer Science and Business Media LLC

Date: 11-02-2015

DOI: 10.1038/NATURE14132

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Publisher: Springer Science and Business Media LLC

Date: 26-07-2022

DOI: 10.1038/S41467-022-31707-4

Abstract: There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy in iduals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 in iduals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

The University Of Edinburgh

Location: United Kingdom of Great Britain and Northern Ireland

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Cardiff University

Location: United Kingdom of Great Britain and Northern Ireland

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QIMR Berghofer Medical Research Institute

Location: Australia

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Translating The Genetic Determinants Of Glaucoma

Start Date: 2019

End Date: 2020

Funder: National Health and Medical Research Council

Translation Of Glaucoma Blindness Genes To Improve Clinical Practice

Start Date: 2018

End Date: 2022

Funder: National Health and Medical Research Council

Identifying Markers Of Risk And Outcome In Ovarian And Breast Cancer Via Efficient Evaluation Of DNA Methylation In Peripheral Blood. Cofunded With Cancer Australia.

Start Date: 2011

End Date: 2014

Funder: National Breast Cancer Foundation

Identification Of Germline Variation That Predicts Progression Free Survival Following Chemotherapy For Advanced Ovarian Cancer

Start Date: 2013

End Date: 2015

Funder: National Health and Medical Research Council

QSKIN: The Genetics Of Skin Cancer

Start Date: 2014

End Date: 2018

Funder: National Health and Medical Research Council

Young Adult Myopia: Genetic And Environmental Associations

Start Date: 2017

End Date: 2020

Funder: National Health and Medical Research Council

Which Modifiable Risk Factors Actually Cause Cancer?

Start Date: 2017

End Date: 2019

Funder: National Health and Medical Research Council

Translating Genetic Determinants Of Glaucoma Into Better Diagnosis And Treatment

Start Date: 2019

End Date: 2023

Funder: National Health and Medical Research Council

High Penetrance Deleterious Mutations In Blinding Glaucoma

Start Date: 2016

End Date: 2018

Funder: National Health and Medical Research Council

A Genome-wide Association Scan For Glaucoma

Start Date: 2009

End Date: 2011

Funder: National Health and Medical Research Council

Genes For Juvenile-onset Myopia

Start Date: 2012

End Date: 2014

Funder: National Health and Medical Research Council

Genetic Etiologies Of Congenital Esotropia

Start Date: 2012

End Date: 2014

Funder: National Health and Medical Research Council

From Discovery To Therapy In Genetic Eye Diseases

Start Date: 2016

End Date: 2021

Funder: National Health and Medical Research Council

ARC Future Fellowships - Grant ID: FT130101902

Start Date: 2014

End Date: 12-2017

Amount: $868,500.00

Funder: Australian Research Council