ORCID Profile
0000-0002-5123-5999
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In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Central Nervous System | Medical Biochemistry and Metabolomics | Regenerative Medicine (incl. Stem Cells and Tissue Engineering) | Medical Biochemistry and Metabolomics not elsewhere classified | Nanobiotechnology
Cardiovascular System and Diseases | Nervous System and Disorders | Blood Disorders |
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3761840
Publisher: Wiley
Date: 12-2007
DOI: 10.1111/J.1442-9071.2007.01612.X
Abstract: To determine what proportion of primary open angle glaucoma (POAG) in Tasmania, Australia is familial. Between 1994 and 1996 an audit of Tasmanian patients diagnosed with glaucoma was performed. Identified probands along with their family members were invited to participate. Family history of POAG was noted and pedigrees constructed. Each participant underwent a detailed examination, including visual acuity, intraocular pressure measurement, gonioscopy, optic disc assessment and visual field testing. Participants were classified as normal, suspect or POAG. Data from 467 participants in the Twins Eye Study in Tasmania (TEST) were used as a reference for the general population. Of 2062 participants examined, 1700 were classified as POAG. A total of 1014 participants (59.6%) belonged to families in which other members were affected (familial glaucoma). Six hundred and fifty-six of these 1014 familial cases (64.8%) had a first-degree relative affected. The number of affected members in the family groups varied from two to 29. Six hundred and eighty-eight participants had no known family history of POAG (sporadic glaucoma). There were significantly more POAG patients with a family history of POAG compared to the TEST population (chi2 = 161.81, P < 0.0001), and for a person with POAG the odds ratio of having a positive family history was 4.1 (95% confidence interval: 3.2-5.2). Approximately 60% of POAG in Tasmania is familial. This percentage is higher than most previous reports of familial glaucoma and emphasizes the importance of genetics in POAG, with major implications for screening and future research.
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
Publisher: Public Library of Science (PLoS)
Date: 11-01-2013
Publisher: Springer Science and Business Media LLC
Date: 02-06-2015
DOI: 10.1038/SREP10375
Abstract: MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultra-high content platforms. We used extensive analytical tools to compute inter- and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical s les using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest.
Publisher: PeerJ
Date: 10-03-2018
DOI: 10.7287/PEERJ.PREPRINTS.26654V1
Abstract: Background. The institutional affiliations and associated collaborative networks that scientists foster during their research careers are salient in the production of high quality science. The phenomenon of multiple institutional affiliations and its relationship to research output remains relatively unexplored in the literature. Methods . We examined 27,612 scientific articles, modelling the citation counts received against the number of authors and affiliations held. Results. In agreement with previous research, we found that teamwork is an important factor in high impact papers, with average citations received increasing concordant with the number of co-authors listed. For articles with more than five co-authors, we noted an increase in average citations received when authors with more than one institutional affiliation contributed to the research. Discussion . Multiple author affiliations may play a positive role in the production of high-impact science. This ‘polygamous’ behavior, sometimes shunned by institutional board, should instead be viewed as meritorious in the pursuit of scientific discovery.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
Publisher: Informa UK Limited
Date: 14-03-2011
DOI: 10.3109/09286586.2010.545933
Abstract: Over 40% of the permanent population of Norfolk Island possesses a unique genetic admixture dating to Pitcairn Island in the late 18(th) century, with descendents having varying degrees of combined Polynesian and European ancestry. We conducted a population-based study to determine the prevalence and causes of blindness and low vision on Norfolk Island. All permanent residents of Norfolk Island aged ≥ 15 years were invited to participate. Participants completed a structured questionnaire/interview and underwent a comprehensive ophthalmic examination including slit-l biomicroscopy. We recruited 781 people aged ≥ 15, equal to 62% of the permanent population, 44% of whom could trace their ancestry to Pitcairn Island. No one was bilaterally blind. Prevalence of unilateral blindness (visual acuity [VA] < 6/60) in those aged ≥ 40 was 1.5%. Blindness was more common in females (P=0.049) and less common in people with Pitcairn Island ancestry (P<0.001). The most common causes of unilateral blindness were age-related macular degeneration (AMD), amblyopia, and glaucoma. Five people had low vision (Best-Corrected VA < 6/18 in better eye), with 4 (80%) due to AMD. People with Pitcairn Island ancestry had a lower prevalence of AMD (P<0.001) but a similar prevalence of glaucoma to those without Pitcairn Island ancestry. The prevalence of blindness and visual impairment in this isolated Australian territory is low, especially amongst those with Pitcairn Island ancestry. AMD was the most common cause of unilateral blindness and low vision. The distribution of chronic ocular diseases on Norfolk Island is similar to mainland Australian estimates.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 02-2018
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 2007
DOI: 10.1167/IOVS.06-0611
Abstract: Approximately 1 in 30 unselected patients with open-angle glaucoma (OAG) have a mutation in the myocilin gene. The purpose of this study was to describe the morphologic features of the optic nerve head (ONH) in myocilin glaucoma. A case-control design was adopted. Sixty-six patients heterozygous for a range of myocilin mutation (cases) were matched in disease severity to 105 patients with OAG known not to have a myocilin mutation (controls), using visual field findings. Quantifiable analysis of the ONH was undertaken of stereoscopic photographs, by using custom software with a z-screen. Subjective grading of the cup depth, lamina cribrosa pore shape and orientation, and the slope of the neuroretinal rim was performed by an examiner masked to the subject's mutation status. Mutation screening was conducted using either direct sequencing or single-stranded conformation polymorphism analysis. Patients with a myocilin mutation had glaucoma diagnosed earlier (P < 0.001) and had higher maximum recorded intraocular pressures (P 0.05) difference in global disc area, global neuroretinal rim area, alpha-parapapillary atrophy, beta-parapapillary atrophy, slope of neuroretinal rim, or visible lamina cribrosa morphology between myocilin mutation carriers and patients with nonmyocilin glaucoma. Disc hemorrhages were identified more frequently in those without mutations (14/209 vs. 1/129), though this was not significant after correction for multiple hypothesis testing. No major structural or morphologic difference of the ONH was detected in pooled data from subjects who had myocilin mutations compared with data from in iduals with nonmyocilin glaucoma.
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.
Publisher: Wiley
Date: 08-2012
DOI: 10.1111/J.1442-9071.2011.02742.X
Abstract: Glaucoma is a sight-threatening disease affecting 3% of the population over the age of 50. Glaucoma is treatable, and severe vision loss can usually be prevented if diagnosis is made at an early stage. Genetic factors play a major role in the pathogenesis of the condition, and therefore, genetic testing to identify asymptomatic at-risk in iduals is a promising strategy to reduce the prevalence of glaucoma blindness. Furthermore, unravelling genetic risk factors for glaucoma would also allow a better understanding of the pathogenesis of the condition and the development of new treatments. The Australian and New Zealand Registry of Advanced Glaucoma is a prospective study that aims to develop a large cohort of glaucoma cases with severe visual field loss to identify novel genetic risk factors for glaucoma blindness. Clinical information and blood are collected from participants after referral by eye practitioners. S les are collected across Australia and New Zealand using postage kits. Our registry has recruited just over 2000 participants with advanced glaucoma, as well as secondary and developmental glaucomas. A positive family history of glaucoma is present in more than half of the advanced glaucoma cases and the age at diagnosis is significantly younger for participants with affected relatives, which reinforces the involvement of genetic factors in glaucoma. With the collection of glaucoma cases recruited so far, our registry aims to identify novel glaucoma genetic risk factors to establish risk profiling of the population and protocols for genetic testing.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2017
DOI: 10.1038/SREP46330
Abstract: Epigenetic variation is implicated in a range of non-communicable diseases, including those of the eye. However, investigating the role of epigenetic variation in central tissues, such as eye or brain, remains problematic and peripheral tissues are often used as surrogates. In this study, matched human blood and eye tissue (n = 8) were obtained post-mortem and DNA methylation profiling performed on blood, neurosensory retina, retinal pigment epithelium (RPE)/choroid and optic nerve tissue using the Illumina Infinium HumanMethylation450 platform. Unsupervised clustering and principal components analysis revealed tissue of origin as the main driver of methylation variation. Despite this, there was a strong correlation of methylation profiles between tissues with ,000 CpG sites found to have similar methylation levels. An additional ~16,000 show similarity across ocular tissues only. A small proportion of probes showing inter-in idual variation in blood co-varied with eye tissues within in iduals, however much of this variation may be genetically driven. An improved understanding of the epigenetic landscape of the eye will have important implications for understanding eye disease. Despite a generally high correlation irrespective of origin, tissue type is the major driver of methylation variation, with only limited covariation between blood and any specific ocular tissue.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2019
DOI: 10.1038/S41598-018-37388-8
Abstract: Mitochondrial haplogroups H1, H2 and UK have previously been reported to be associated with proliferative diabetic retinopathy (PDR) in Caucasian patients with diabetes. We aimed to replicate this finding with a larger s le and expand the analysis to include different severities of DR, and diabetic macular edema (DME). Caucasian participants (n = 2935) with either type 1 or type 2 diabetes from the Australian Registry of Advanced Diabetic Retinopathy were enrolled in this study. Twenty-two mitochondrial single nucleotide polymorphisms were genotyped by MassArray and haplogroups reconstructed using Haplogrep. Chi square tests and logistic regressions were used to test associations between haplogroup and DR phenotypes including any DR, non-proliferative DR (NPDR), proliferative DR (PDR) and DME. After stratifying the s les in type 1 and type 2 diabetes groups, and adjusting for sex, age, diabetes duration, concurrent HbA1c and hypertension, neither haplogroups H1, H2, UK, K or JT were associated with any DR, NPDR, PDR or DME.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.SCR.2021.102568
Abstract: Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease that results in immune cell infiltration of the central nervous system (CNS) and demyelination in young adults. Substantial progress has been made in developing disease modifying therapies for people with relapsing-remitting MS, but options remain limited for people with primary progressive MS (PPMS). PPMS accounts for ∼15% of MS diagnoses. Herein, we generated a human induced pluripotent stem cell line (hiPSC) from a person with clinically definite PPMS. This disease-specific hiPSC line will be useful for studying PPMS in vitro, allowing the generation of immune and CNS cell types.
Publisher: American Medical Association (AMA)
Date: 07-2006
DOI: 10.1001/ARCHOPHT.124.7.950
Abstract: To determine whether there is a difference in disease severity between familial and sporadic primary open-angle glaucoma (POAG). A cross-sectional study design compared the distribution of Glaucoma Inheritance Study in Tasmania (GIST) severity scores of patients with genealogically confirmed familial POAG and those with sporadic POAG. The GIST severity scores provide a combined weighting of glaucoma severity based on findings from visual field defects and optic disc analysis, with and without intraocular pressure. A Poisson regression analysis, t test, and chi(2) tests were performed. One thousand twelve (59.5%) of 1700 subjects had familial glaucoma. The mean +/- SD age at examination was greater in the sporadic POAG group compared with the familial group (72.6 +/- 10.3 years vs 70.6 +/- 12.6 years P = .001). The family group was significantly younger at diagnosis than the sporadic group (mean +/- SD, 61.4 +/- 13.0 years vs 64.0 +/- 12.6 years P<.001). The GIST severity scores were significantly skewed toward greater disease severity in the familial group compared with the sporadic group (P<.001). Identifying in iduals at risk of severe POAG will be more successful if screening programs are developed with appropriate weighting toward those with a positive family history of the disease.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-09-2017
Abstract: Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, pharmacological treatments in these diseases are limited due to the lack of knowledge of underlying disease mechanisms, partly because appropriate human models to study AMD and related MDs are lacking. Furthermore, in the living human eye, the entire retina acts as a functional unit, making it difficult to investigate the specific contribution of a particular retinal cell type in the disease. Here, we established human models of multiple MDs, which demonstrated similar molecular and phenotypic manifestations within these diseases. Furthermore, we showed that dysfunction of an in idual cell type, retinal pigment epithelium cells in the retina, is sufficient for the development of key pathological features in these MDs.
Publisher: Frontiers Media SA
Date: 10-09-2020
Publisher: Wiley
Date: 19-12-2013
DOI: 10.1111/CEO.12256
Abstract: The objective of this study was to characterize the causes of ocular trauma and determine the risk factors for infection and vision loss following ocular trauma in the Solomon Islands. A prospective clinic-based study. A total of 507 patients with ocular trauma who were reviewed at the National Referral Hospital in Honiara or one of five provincial eye clinics were included. An interview-based questionnaire to determine the circumstances of ocular trauma, and an ocular examination to elicit the trauma sustained,infectious sequelae and the visual outcome. Visual acuity. Males were significantly more likely to have ocular trauma than females (P = 0.01). The major cause of ocular trauma in young boys and girls was being poked by a stick, followed by lime burns in young boys. For both genders, physical violence resulted in most injuries across all adult age groups. Microbial keratitis complicated 4.4% of ocular trauma. Monocular vision impairment (<6/18) occurred in 5.5% of participants and was more likely to occur if female (P = 0.02). Ocular trauma is a significant cause of visual morbidity in the Solomon Islands. The results from this prospective study provide a basis for planning blindness prevention programmes in the Western Pacific.
Publisher: Wiley
Date: 03-10-2016
DOI: 10.1002/MGG3.248
Publisher: Springer Science and Business Media LLC
Date: 10-04-2020
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.
Publisher: Wiley
Date: 07-2006
DOI: 10.1111/J.1442-9071.2006.01268.X
Abstract: Glaucoma, which is a complex heterogeneous disease, presents an ideal case for genetic investigation. Primary open-angle glaucoma (POAG) is the commonest subtype and will be the focus of this review. When detected early, POAG is amenable to therapeutic intervention. Unfortunately, current population-based clinical screening lacks efficacy. If in iduals with a genetic predisposition for developing POAG can be identified, then efficient and cost-effective population-based screening programs could be designed. Although considerable inroads have been made in understanding the natural history of POAG caused by mutations in the myocilin and optineurin genes, other POAG genes accounting for most cases remain to be identified. This review explores the genetic mechanisms that have been unequivocally linked to the glaucomatous process and then discusses potential avenues for future breakthroughs.
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).
Publisher: Springer Science and Business Media LLC
Date: 26-05-2023
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-04-0007
DOI: 10.1167/IOVS.11-7258
Publisher: Mary Ann Liebert Inc
Date: 11-2019
DOI: 10.1089/HUM.2019.021
Abstract: Safe delivery of CRISPR/Cas endonucleases remains one of the major barriers to the widespread application of
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.EXER.2016.03.013
Abstract: Pseudoexfoliation (PEX) syndrome is a systemic disease involving the extracellular matrix. It increases the risk of glaucoma, an irreversible cause of blindness, and susceptibility to heart disease, stroke and hearing loss. Single nucleotide polymorphisms (SNPs) in the LOXL1 (Lysyl oxidase-like 1) gene are the major known genetic risk factor for PEX syndrome. Two coding SNPs, rs1048861 (G > T Arg141Leu) and rs3825942 (G > A Gly153Asp), in the LOXL1 gene are strongly associated with the disease risk in multiple populations worldwide. In the present study, we investigated functional effects of these SNPs on the LOXL1 protein. We show through molecular modelling that positions 141 and 153 are likely surface residues and hence possible recognition sites for protein-protein interactions the Arg141Leu and Gly153Asp substitutions cause charge changes that would lead to local differences in protein electrostatic potential and in turn the potential to modify protein-protein interactions. In RFL-6 rat fetal lung fibroblast cells ectopically expressing the LOXL1 protein variants related to PEX (Arg141_Gly153, Arg141_Asp153 or Leu141_Gly153), immunoprecipitation of the secreted variants showed differences in their processing by endogenous proteins, possibly Bone morphogenetic protein-1 (BMP-1) that cleaves and leads to enzymatic activation of LOXL1. Immunofluorescence labelling of the ectopically expressed protein variants in RFL-6 cells showed no significant difference in their extracellular accumulation tendency. In conclusion, this is the first report of a biological effect of the coding SNPs in the LOXL1 gene associated with PEX syndrome, on the LOXL1 protein. The findings indicate that the disease associated coding variants themselves may be involved in the manifestation of PEX syndrome.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 08-2013
Publisher: Springer Science and Business Media LLC
Date: 13-01-2006
DOI: 10.1007/S00417-005-0218-X
Abstract: Photodynamic therapy (PDT) has been used in the treatment of choroidal neovascularisation secondary to age-related macular degeneration (AMD). This study prospectively investigated patients' subjective change in visual function following PDT as treatment for AMD. Eighty-two consecutive patients receiving PDT in Tasmania, Australia, between May and November 2003 were recruited. In conjunction with a comprehensive clinical examination, the Visual Function-14 (VF-14) questionnaire was administered. Final follow-up occurred between February and March 2005. The VF-14 was scored by traditional summary scoring and by Rasch analysis. Five of the 82 (6.1%) subjects recruited were excluded from analysis. PDT was performed on average 5.7+/-2.6 times per patient. Raw VF-14 scores tended towards being significantly lower at follow-up than at baseline (67.6+/-27.2 against 64.5+/-27.7 P=0.052), and did significantly deteriorate using a collapsed Rasch analysis (P=0.0102). Following treatment, 38 (47.5%) eyes had lost three or more Snellen lines of best-corrected visual acuity. Patients undergoing PDT typically report reasonable visual function. In parallel with visual acuity, self-reported visual function may deteriorate slightly after PDT for AMD, but not as much as reported in untreated AMD.
Publisher: Wiley
Date: 10-12-2012
DOI: 10.1111/CEO.12020
Abstract: Inherited retinal disease represents a significant cause of blindness and visual morbidity worldwide. With the development of emerging molecular technologies, accessible and well-governed repositories of data characterising inherited retinal disease patients is becoming increasingly important. This manuscript introduces such a repository. Participants were recruited from the Retina Australia membership, through the Royal Australian and New Zealand College of Ophthalmologists, and by recruitment of suitable patients attending the Sir Charles Gairdner Hospital visual electrophysiology clinic. Four thousand one hundred ninety-three participants were recruited. All participants were members of families in which the proband was diagnosed with an inherited retinal disease (excluding age-related macular degeneration). Clinical and family information was collected by interview with the participant and by examination of medical records. In 2001, we began collecting DNA from Western Australian participants. In 2009 this activity was extended Australia-wide. Genetic analysis results were stored in the register as they were obtained. The main outcome measurement was the number of DNA s les (with associated phenotypic information) collected from Australian inherited retinal disease-affected families. DNA was obtained from 2873 participants. Retinitis pigmentosa, Stargardt disease and Usher syndrome participants comprised 61.0%, 9.9% and 6.4% of the register, respectively. This resource is a valuable tool for investigating the aetiology of inherited retinal diseases. As new molecular technologies are translated into clinical applications, this well-governed repository of clinical and genetic information will become increasingly relevant for tasks such as identifying candidates for gene-specific clinical trials.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Wiley
Date: 15-08-2014
DOI: 10.1111/CEO.12388
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.AJO.2010.06.028
Abstract: To examine the relationship of birth weight with ocular measures in a Caucasian twin population. Cross-sectional study of 1498 twins (308 monozygotic and 441 dizygotic pairs) aged between 5 to 80 years participating in the Australian Twins Eye Study. All participants underwent ophthalmic examination including bilateral cycloplegic autorefraction, keratometry, interpupillary distance (IPD), central corneal thickness, intraocular pressure (IOP), and retinal photography. Birth weight and gestation were obtained from a self-administered questionnaire. A subset of the twins also participated in the Tasmanian Infant Health Study (288) and the Childhood Blood Pressure Study (184), which collected data on birth parameters allowing for verification of data. Linear mixed models were used for the main analysis. Both the within-pair (β(w) 0.27, 95% confidence interval [CI] 0.15, 0.38 mm per kg increase in birth weight, P < .001) and between-pair associations (β(B) 0.22, 95% CI 0.08, 0.35, P = .002) of birth weight with axial length were significant and of similar magnitude (difference in effect, P = .56), after adjusting for relevant confounders. In contrast, birth weight was negatively associated with corneal curvature (β(w) -0.82, 95% CI -1.09, -0.55 diopters per kg increase β(B) -0.69, 95% CI -0.98, -0.41, both P < .001). These associations remained significant within dizygotic and monozygotic pairs. Refraction, anterior chamber depth, IPD, IOP, and optic disc parameters are unrelated to birth weight. Consistent with previous studies in singleton children, lower birth weight is associated with shorter axial length and more curved corneas in this twin study. This also adds new insights into the emmetropization process.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2010
DOI: 10.1007/S00439-009-0729-3
Abstract: Osteogenesis imperfecta (OI) is a rare connective tissue disorder caused by mutations in the type I collagen genes, COL1A1 and COL1A2, and is characterised by low bone mass and bone fragility. In this study, we explored the relationship between type 1 collagen genes and the quantitative trait central corneal thickness (CCT). CCT was measured in a cohort of 28 Australian type I OI patients and mean CCT was found to be significantly lower compared to a normal population (P < 0.001). We then investigated CCT and corneal collagen fibril diameter and density in a mouse model of OI with a col1a2 mutation. Mean CCT was significantly lower in mutant mice (P = 0.002), as was corneal collagen fibril diameter (P = 0.034), whilst collagen fibril density was significantly greater in mutants (P = 0.034). Finally, we conducted a genetic study to determine whether common single nucleotide polymorphisms (SNPs) in COL1A1 and COL1A2 are associated with CCT variation in the normal human population. Polymorphism rs2696297 (P = 0.003) in COL1A1 and a three SNP haplotype in COL1A2 (P = 0.007) were all significantly associated with normal CCT variation. These data implicate type 1 collagen in the determination of CCT in both OI patients and normal in iduals. This provides the first evidence of quantitative trait loci that influence CCT in a normal population and has potential implications for investigating genes involved in glaucoma pathogenesis, a common eye disease in which the severity and progression is influenced by CCT.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2018
Abstract: We used single cell sequencing technology to characterize the transcriptomes of 1,174 human embryonic stem cell-derived retinal ganglion cells (RGCs) at the single cell level. The human embryonic stem cell line BRN3B-mCherry (A81-H7), was differentiated to RGCs using a guided differentiation approach. Cells were harvested at day 36 and prepared for single cell RNA sequencing. Our data indicates the presence of three distinct subpopulations of cells, with various degrees of maturity. One cluster of 288 cells showed increased expression of genes involved in axon guidance together with semaphorin interactions, cell-extracellular matrix interactions and ECM proteoglycans, suggestive of a more mature RGC phenotype.
Publisher: Wiley
Date: 14-06-2011
DOI: 10.1111/J.1442-9071.2011.02579.X
Abstract: We aimed to determine the prevalence and associations of refractive error on Norfolk Island. Population-based study on Norfolk Island, South Pacific. All permanent residents on Norfolk Island aged ≥ 15 years were invited to participate. Patients underwent non-cycloplegic autorefraction, slit-l biomicroscope examination and biometry assessment. Only phakic eyes were analysed. Prevalence and multivariate associations of refractive error and myopia. There were 677 people (645 right phakic eyes, 648 left phakic eyes) aged ≥ 15 years were included in this study. Mean age of participants was 51.1 (standard deviation 15.7 range 15-81). Three hundred and seventy-six people (55.5%) were female. Adjusted to the 2006 Norfolk Island population, prevalence estimates of refractive error were as follows: myopia (mean spherical equivalent ≥ -1.0 D) 10.1%, hypermetropia (mean spherical equivalent ≥ 1.0 D) 36.6%, and astigmatism 17.7%. Significant independent predictors of myopia in the multivariate model were lower age (P < 0.001), longer axial length (P < 0.001), shallower anterior chamber depth (P = 0.031) and increased corneal curvature (P < 0.001). Significant independent predictors of refractive error were increasing age (P < 0.001), male gender (P = 0.009), Pitcairn ancestry (P = 0.041), cataract (P < 0.001), longer axial length (P < 0.001) and decreased corneal curvature (P < 0.001). The prevalence of myopia on Norfolk Island is lower than on mainland Australia, and the Norfolk Island population demonstrates ethnic differences in the prevalence estimates. Given the significant associations between refractive error and several ocular biometry characteristics, Norfolk Island may be a useful population in which to find the genetic basis of refractive error.
Publisher: American Medical Association (AMA)
Date: 02-2021
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.SCR.2017.05.007
Abstract: We report the generation of the hiPSC line CERAi001-A-6 from primary human dermal fibroblasts. Reprogramming was performed using episomal vector delivery of OCT4, SOX2, KLF4, L-MYC, LIN28 and shRNA for p53.
Publisher: American Medical Association (AMA)
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 16-10-2013
DOI: 10.1038/502303E
Publisher: Elsevier BV
Date: 09-2017
Abstract: Patient-specific induced pluripotent stem cells (iPSCs) have tremendous potential for development of regenerative medicine, disease modeling, and drug discovery. However, the processes of reprogramming, maintenance, and differentiation are labor intensive and subject to intertechnician variability. To address these issues, we established and optimized protocols to allow for the automated maintenance of reprogrammed somatic cells into iPSCs to enable the large-scale culture and passaging of human pluripotent stem cells (PSCs) using a customized TECAN Freedom EVO. Generation of iPSCs was performed offline by nucleofection followed by selection of TRA-1-60-positive cells using a Miltenyi MultiMACS24 Separator. Pluripotency markers were assessed to confirm pluripotency of the generated iPSCs. Passaging was performed using an enzyme-free dissociation method. Proof of concept of differentiation was obtained by differentiating human PSCs into cells of the retinal lineage. Key advantages of this automated approach are the ability to increase s le size, reduce variability during reprogramming or differentiation, and enable medium- to high-throughput analysis of human PSCs and derivatives. These techniques will become increasingly important with the emergence of clinical trials using stem cells.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Informa UK Limited
Date: 2007
DOI: 10.1080/13816810701356676
Abstract: PAX6 is a key regulator of eye development and there are many well recognized ophthalmic sequelae of mutations at this locus. The 14 exon PAX6 gene is well conserved across species and phyla. Coding region mutations manifest in a variety of phenotypes. Predicted premature protein truncations are generally associated with classical aniridia. Missense mutations are often found in cases with variant phenotypes such as ectopia pupillae isolated foveal hypoplasia nystagmus and hyaloid vessel proliferation. The locus has also been implicated, through a genome-wide sib-pair scan, to be important in the normal variation of myopia. We investigated the association between identified PAX6 mutations and refractive error in Australian patients from four pedigrees. Two of eight subjects with a 1410delC PAX6 mutation had a mean spherical equivalence < -9D, whilst a mean spherical equivalence < or = -5D was recorded in two from four subjects with an Arg240Stop PAX6 mutation and one of two subjects with a Glu93Stop mutation. One in idual identified with a Pro346Ala PAX6 mutation had a mean spherical equivalence of +2.8 D. Thus, our observations generally support other incidental findings, that PAX6 mutation, particularly predicted haploinsufficiency, may be associated with extreme refractive error, although the mechanism by which this occurs is not clear.
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.
Publisher: Springer Science and Business Media LLC
Date: 30-03-2020
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.
Publisher: Springer Science and Business Media LLC
Date: 05-2009
Abstract: Hereditary optic neuropathies are a prominent cause of blindness in both children and adults. The disorders in this group share many overlapping clinical characteristics, including morphological changes that occur at the optic nerve head. Accurate and prompt clinical diagnosis, supplemented with imaging when indicated, is essential for optimum management of the relevant optic neuropathy and appropriate counseling of the patient on its natural history. Patient history, visual field assessment, optic disc findings and imaging are the cornerstones of a correct diagnosis. This Review highlights the characteristic optic nerve head features that are common to the various hereditary optic neuropathies, and describes the features that enable the conditions to be differentiated.
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)).
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.OPHTHA.2015.05.004
Abstract: To investigate associations between single nucleotide polymorphisms (SNPs) in the VEGFC gene and the development of diabetic retinopathy (DR) in white patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Cross-sectional, case control study. White patients with T1DM or T2DM (n = 2899) were recruited from ophthalmology and endocrine clinics in Australia and the United Kingdom. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be receiving oral hypoglycemic treatment or insulin. Participants were categorized according to their worst-ever DR grading, as having "no DR" (no history of nonproliferative DR [NPDR], proliferative DR [PDR], or diabetic macular edema [DME]) or "any DR" (further subclassified as NPDR or PDR, without or with DME). Clinical characteristics, glycemic control (hemoglobin A1c [HbA1c]), and presence of diabetic complications were determined at recruitment. Genotyping was performed for 13 VEGFC tag SNPs. Odds ratios (ORs) were determined for associations with DR of VEGFC tag SNPs, in idually and within haplotypes. Logistic regression was used to adjust for clinical covariates, including DM type, age, sex, DM duration, hypertension, nephropathy, HbA1c, and smoking. Participants with DM but "no DR" (n = 980) were compared with 1919 participants with DM and "any DR." Three VEGFC SNPs were associated with DR after logistic regression: rs17697419 (P = 0.001 OR, 0.67 confidence interval [CI], 0.52-0.85), rs17697515 (P = 0.001 OR, 0.62 CI, 0.47-0.81), and rs2333526 (P = 0.005 OR, 0.69 CI, 0.54-0.90). rs17697515 Was also specifically associated with DME in those with T2DM (P = 0.004 OR, 0.53 CI, 0.35-0.82). Haplotype analysis revealed 2 significantly associated haplotypes, both protective against DR development. Significant associations were found between VEGFC tag SNPs (in idually and within haplotypes) and the presence of any DR or DME in white participants with T1DM and T2DM.
Publisher: Cold Spring Harbor Laboratory
Date: 22-09-2017
DOI: 10.1101/191395
Abstract: We used human embryonic stem cell-derived retinal ganglion cells (RGCs) to characterize the transcriptome of 1,174 cells at the single cell level. The human embryonic stem cell line BRN3B-mCherry A81-H7 was differentiated to RGCs using a guided differentiation approach. Cells were harvested at day 36 and subsequently prepared for single cell RNA sequencing. Our data indicates the presence of three distinct subpopulations of cells, with various degrees of maturity. One cluster of 288 cells upregulated genes involved in axon guidance together with semaphorin interactions, cell-extracellular matrix interactions and ECM proteoglycans, suggestive of a more mature phenotype.
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.
Publisher: Informa UK Limited
Date: 04-2012
DOI: 10.1586/EOP.12.11
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 09-2009
DOI: 10.1167/IOVS.08-3271
Abstract: Many ocular parameters show strong heritable tendencies. The significance of central corneal thickness (CCT) in the context of glaucoma has been the subject of much debate recently, but its heritability has not been extensively explored. This study was designed to investigate the parent-child heritability of CCT among groups who have CCT considered to be at the extreme ends of the normal range. Index cases were recruited through a tertiary referral center if their CCT was greater than 578 microm (thick) or less than 510 microm (thin), representing +/-1 SD from a previously published meta-analysis mean of 544 microm (34 microm SD). Subsequently, CCT was measured in all available family members of the index cases. Family units were then analyzed to establish the degree of heritability of CCT from parent to child. Thirty-three index cases were included in the analysis (10 >1 SD and 23 <1 SD from the meta-analysis CCT mean). The mean CCT of the children of index cases with a CCT more than 1 SD from the mean (n = 15) and less than 1 SD from the mean (n = 40) was 568 microm (32 microm SD) and 521 microm (22 microm SD), respectively (t = 6.14 P < 0.0001). The parent-child heritability estimate for CCT was h(2) = 0.68 (95% CI, 0.64-0.73). These results indicate that CCT shows strong parent-child heritability, with offspring likely to demonstrate CCT similar to the parental index case.
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.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-02-2019
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 12-07-2022
DOI: 10.1167/TVST.11.7.8
Publisher: Springer Science and Business Media LLC
Date: 25-09-2017
Publisher: Elsevier BV
Date: 2022
Publisher: Springer International Publishing
Date: 06-11-2014
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.AJO.2012.04.023
Abstract: To ascertain if single nucleotide polymorphisms (SNPs) involved in the determination of central corneal thickness, optic disc area, and vertical cup-to-disc ratio (VCDR) also are associated with open-angle glaucoma (OAG). Retrospective case-control genetic association study. A total of 16 SNPs associated with central corneal thickness, optic disc area, and VCDR were genotyped in 876 OAG cases and 883 normal controls. To determine if the SNPs were also correlated with OAG severity, the cohort was stratified into advanced OAG (n = 326) and nonadvanced OAG (n = 550). Both the cases and controls were of European descent and were recruited from within Australia. Two VCDR SNPs were found to be significantly associated with OAG after correction for multiple testing. The 2 SNPs were rs10483727, found adjacent to the SIX1 gene (P = 6.2 × 10(-06) odds ratio, 1.38 95% confidence interval, 1.20 to 1.59), and rs1063192, found within the CDKN2B gene (P = 2.2 × 10(-05) odds ratio, 0.74 95% confidence interval, 0.64 to 0.85). The CDKN2B variant rs1063192 also was found to be associated more strongly with advanced OAG. The findings from this study indicate that variants influencing VCDR are also risk alleles for OAG in our Australian cohort of European descent. The identification of SIX1 and CDKN2B as susceptibility loci will assist in understanding the pathologic mechanisms involved in the development of OAG.
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.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 23-07-2014
Abstract: To investigate the association between serum vitamin D levels and myopia in young adults. A total of 946 in iduals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D₃ (25(OH)D₃) concentrations were determined using mass spectrometry. The association between serum 25(OH)D₃ concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D₃ concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D₃ concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63 confidence interval [95% CI] 1.71-4.05 P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07 95% CI 1.29-3.32 P = 0.002). Myopic participants had significantly lower 25(OH)D₃ concentrations. The prevalence of myopia was significantly higher in in iduals with vitamin D deficiency compared to the in iduals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D₃ concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure.
Publisher: Wiley
Date: 30-09-2019
DOI: 10.1111/CEO.13381
Abstract: Artificial intelligence (AI) has emerged as a major frontier in computer science research. Although AI has broad application across many medical fields, it will have particular utility in ophthalmology and will dramatically change the diagnostic and treatment pathways for many eye conditions such as corneal ectasias, glaucoma, age-related macular degeneration and diabetic retinopathy. However, given that AI has primarily been driven as a computer science, its concepts and terminology are unfamiliar to many medical professionals. Important key terms such as machine learning and deep learning are often misunderstood and incorrectly used interchangeably. This article presents an overview of AI and new developments relevant to ophthalmology.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-03-2017
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.
Publisher: Wiley
Date: 31-05-2022
DOI: 10.1111/ENE.15390
Abstract: Although fundoscopy is a crucial part of the neurological examination, it is challenging, under‐utilized and unreliably performed. The aim was to determine the prevalence of fundus pathology amongst neurology inpatients and the diagnostic accuracy of current fundoscopy practice compared with systematic screening with smartphone fundoscopy (SF) and portable non‐mydriatic fundus photography (NMFP). This was a prospective cross‐sectional surveillance and diagnostic accuracy study on adult patients admitted under neurology in an Australian hospital. Inpatients were randomized to initial NMFP (RetinaVue 100, Welch Allyn) or SF (D‐EYE) followed by a crossover to the alternative modality. Images were graded by neurology doctors, using telemedicine consensus neuro‐ophthalmology NMFP grading as the reference standard. Feasibility parameters included ease, comfort and speed. Of 79 enrolled patients, 14.1% had neurologically relevant pathology (seven, disc pallor one, hypertensive retinopathy three, disc swelling). The neurology team performed direct ophthalmoscopy in 6.6% of cases and missed all abnormalities. SF had a sensitivity of 30%–40% compared with NMFP (45.5%) however, it had a lower rate of screening failure (1% vs. 13%, p 0.001), a shorter examination time (1.10 vs. 2.25 min, p 0.001) and a slightly higher patient comfort rating (9.2 vs. 8/10, p 0.001). Our study demonstrates a clinically significant prevalence of fundus pathology amongst neurology inpatients which was missed by current fundoscopy practices. Portable NMFP screening appears more accurate than SF, whilst both are diagnostically superior to routine fundoscopic practice, feasible and well tolerated by patients.
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2020
DOI: 10.1101/2020.06.21.163766
Abstract: The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) - cells that can be differentiated into any cell type of the three germ layers - has provided a foundation for in vitro human disease modelling 1,2 , drug development 1,2 , and population genetics studies 3,4 . In the majority of instances, the expression levels of genes, plays a critical role in contributing to disease risk, or the ability to identify therapeutic targets. However, while the effect of the genetic background of cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of in idual cells. Differences in the effect of genetic variation on the gene expression of different cell-types, would provide significant resolution for in vitro research using preprogramed cells. By bringing together single cell RNA sequencing 15–21 and population genetics, we now have a framework in which to evaluate the cell-types specific effects of genetic variation on gene expression. Here, we performed single cell RNA-sequencing on 64,018 fibroblasts from 79 donors and we mapped expression quantitative trait loci (eQTL) at the level of in idual cell types. We demonstrate that the large majority of eQTL detected in fibroblasts are specific to an in idual sub-type of cells. To address if the allelic effects on gene expression are dynamic across cell reprogramming, we generated scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type specific eQTL in iPSCs, and show that that the eQTL in fibroblasts are almost entirely disappear during reprogramming. This work provides an atlas of how genetic variation influences gene expression across cell subtypes, and provided evidence for patterns of genetic architecture that lead to cell-types specific eQTL effects.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1038/NG.3482
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.BBALIP.2018.04.007
Abstract: The human retina is a complex structure of organised layers of specialised cells that support the transmission of light signals to the visual cortex. The outermost layer of the retina, the retinal pigment epithelium (RPE), forms part of the blood retina barrier and is implicated in many retinal diseases. Lysophosphatidic acid (LPA) is a bioactive lipid exerting pleiotropic effects in various cell types, during development, normal physiology and disease. Its producing enzyme, AUTOTAXIN (ATX), is highly expressed by the pigmented epithelia of the human eye, including the RPE. Using human pluripotent stem cell (hPSC)-derived retinal cells, we interrogated the role of LPA in the human RPE and photoreceptors. hPSC-derived RPE cells express and synthesize functional ATX, which is predominantly secreted apically of the RPE, suggesting it acts in a paracrine manner to regulate photoreceptor function. In RPE cells, LPA regulates tight junctions, in a receptor-dependent mechanism, with an increase in OCCLUDIN and ZONULA OCCLUDENS (ZO)-1 expression at the cell membrane, accompanied by an increase in the transepithelial resistance of the epithelium. High concentration of LPA decreases phagocytosis of photoreceptor outer segments by the RPE. In hPSC-derived photoreceptors, LPA induces morphological rearrangements by modulating the actin myosin cytoskeleton, as evidenced by Myosin Light Chain l membrane relocation. Collectively, our data suggests an important role of LPA in the integrity and functionality of the healthy retina and blood retina barrier.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.EXER.2009.05.001
Abstract: Pseudoexfoliation (PEX) syndrome is the commonest cause of secondary glaucoma. Many extracellular matrix proteins and elastic fibre structure components are present in the pathological PEX deposits in the anterior segment of the eye including the anterior lens capsule. Common coding variants in the lysyl oxidase-like 1 (LOXL1) gene, involved in cross-linking elastin, have been reported to be strongly associated with PEX syndrome in various human populations. The mechanism by which the LOXL1 protein contributes to the formation of PEX material is unknown. A comprehensive map of the component proteins of PEX deposits can aid the understanding of disease pathogenesis. The purpose of this study was to identify additional protein constituents of pathological PEX deposits. We employed a novel proteomics approach by performing mass spectrometry on "isolated" PEX material surgically removed from the anterior lens capsule of affected eyes. This approach led to the identification of LOXL1 protein and Apolipoprotein E (ApoE) in PEX material. Previously identified protein constituents, latent-transforming growth factor beta-binding protein-2, complement 3 and clusterin were also detected. Immunohistochemical analysis of lens capsules from affected eyes confirmed the presence of both LOXL1 and ApoE in pathological PEX deposits. ApoE is a novel component of these deposits. This is the first report where a direct analytical approach has led to the identification of LOXL1 in PEX deposits and is consistent with its detection in these deposits by immunolabelling in another recent report. LOXL1 is both genetically associated with PEX syndrome and present in pathological PEX deposits. Hence it clearly has an important and direct role in pathophysiology of the disease. In conclusion, additional as yet unknown components are present in pathological PEX deposits and mass spectrometry of "isolated" PEX material is an effective strategy for their identification.
Publisher: Oxford University Press (OUP)
Date: 20-09-2016
DOI: 10.1093/HMG/DDW319
Publisher: Elsevier BV
Date: 08-2023
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.PRETEYERES.2009.05.004
Abstract: Morphometrics, a branch of morphology, represents the study of size and shape components of biological form and their variation in the population. Assessment of optic disc morphology is essential in the diagnosis and management of many ophthalmic disorders. Much work has been performed to characterize size-related parameters of the optic disc however, limited information is available on shape variation in the general population. In contrast to optic disc or cup sizes, which are conceptually meaningful variables with a defined unit of measurement, there are few metric constructs by which to quantify, visualize and interpret variation in optic disc or cup shape. This has significance in ophthalmic diseases with a genetic basis as recent evidence has suggested that optic disc shape may be heritable. Conventional optic disc shape measures of 'ovality' and 'form-factor' reduce a complex structure to a single number and eliminate information of potential diagnostic relevance from further analyses. The recent advent of 'geometric morphometrics', a branch of statistics that incorporates tools from geometry, biometrics and computer graphics in the quantitative analysis of biological forms, has enabled spatial relationships in shape data to be retained during analysis. The analytical methods employed in geometric morphometrics can be separated into two distinct groups: landmark-based (e.g. Procrustes analysis, thin-plate splines) and boundary outline techniques (e.g. Fourier analysis). In this review, we summarize current approaches to the study of optic disc morphology, discuss the underlying theory of geometric morphometrics within the context of analytical techniques and then explore the contemporary relevance of the subject matter to several biological fields. Finally we illustrate the potential application of geometric morphometrics to the specific problem of optic disc shape and glaucoma assessment.
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
Publisher: Impact Journals, LLC
Date: 26-04-2016
Publisher: Elsevier BV
Date: 04-2021
Publisher: Public Library of Science (PLoS)
Date: 28-06-2013
Publisher: AMPCo
Date: 05-2014
DOI: 10.5694/MJA14.00086
Publisher: American Diabetes Association
Date: 08-07-2009
DOI: 10.2337/DB09-0059
Abstract: Diabetic retinopathy is a sight-threatening microvascular complication of diabetes with a complex multifactorial pathogenesis. A systematic meta-analysis was undertaken to collectively assess genetic studies and determine which previously investigated polymorphisms are associated with diabetic retinopathy. All studies investigating the association of genetic variants with the development of diabetic retinopathy were identified in PubMed and ISI Web of Knowledge. Crude odds ratios (ORs) and 95% CIs were calculated for single nucleotide polymorphisms and microsatellite markers previously investigated in at least two published studies. Twenty genes and 34 variants have previously been studied in multiple cohorts. The aldose reductase (AKR1B1) gene was found to have the largest number of polymorphisms significantly associated with diabetic retinopathy. The z−2 micro satellite was found to confer risk (OR 2.33 [95% CI 1.49–3.64], P = 2 × 10−4) in type 1 and type 2 diabetes and z+2 to confer protection (0.58 [0.36–0.93], P = 0.02) against diabetic retinopathy in type 2 diabetes regardless of ethnicity. The T allele of the AKR1B1 promoter rs759853 variant is also significantly protective against diabetic retinopathy in type 1 diabetes (0.5 [0.35–0.71], P = 1.00 × 10−4), regardless of ethnicity. These associations were also found in the white population alone (P & 0.05). Polymorphisms in NOS3, VEGF, ITGA2, and ICAM1 are also associated with diabetic retinopathy after meta-analysis. Variations within the AKR1B1 gene are highly significantly associated with diabetic retinopathy development irrespective of ethnicity. Identification of genetic risk factors in diabetic retinopathy will assist in further understanding of this complex and debilitating diabetes complication.
Publisher: Cambridge University Press (CUP)
Date: 10-2009
Abstract: Visual impairment is a leading cause of morbidity and poor quality of life in our community. Unravelling the mechanisms underpinning important blinding diseases could allow preventative or curative steps to be implemented. Twin siblings provide a unique opportunity in biology to discover genes associated with numerous eye diseases and ocular biometry. Twins are particularly useful for quantitative trait analysis through genome-wide association and linkage studies. Although many studies involving twins rely on twin registries, we present our approach to the Twins Eye Study in Tasmania to provide insight into possible recruitment strategies, expected participation rates and potential examination strategies that can be considered by other researchers for similar studies. Five separate avenues for cohort recruitment were adopted: (1) piggy-backing existing studies where twins had been recruited, (2) utilizing the national twin registry, (3) word-of-mouth and local media publicity, (4) directly approaching schools, and finally (5) collaborating with other research groups studying twins.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-2005
DOI: 10.1167/IOVS.04-1497
Abstract: A classic twin study was performed to determine the heritability of central corneal thickness (CCT), an important parameter in glaucoma assessment. The concordance of CCT between monozygotic (MZ) and dizygotic (DZ) twins was compared. A total of 256 twin pairs (131 MZ and 125 DZ) were recruited from three centers: the Twin Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Twins U.K. Adult Registry held at St. Thomas' Hospital in London. As part of an extensive ophthalmic evaluation, CCT was measured by ultrasound pachymetry. Structural equation modeling with the Mx program (Department of Psychiatry, Medical College of Virginia, Richmond, VA) was used to determine the heritability of CCT. The mean age of subjects was 38 years (range, 8-81). The mean CCT of all eyes examined was 544.5 +/- 37.3 mum (SD). The CCT measurements correlated more highly in MZ twins than in DZ twins, with intraclass correlation coefficients of 0.95 and 0.52, respectively, suggesting a strong genetic influence. A model of additive genetic and unique environmental effects provided the best fit, yielding a heritability of 0.95 (95% confidence interval [CI], 0.93-0.96) with the remaining variation being attributable to unique environmental factors. In this study of Australian and U.K. twins, genetic factors were shown to be of major importance in CCT, with a heritability of 0.95.
Publisher: Wiley
Date: 16-08-2007
DOI: 10.1111/J.1399-0004.2007.00864.X
Abstract: Analysis of CYP1B1 in primary congenital glaucoma (PCG) patients from various ethnic populations indicates that allelic heterogeneity is high, and some mutations are population specific. No study has previously reported the rate or spectrum of CYP1B1 mutations in Australian PCG patients. The aim of this study is to determine the frequency of CYP1B1 mutations in our predominately Caucasian, Australian cohort of PCG cases. Thirty-seven probands were recruited from South-Eastern Australia, along with 100 normal control subjects. Genomic DNA was extracted and the coding regions of CYP1B1 analysed by direct sequencing. Sequence analysis identified 10 different CYP1B1 disease-causing variants in eight probands (21.6%). Five subjects were compound heterozygotes, two subjects heterozygous and one homozygous for CYP1B1 mutations. Three missense mutations are novel (D192Y, G329D, and P400S). None of the novel mutations identified were found in normal controls. One normal control subject was heterozygous for the previously reported CYP1B1 R368H mutation. Six previously described probable polymorphisms were also identified. Mutations in CYP1B1 account for approximately one in five PCG cases from Australia. Our data also supported the high degree of allelic heterogeneity seen in similar studies from other ethnic populations, thereby underscoring the fact that other PCG-related genes remain to be identified.
Publisher: Oxford University Press (OUP)
Date: 29-07-2015
DOI: 10.1002/STEM.2101
Abstract: Cardiac resident stem cells (CRSCs) hold much promise to treat heart disease but this remains a controversial field. Here, we describe a novel population of CRSCs, which are positive for W8B2 antigen and were obtained from adult human atrial appendages. W8B2+ CRSCs exhibit a spindle-shaped morphology, are clonogenic and capable of self-renewal. W8B2+ CRSCs show high expression of mesenchymal but not hematopoietic nor endothelial markers. W8B2+ CRSCs expressed GATA4, HAND2, and TBX5, but not C-KIT, SCA-1, NKX2.5, PDGFRα, ISL1, or WT1. W8B2+ CRSCs can differentiate into cardiovascular lineages and secrete a range of cytokines implicated in angiogenesis, chemotaxis, inflammation, extracellular matrix remodeling, cell growth, and survival. In vitro, conditioned medium collected from W8B2+ CRSCs displayed prosurvival, proangiogenic, and promigratory effects on endothelial cells, superior to that of other adult stem cells tested, and additionally promoted survival and proliferation of neonatal rat cardiomyocytes. Intramyocardial transplantation of human W8B2+ CRSCs into immunocompromised rats 1 week after myocardial infarction markedly improved cardiac function (∼40% improvement in ejection fraction) and reduced fibrotic scar tissue 4 weeks after infarction. Hearts treated with W8B2+ CRSCs showed less adverse remodeling of the left ventricle, a greater number of proliferating cardiomyocytes (Ki67+cTnT+ cells) in the remote region, higher myocardial vascular density, and greater infiltration of CD163+ cells (a marker for M2 macrophages) into the border zone and scar regions. In summary, W8B2+ CRSCs are distinct from currently known CRSCs found in human hearts, and as such may be an ideal cell source to repair myocardial damage after infarction. Stem Cells 2015 :3100–3113
Publisher: Elsevier BV
Date: 10-2023
Publisher: Oxford University Press (OUP)
Date: 10-04-2015
DOI: 10.1093/HMG/DDV128
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.EXER.2018.07.019
Abstract: Herein, we review the safety, efficacy, regulatory standards and ethical implications of the use of stem cells in ocular disease. A literature review was conducted, registered clinical trials reviewed, and expert opinions sought. Guidelines and codes of conduct from international societies and professional bodies were also reviewed. Collated data is presented on current progress in the field of ocular regenerative medicine, future challenges, the clinical trial process and ethical considerations in stem cell therapy. A greater understanding of the function and location of ocular stem cells has led to rapid advances in possible therapeutic applications. However, in the context of significant technical challenges and potential long-term complications, it is imperative that stem cell practices operate within formal clinical trial frameworks. While there remains broad scope for innovation, ongoing evidence-based review of potential interventions and the development of standardized protocols are necessary to ensure patient safety and best practice in ophthalmic care.
Publisher: Elsevier BV
Date: 11-2014
Publisher: Cold Spring Harbor Laboratory
Date: 19-08-2021
DOI: 10.1101/2021.08.19.457030
Abstract: The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and under different conditions. Human induced pluripotent stem cells (hiPSCs) are uniquely suited to study these context-dependent effects, but to do so requires cell lines from hundreds or potentially thousands of in iduals. Village cultures, where multiple hiPSC lines are cultured and differentiated together in a single dish, provide an elegant solution for scaling hiPSC experiments to the necessary s le sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned back to a donor line using single cell sequencing, and addressing whether line-specific signaling alters the transcriptional profiles of companion lines in a village culture. We generated single cell RNA sequence data from hiPSC lines cultured independently (uni-culture) and in villages at three independent sites. We show that the transcriptional profiles of hiPSC lines are highly consistent between uni- and village cultures for both fresh (0.46 R 0.88) and cryopreserved s les (0.46 R 0.62). Using a mixed linear model framework, we estimate that the proportion of transcriptional variation across cells is predominantly due to donor effects, with minimal evidence of variation due to culturing in a village system. We demonstrate that the genetic, epigenetic or hiPSC line-specific effects on gene expression are consistent whether the lines are uni- or village-cultured (0.82 R 0.94). Finally, we identify the consistency in the landscape of cell states between uni- and village-culture systems. Collectively, we demonstrate that village methods can be effectively used to detect hiPSC line-specific effects including sensitive dynamics of cell states.
Publisher: Wiley
Date: 11-05-2016
DOI: 10.1111/AOS.13082
Publisher: BMJ
Date: 09-2005
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.COPH.2019.09.003
Abstract: Human pluripotent stem cells can be differentiated into specific, relevant cell types of interest including the cells of the retina and optic nerve. These cells can then be used to study fundamental biology as well as disease modelling and subsequent screening of potential treatments. Many models of differentiation and modelling have relied on two-dimensional monocultures of specific cell types, which are not representative of the complexity of the human retina and optic nerve. Hence, more complex models of the human retina and optic nerve are required. Three-dimensional organoids and emerging cell culture methods may provide more physiologically relevant models to study developmental biology and pathology of the retina and optic nerve.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2022
DOI: 10.1038/S41598-022-12210-8
Abstract: Bietti crystalline dystrophy (BCD) is an inherited retinal disease (IRD) caused by mutations in the CYP4V2 gene. It is a relatively common cause of IRD in east Asia. A number of features of this disease make it highly amenable to gene supplementation therapy. This study aims to validate a series of essential precursor in vitro experiments prior to developing a clinical gene therapy for BCD. We demonstrated that HEK293, ARPE19, and patient induced pluripotent stem cell (iPSC)-derived RPE cells transduced with AAV2 vectors encoding codon optimization of CYP4V2 (AAV2.coCYP4V2) resulted in elevated protein expression levels of CYP4V2 compared to those transduced with AAV2 vectors encoding wild type CYP4V2 (AAV2.wtCYP4V2), as assessed by immunocytochemistry and western blot. Similarly, we observed significantly increased CYP4V2 enzyme activity in cells transduced with AAV2.coCYP4V2 compared to those transduced with AAV2.wtCYP4V2. We also showed CYP4V2 expression in human RPE/choroid explants transduced with AAV2.coCYP4V2 compared to those transduced with AAV2.wtCYP4V2. These preclinical data support the further development of a gene supplementation therapy for a currently untreatable blinding condition—BCD. Codon-optimized CYP4V2 transgene was superior to wild type in terms of protein expression and enzyme activity. Ex vivo culture of human RPE cells provided an effective approach to test AAV-mediated transgene delivery.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.OPHTHA.2015.12.008
Abstract: Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea. Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes. Four ERED families, including 28 affected and 17 unaffected in iduals. HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos. Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results. Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype. The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.
Publisher: BMJ
Date: 24-07-2008
Abstract: Autosomal dominant optic atrophy (ADOA) is a genetically heterogenous disease. However, a large proportion of this disease is accounted for by mutations in OPA1. The aim of this longitudinal study was to investigate disease progression in Australian ADOA patients with confirmed OPA1 mutations. Probands with characteristic clinical findings of ADOA were screened for OPA1 mutations, and relatives of identified mutation carriers were invited to participate. Disease progression was determined by sequential examination or using historical records over a mean of 9.6 (range 1-42) years. OPA1 mutation carriers (n = 158) were identified in 11 ADOA pedigrees. Sixty-nine mutation carriers were available for longitudinal follow-up. Using the right eye as the default, best-corrected visual acuity (BCVAR) remained unchanged (defined as visual acuity at or within one line of original measurement) in 43 patients (62%). BCVAR worsened by 2 lines in 13 patients (19%). BCVAR deteriorated by more than 2 lines in six patients (9%). Ten per cent of patients had an improvement in visual acuity. Mean time to follow-up was 9.6 years with the mean visual acuity being 6/18 for both the initial and subsequent measurements. There was no statistical significance in the rate of BCVAR loss across different OPA1 mutations (p = 0.55). OPA1-related ADOA generally progresses slowly and functional visual acuity is usually maintained. Longitudinal disease studies are important to enable appropriate counselling of patients. This study enables a better understanding of the natural history of ADOA.
Publisher: Elsevier BV
Date: 07-2021
Publisher: BMJ
Date: 09-03-2012
DOI: 10.1136/BJOPHTHALMOL-2011-301255
Abstract: Conjunctival ultraviolet autofluorescence (UVAF) photography was developed to detect and characterise pre-clinical sunlight-induced UV damage. The reliability of this measurement and its relationship to outdoor activity are currently unknown. 599 people aged 16-85 years in the cross-sectional Norfolk Island Eye Study were included in the validation study. 196 UVAF in idual photographs (49 people) and 60 UVAF photographs (15 people) of Norfolk Island Eye Study participants were used for intra- and inter-observer reliability assessment, respectively. Conjunctival UVAF was measured using UV photography. UVAF area was calculated using computerised methods by one grader on two occasions (intra-observer analysis) or two graders (inter-observer analysis). Outdoor activity category, during summer and winter separately, was determined with a UV questionnaire. Total UVAF equalled the area measured in four conjunctival areas (nasal/temporal conjunctiva of right and left eyes). Intra-observer (ρ_c=0.988, 95% CI 0.967 to 0.996, p<0.001), and inter-observer concordance correlation coefficients (ρ_c=0.924, 95% CI 0.870 to 0.956, p<0.001) of total UVAF exceeded 0.900. When grouped according to 10 mm(2) total UVAF increments, intra- and inter-observer reliability was very good (κ=0.81) and good (κ=0.71), respectively. Increasing time outdoors was strongly with increasing total UVAF in summer and winter (p(trend) <0.001). Intra- and inter-observer reliability of conjunctival UVAF is high. In this population, UVAF correlates strongly with the authors' survey-based assessment of time spent outdoors.
Publisher: Cold Spring Harbor Laboratory
Date: 11-07-2020
DOI: 10.1101/2020.07.10.198143
Abstract: Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified genetic risk factors for AMD, including the TMEM97 locus. TMEM97 encodes the Sigma-2 receptor which is involved in apoptosis and cytotoxicity across a range of neurodegenerative diseases. However, the expression pattern of TMEM97 in the human retina and its functional role in retinal cells has remained elusive. Here we utilised CRISPR interference (CRISPRi) to investigate the functional role of TMEM97 in the retina. Transcriptome analysis of all major cell types within the human retina showed that TMEM97 is expressed in the RPE, retinal ganglion cells (RGCs) and amacrine cells. Using CRISPRi, we performed loss-of-function study of TMEM97 in the human RPE cell line, ARPE19. We generated a stable ARPE19 cell line expressing dCas9-KRAB which facilitated knockdown of TMEM97 using specific sgRNAs. Our results show that knockdown of TMEM97 in ARPE19 exerts a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports the role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi cell line generated here provided an useful in vitro tool for functional studies of other AMD-associated genes.
Publisher: Cold Spring Harbor Laboratory
Date: 03-10-2009
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.
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.
Publisher: Elsevier BV
Date: 2015
Publisher: Elsevier BV
Date: 2023
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 18-05-2018
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 10-2021
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.OPHTHA.2012.02.004
Abstract: Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed to dissect the association further and to determine genotype-phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients. Comparative case series and case-control study. One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies. Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG). Intraocular pressure and vertical cup-to-disc ratio (VCDR). Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003 β = 0.016 standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001 β = -2.135 standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009 odds ratio, 0.63 95% confidence interval, 0.48-0.83). Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2012
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2022
DOI: 10.1101/2022.06.07.495067
Abstract: Directed evolution uses cycles of gene ersification and selection to generate proteins with novel properties. While traditionally directed evolution is performed in prokaryotic systems, recently a mammalian directed evolution system (viral evolution of genetically actuating sequences, or “VEGAS”) has been described. Here we report that the VEGAS system has major limitations precluding its use for directed evolution. The primary technical issue with the VEGAS system is an immediate contamination with “cheater” particles that bypass directed evolution circuits. By sequencing we find these cheater particles contain Sindbis structural genes instead of the intended directed evolution target transgene. These cheaters outcompete the VEGAS transgenes within 2 rounds of transduction but cannot themselves activate synthetic circuits that drive expression of Sindbis structural genes, preventing directed evolution c aigns. Similar results have been obtained in independent labs. Taken together, the VEGAS system does not work as described and, without significant redesign to suppress cheaters, cannot be used for mammalian directed evolution c aigns.
Publisher: MDPI AG
Date: 16-01-2023
DOI: 10.3390/IJMS24021766
Abstract: Neurodegenerative diseases present a progressive loss of neuronal structure and function, leading to cell death and irrecoverable brain atrophy. Most have disease-modifying therapies, in part because the mechanisms of neurodegeneration are yet to be defined, preventing the development of targeted therapies. To overcome this, there is a need for tools that enable a quantitative assessment of how cellular mechanisms and erse environmental conditions contribute to disease. One such tool is genetically encodable fluorescent biosensors (GEFBs), engineered constructs encoding proteins with novel functions capable of sensing spatiotemporal changes in specific pathways, enzyme functions, or metabolite levels. GEFB technology therefore presents a plethora of unique sensing capabilities that, when coupled with induced pluripotent stem cells (iPSCs), present a powerful tool for exploring disease mechanisms and identifying novel therapeutics. In this review, we discuss different GEFBs relevant to neurodegenerative disease and how they can be used with iPSCs to illuminate unresolved questions about causes and risks for neurodegenerative disease.
Publisher: American Medical Association (AMA)
Date: 2007
DOI: 10.1001/ARCHOPHT.125.1.98
Abstract: To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation. All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene. Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 in iduals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian in iduals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant. Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation. Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.
Publisher: MDPI AG
Date: 08-02-2023
DOI: 10.3390/IJMS24043417
Abstract: Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified genetic risk factors for AMD however, the expression profile and functional role of many of these genes remain elusive in human RPE. To facilitate functional studies of AMD-associated genes, we developed a human RPE model with integrated CRISPR interference (CRISPRi) for gene repression by generating a stable ARPE19 cell line expressing dCas9-KRAB. We performed transcriptomic analysis of the human retina to prioritise AMD-associated genes and selected TMEM97 as a candidate gene for knockdown study. Using specific sgRNAs, we showed that knockdown of TMEM97 in ARPE19 reduced reactive oxygen species (ROS) levels and exerted a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports a potential role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi RPE platform generated here provided a useful in vitro tool for functional studies of AMD-associated genes.
Publisher: Mary Ann Liebert Inc
Date: 2019
DOI: 10.1089/HUM.2018.033
Abstract: The CRISPR/Cas system could provide an efficient and reliable means of editing the human genome and has the potential to revolutionize modern medicine however, rapid developments are raising complex ethical issues. There has been significant scientific debate regarding the acceptability of some applications of CRISPR/Cas, with leaders in the field highlighting the need for the lay public's views to shape expert discussion. As such, we sought to determine the factors that influence public opinion on gene editing. We created a 17-item online survey translated into 11 languages and advertised worldwide. Topic modeling was used to analyze textual responses to determine what factors influenced respondents' opinions toward human somatic or embryonic gene editing, and how this varied among respondents with differing attitudes and demographic backgrounds. A total of 3,988 free-text responses were analyzed. Respondents had a mean age of 32 (range, 11-90) years, and 37% were female. The most prevalent topics cited were Future Generations, Research, Human Editing, Children, and Health. Respondents who disagreed with gene editing for health-related purposes were more likely to cite the topic Better Understanding than those who agreed to both somatic and embryonic gene editing. Respondents from Western backgrounds more frequently discussed Future Generations, compared with participants from Eastern countries. Religious respondents did not cite the topic Religious Beliefs more frequently than did nonreligious respondents, whereas Christian respondents were more likely to cite the topic Future Generations. Our results suggest that public resistance to human somatic or embryonic gene editing does not stem from an inherent mistrust of genome modification, but rather a desire for greater understanding. Furthermore, we demonstrate that factors influencing public opinion vary greatly amongst demographic groups. It is crucial that the determinants of public attitudes toward CRISPR/Cas be well understood so that the technology does not suffer the negative public sentiment seen with previous genetic biotechnologies.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2013
DOI: 10.1038/NG0613-712B
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-06-2022
DOI: 10.1167/IOVS.63.6.25
Publisher: BMJ
Date: 05-2021
DOI: 10.1136/BMJOPHTH-2021-000749
Abstract: To compare the visual outcomes of intravitreal antivascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in a real-world setting. Retrospective analysis of data from the Tasmanian Ophthalmic Biobank database. The median change in best-corrected visual acuity (BCVA) between baseline and 12 months post initiating intravitreal anti-VEGF treatment were compared between the three diseases. Final BCVA, central macular thickness (CMT), cumulative number of injections and overall predictors of change in BCVA and CMT were also determined. At 12 months, change in BCVA was significantly different between nAMD, DMO and RVO cohorts (p=0.032), with lower median change for DMO (2 letters, range −5 to 20) than for RVO (11 letters, range −20 to 35). Likewise, CMT change was significantly different between the three cohorts (p=0.022), with a smaller reduction in CMT in DMO (−54 µm, range −482 to 50) than RVO patients (−137 µm, range −478 to 43 p=0.033). Total number of injections received (p=0.028) and final BCVA score (p=0.024) were also significantly different between the groups. Baseline BCVA was a negative predictor (p=0.042) and baseline CMT a positive predictor (p .001) of outcome. After adjusting for baseline BCVA and CMT, diagnosis of nAMD or RVO was a predictor of visual improvement compared with the DMO. At the end of 12 months, nAMD and RVO cohorts had the greatest improvement in BCVA, however the final BCVA for DMO was significantly better than for nAMD.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-03-2021
Abstract: A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associations with eye color.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2021
DOI: 10.1186/S13059-021-02293-3
Abstract: The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) has provided a foundation for in vitro human disease modelling, drug development and population genetics studies. Gene expression plays a critical role in complex disease risk and therapeutic response. However, while the genetic background of reprogrammed cell lines has been shown to strongly influence gene expression, the effect has not been evaluated at the level of in idual cells which would provide significant resolution. By integrating single cell RNA-sequencing (scRNA-seq) and population genetics, we apply a framework in which to evaluate cell type-specific effects of genetic variation on gene expression. Here, we perform scRNA-seq on 64,018 fibroblasts from 79 donors and map expression quantitative trait loci (eQTLs) at the level of in idual cell types. We demonstrate that the majority of eQTLs detected in fibroblasts are specific to an in idual cell subtype. To address if the allelic effects on gene expression are maintained following cell reprogramming, we generate scRNA-seq data in 19,967 iPSCs from 31 reprogramed donor lines. We again identify highly cell type-specific eQTLs in iPSCs and show that the eQTLs in fibroblasts almost entirely disappear during reprogramming. This work provides an atlas of how genetic variation influences gene expression across cell subtypes and provides evidence for patterns of genetic architecture that lead to cell type-specific eQTL effects.
Publisher: Springer Science and Business Media LLC
Date: 21-12-2015
DOI: 10.1038/NG.3448
Publisher: Impact Journals, LLC
Date: 16-02-2023
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.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JPEDS.2015.10.048
Abstract: To investigate whether being anesthesia administered at least once in early life influenced 3 main proxies of visual function: visual acuity, refractive error, and optic nerve health in young adulthood. At age 20 years, participants of the Western Australian Pregnancy Cohort Study had comprehensive ocular examinations including visual acuity, postcycloplegic refraction, and multiple scans of the optic disc. We identified in iduals who had at least 1 procedure requiring anesthesia during the first 3 years of life (between 1990 and 1994) and compared their visual outcomes with nonexposed in iduals. We excluded 40 participants with strabismus or other ophthalmic disease or surgery and 136 with non-European background. Of 834 participants, 15.2% (n = 127) were exposed to anesthesia at least once before age 3 years. In both exposed and nonexposed groups, median visual acuity (measured using the logarithm of the minimum angle of resolution [LogMAR] chart) was -0.06 LogMAR in the right eye and -0.08 LogMAR in the left eye (P > .05). Median spherical equivalent refractive error was +0.44 diopters (IQR -0.25, +0.63) and +0.31 diopters (IQR -0.38, +0.63) in the exposed and nonexposed group, respectively (P = .126). No difference was detected in mean global retinal nerve fiber layer thickness of the 2 groups (100.7 vs 100.1 μm, P = .830). We were unable to demonstrate an association of exposure to anesthesia as a child with reduced visual acuity or increased myopia or thinning of retinal nerve fiber layer. These findings support the view that anesthesia is unlikely to impair visual development, but further work is needed to establish whether more subtle defects are present and repeated exposures have any effects.
Publisher: Elsevier BV
Date: 02-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2014
Publisher: Hindawi Limited
Date: 02-2008
DOI: 10.1002/HUMU.20634
Abstract: Glaucoma, a complex heterogenous disease, is the leading cause for optic nerve-related blindness worldwide. Since 1997, when mutations in the myocilin (MYOC) gene were identified as causing juvenile onset as well as a proportion of primary open-angle glaucoma (POAG), more than 180 variants have been documented. Approximately one in 30 unselected patients with POAG have a disease-causing myocilin mutation and it has been shown that firm genotype-phenotype correlations exist. We have compiled an online catalog of myocilin variants and their associated phenotypes. This locus-specific resource, to which future submissions can be made, is available online (www.myocilin.com last accessed 28 August 2007). The database, constructed using MySQL, contains three related sheets that contain data pertaining to the information source, variant identified, and relevant study data, respectively. The website contains a list of all identified variants and summary statistics as well as background genomic information, such as the annotated sequence and cross-protein/species homology. Phenotypic data such as the mean+/-standard deviation (SD) age at POAG diagnosis, mean+/-SD maximum recorded intraocular pressure, proportion of patients requiring surgical intervention, and age-related penetrance can be viewed by selecting a particular mutation. Approximately 40% of the identified sequence variants have been characterized as disease causing, with the majority ( approximately 85%) of these being missense mutations. Preliminary data generated from this online resource highlight the strong genotype-phenotype correlations associated with specific myocilin mutations. The large-scale assimilation of relevant data allows for accurate comprehensive genetic counseling and the translation of genomic information into the clinic.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 07-2020
Publisher: EMBO
Date: 22-08-2019
Publisher: Cold Spring Harbor Laboratory
Date: 09-02-2016
DOI: 10.1101/039156
Abstract: CRISPR/Cas has recently been adapted to enable efficient editing of the mammalian genome, opening novel avenues for therapeutic intervention of inherited diseases. In seeking to disrupt Yellow Fluorescent Protein (YFP) in a Thy1-YFP transgenic mouse, we assessed the feasibility of utilising the adeno-associated virus 2 (AAV2) to deliver CRISPR/Cas for gene modification of retinal cells in vivo . sgRNA plasmids were designed to target YFP and after in vitro validation, selected guides were cloned into a dual AAV system. One AAV2 construct was used to deliver SpCas9 and the other delivered sgRNA against YFP or LacZ (control) in the presence of mCherry. Five weeks after intravitreal injection, retinal function was determined using electroretinography and CRISPR/Casmediated gene modifications were quantified in retinal flat mounts. AAV2-mediated in vivo delivery of SpCas9 with sgRNA targeting YFP , significantly reduced the number of YFP fluorescent cells of the inner retina of our transgenic mouse model. Overall, we found an 84.0% (95% CI: 81.8-86.9) reduction of YFP-positive cells in YFP -sgRNA infected retinal cells compared to eyes treated with LacZ -sgRNA. Electroretinography profiling found no significant alteration in retinal function following AAV2-mediated delivery of CRISPR/Cas components compared to contralateral untreated eyes. Thy1-YFP transgenic mice were used as a rapid quantifiable means to assess the efficacy of CRISPR/Cas-based retinal gene modification in vivo . We demonstrate that genomic modification of cells in the adult retina can be readily achieved by viral mediated delivery of CRISPR/Cas.
Publisher: Oxford University Press (OUP)
Date: 15-04-2010
DOI: 10.1093/HMG/DDQ144
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1007/S00592-016-0850-4
Abstract: This study aimed to investigate whether the single-nucleotide polymorphism (SNP) rs2910164 residing within microRNA-146a (miR-146a) is associated with diabetic microvascular complications diabetic nephropathy (DN), proliferative diabetic retinopathy (PDR) or diabetic macular oedema (DME) in either Caucasian patients with type 1 (T1DM) or type 2 (T2DM) diabetes mellitus. Caucasian patients with T1DM (n = 733) or T2DM (n = 2215) were recruited from ophthalmology, renal and endocrine clinics in Australia and the UK. Patients with T2DM were required to have diabetes mellitus (DM) for at least 5 years and be on treatment with oral hypoglycaemic drugs or insulin. In total, 890 participants had DN (168 with T1DM and 722 with T2DM), 731 had PDR (251 with T1DM and 480 with T2DM) and 1026 had DME (170 with T1DM and 856 with T2DM). Participants were genotyped for SNP rs2910164 in miR-146a. Analyses investigating association were adjusted for relevant clinical covariates including age, sex, DM duration, HbA1c and hypertension. A significant association was found between the C allele of rs2910164 and DN in the T1DM group (OR 1.93 CI 1.23-3.03 P = 0.004), but no association found in the T2DM group (OR 1.05 CI 0.83-1.32 P = 0.691). In the subset of T2DM patients, the C allele was specifically associated with DME (OR 1.25 CI 1.03-1.53 P = 0.025). No association with DME was found in the T1DM group (OR 0.87 CI 0.54-1.42) P = 0.583), or with PDR for either type of DM. Rs2910164 is significantly associated with microvascular complications DN in patients with T1DM and DME in patients with T2DM.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2023
DOI: 10.1186/S40942-023-00453-0
Abstract: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the standard of care for diabetic macular edema (DME), a common complication of diabetes. This study aimed to identify factors influencing DME intravitreal anti-VEGF treatment outcomes in real-world practice. This was a multi-center retrospective observational study using medical chart review of participants receiving anti-VEGF injections for DME (N = 248). Demographic and clinical variables were assessed for association with best corrected visual acuity (BCVA) and central macular thickness (CMT) outcomes using regression models. There was a significant improvement in BCVA (p 0.001) and CMT (p 0.001) after 12 months of treatment, although 21% of participants had decreased BCVA, and 41% had a 10% CMT reduction at 12 months. Higher baseline BCVA (p = 0.022, OR=-0.024, 95% CI=-0.046,-0.004) and longer duration of diabetic retinopathy (p = 0.048, OR=-0.064, 95% CI=-0.129,-0.001) were negative predictors for BCVA response, whereas Aflibercept treatment (p = 0.017, OR = 1.107, 95% CI = 0.220,2.051) compared with other drugs and a positive “early functional response” (p 0.001, OR=-1.393, 95% CI=-1.946,-0.857) were positive predictors. A higher baseline CMT (p 0.001, OR = 0.019, 95% CI = 0.012,0.0261) and an “early anatomical response”, (p 0.001, OR=-1.677, 95% CI=-2.456, -0.943) were predictors for greater reduction in CMT. Overall, the variables could predict only 23% of BCVA and 52% of CMT response. The study shows a significant proportion of DME patients do not respond to anti-VEGF therapy and identifies several clinical predictors for treatment outcomes. The study was approved through the Human Research Ethics Committee, University of Tasmania (approval number H0012902), and the Southern Adelaide Clinical Human Research Ethics Committee (approval number 86 − 067).
Publisher: Oxford University Press (OUP)
Date: 22-11-2017
DOI: 10.1093/BIOINFORMATICS/BTW675
Abstract: The Ark is an open-source web-based tool that allows researchers to manage health and medical research data for humans and animals without specialized database skills or programming expertise. The system provides data management for core research information including demographic, phenotype, biospecimen and pedigree data, in addition to supporting typical investigator requirements such as tracking participant consent and correspondence, whilst also being able to generate custom data exports and reports. The Ark is ‘study generic’ by design and highly configurable via its web interface, allowing researchers to tailor the system to the specific data management requirements of their study. Source code for The Ark can be obtained freely from the website github.com/The-Ark-Informatics/ark/. The source code can be modified and redistributed under the terms of the GNU GPL v3 license. Documentation and a pre-configured virtual appliance can be found at the website sphinx.org.au/the-ark/. Supplementary data are available at Bioinformatics online.
Publisher: Cold Spring Harbor Laboratory
Date: 18-10-2019
DOI: 10.1101/19009183
Abstract: Early diagnosis and intervention is essential to achieve optimal outcomes for most pediatric eye diseases. Educating parents/caregivers to recognize early signs of disease and consult a healthcare professional is critical to achieving this aim. We evaluate the effectiveness of an eye-health information p hlet on parents’ level of concern and their help-seeking intention if they observed leukocoria or strabismus. Pregnant women attending a metropolitan antenatal clinic were recruited to the study. Participants were randomly assigned to receive a p hlet on either pediatric eye health (intervention) or strategies for play (control). The primary outcome measure was a change in the parents’ level of concern if they observed leukocoria or strabismus. The secondary outcome measure was a change in their help-seeking intention if either sign was observed. Of the 518 women enrolled, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] p=0.005]) and were less likely to have a delayed help-seeking intention. (OR 0.560 [CI 0.382-0.817] p =0.003) No change in the level of concern for strabismus was identified between the groups however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] p=0.016). Providing parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed. ANZCTR.org.au identifier: ACTRN12617001431314p World Health Organization Universal Trial Number: U1111-1203-0485 This study reports the results of a randomised controlled trial evaluating a novel, evidence-based, theory-informed pediatric eye-health information p hlet for parents. Lack of parental awareness of signs of pediatric eye disease (leukocoria and strabismus) delays consultation with healthcare professionals (help-seeking), contributing to late diagnosis and poor outcomes. Providing parents with relevant health information can improve their child’s health outcomes. Using an RCT to evaluate a novel health intervention, this study demonstrates that providing parents with evidence-based, theory informed pediatric eye-health information can improve their knowledge and help-seeking intentions if leukocoria or strabismus are observed in their child.
Publisher: MDPI AG
Date: 06-04-2022
DOI: 10.3390/IJMS23074042
Abstract: Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME) however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8) one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8) and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 13-02-2013
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-07-2012
DOI: 10.1167/IOVS.11-9047
Abstract: Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG. Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion. The data suggest that in iduals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli. This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene.
Publisher: Cold Spring Harbor Laboratory
Date: 10-2023
Publisher: Wiley
Date: 04-2008
Publisher: Springer Science and Business Media LLC
Date: 16-03-2021
DOI: 10.1007/S12015-021-10147-5
Abstract: Apolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer's disease (AD), with the presence of APOE-ε4 associated with increased risk of developing AD. Here, we reprogrammed human fibroblasts from in iduals with different APOE-ε genotypes into induced pluripotent stem cells (iPSCs), and generated isogenic lines with different APOE profiles. Following characterisation of the newly established iPSC lines, we used an unguided/unpatterning differentiation method to generate six-month-old cerebral organoids from all iPSC lines to assess the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified variabilities in the organoids' cell composition between cell lines, and between batches of differentiation for each cell line. We observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau when using the CRISPR-edited APOE isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the cell-line-to-cell-line and batch-to-batch variabilities need to be considered when using cerebral organoids.
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 13-02-2019
DOI: 10.1101/548297
Abstract: Retinal neovascularization is a severe complication of proliferative diabetic retinopathy. MicroRNAs (miRNAs) are master regulators of gene expression that play important roles in retinal neovascularization. Here, we investigated the retinal miRNA expression profile in a rat model of oxygen-induced retinopathy (OIR) through miRNA-Seq. We found that miR-143-3p, miR-126-3p, miR-150-5p and miR-145-5p were significantly down-regulated in the retina of OIR rats, and directly involved in the development of retinal neovascularization. Of these identified miRNAs, miR-143 is enriched in retina and was first reported being associated with pathological retinal angiogenesis. Our RNA-Seq data further suggested that miR-143 alleviates retinal neovascularization by mediating the inflammation/stress pathways via Fos . Moreover, the computational analysis indicated that Transforming Growth Factor-beta Activated Kinase 1 ( TAK1 ) is involved in several key pathways associated with the dysregulated miRNAs. The pharmacological inhibition of TAK1 suppressed angiogenesis in vitro and retinal neovascularization in vivo . Our data highlight the utility of next-generation sequencing in the development of therapeutics for ocular neovascularization and further suggest that therapeutic targeting the dysregulated miRNAs or TAK1 may be a feasible adjunct therapeutic approach in patients with retinal neovascularization.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2016
DOI: 10.1038/NG.3540
Abstract: Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.
Publisher: Elsevier BV
Date: 06-2022
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.
Publisher: American Medical Association (AMA)
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
DOI: 10.1038/S41598-020-69524-8
Abstract: SIX1/SIX6 polymorphism has been shown to be associated with glaucoma. Studies have also found that, in older adults, retinal nerve fibre layer (RNFL) thickness is significantly thinned with each copy of the risk allele in SIX1/SIX6 . However, it is not known whether these genetic variants exert their effects in younger in iduals. Comparing a healthy young adult with an older adult cohort (mean age 20 vs 63 years), both of Northern European descent, we found that there was no significant RNFL thinning in each copy of the risk alleles in SIX1/SIX6 in the eyes of younger in iduals. The older cohort showed an unexpectedly thicker RNFL in the nasal sector with each copy of the risk allele for both the SIX1 (rs10483727) and SIX6 (rs33912345) variants. In the temporal sector, thinner RNFL was found with each copy of the risk allele in rs33912345 with a decrease trend observed in rs10483727. Our results suggest that SIX1/SIX6 gene variants exert their influence later in adult life.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2009
DOI: 10.1038/EYE.2009.37
Abstract: The aim of this study was to investigate the causes of mortality in in iduals with open-angle glaucoma (OAG). All-cause mortality data from the Registry of Births, Deaths and Marriages for the Australian state of Tasmania, for all people who were at least 40 years of age at the time of death, were classified using International Classification of Diseases-10 guidelines. This information was cross-referenced to identify participants in the Glaucoma Inheritance Study in Tasmania (GIST) who had died. Contingency tables were used for crude analysis and then models were constructed, adjusting for age at death as well as gender. Between 1996 and 2005, a total of 33 879 deaths were recorded. Data were unavailable for 4868 (14.4%) people. The mean age at death for the study s le was 78.4+/-11.5 (range 41-109) years. Of those cases known to have OAG by their participation in GIST (n=2409), full mortality data were available for 741 (92.0%). Following adjustment for the age at death and male gender, the odds ratio for death due to ischaemic heart disease in people with OAG compared to the general population not known to have OAG was significant (OR=1.30, 95% CI: 1.08-1.56 P=0.006). Crude analysis revealed that there were significantly fewer people with OAG who died due to metastatic cancer (P<0.001) however, this did not remain significant following adjustment for age and gender. The pathoaetiological relationship between OAG and ischaemic heart disease is unclear and requires further investigation. Increased awareness of the association between cardiovascular disease and OAG is warranted.
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.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.PRETEYERES.2016.05.001
Abstract: The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) and CRISPR-associated protein (Cas) system has enabled an accurate and efficient means to edit the human genome. Rapid advances in this technology could results in imminent clinical application, and with favourable anatomical and immunological profiles, ophthalmic disease will be at the forefront of such work. There have been a number of breakthroughs improving the specificity and efficacy of CRISPR/Cas-mediated genome editing. Similarly, better methods to identify off-target cleavage sites have also been developed. With the impending clinical utility of CRISPR/Cas technology, complex ethical issues related to the regulation and management of the precise applications of human gene editing must be considered. This review discusses the current progress and recent breakthroughs in CRISPR/Cas-based gene engineering, and outlines some of the technical issues that must be addressed before gene correction, be it in vivo or in vitro, is integrated into ophthalmic care. We outline a clinical pipeline for CRISPR-based treatments of inherited eye diseases and provide an overview of the important ethical implications of gene editing and how these may influence the future of this technology.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
Publisher: Springer Science and Business Media LLC
Date: 25-09-2020
DOI: 10.1038/S41467-020-18715-Y
Abstract: Precision genome engineering has dramatically advanced with the development of CRISPR/Cas base editing systems that include cytosine base editors and adenine base editors (ABEs). Herein, we compare the editing profile of circularly permuted and domain-inlaid Cas9 base editors, and find that on-target editing is largely maintained following their intradomain insertion, but that structural permutation of the ABE can affect differing RNA off-target events. With this insight, structure-guided design was used to engineer an SaCas9 ABE variant (microABE I744) that has dramatically improved on-target editing efficiency and a reduced RNA-off target footprint compared to current N-terminal linked SaCas9 ABE variants. This represents one of the smallest AAV-deliverable Cas9-ABEs available, which has been optimized for robust on-target activity and RNA-fidelity based upon its stereochemistry.
Publisher: BMJ
Date: 06-2021
DOI: 10.1136/BMJOPEN-2020-048361
Abstract: Voretigene neparvovec-rzyl (Luxturna) was approved by the Australian Therapeutic Goods Administration on 4 August 2020 for the treatment of biallelic mutations in the RPE65 gene, a rare cause of congenital and adult-onset retinal dystrophy (predominantly Leber congenital amaurosis). Previous studies have shown that in iduals who might participate in gene therapy trials overestimate clinical effect and underestimate risks. However, little is known about the perspectives of patients who may be offered approved gene therapy treatment for ocular conditions (as distinct from participating in clinical trials of gene therapy). The main objective of this study is to develop a tool to assess knowledge, attitudes and perceptions of approved and future genetic therapies among potential recipients of ocular gene therapy. In addition, we aim to assess the quality of life, attitudes towards clinical trials and vision-related quality of life among this cohort. A new ‘Attitudes to Gene Therapy for the Eye’ tool will be developed following consultation with people with inherited retinal disease (IRD) and content matter experts. Australians with IRD or their guardians will be asked to complete an internet-based survey comprising existing quality of life and visual function instruments and items for the newly proposed tool. We expect to recruit 500 survey participants from patient support groups, the practices of Australian ophthalmologists who are specialists in IRD and Australian ophthalmic research institutions. Launch is anticipated early 2021. Responses will be analysed using item response theory methodology. This study has received ethics approval from the University of Melbourne (#2057534). The results of the study will be published in a peer-reviewed journal and will be presented at relevant conferences. Organisations involved in recruitment, and the Patient Engagement Advisory committee will assist the research team with dissemination of the study outcomes.
Publisher: Informa UK Limited
Date: 21-12-2018
DOI: 10.1080/13816810.2017.1413659
Abstract: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. We identified one CpG site (F1:13-14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 15-02-2018
DOI: 10.1167/TVST.7.1.18
Publisher: American Medical Association (AMA)
Date: 07-2015
DOI: 10.1001/JAMAOPHTHALMOL.2015.0980
Abstract: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty in iduals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%] P = .02 odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%] P = .02 odds ratio, 2.0 [95% CI, 0.3-0.9]). In iduals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB F1,126 = 5.90 P = .02 partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years F1,122 = 7.18 P = .008 ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.
Publisher: Informa UK Limited
Date: 03-2015
DOI: 10.1111/CXO.12209
Abstract: The aim was to determine whether latitudinal (Queensland versus Tasmania) variation in reported disease frequency in Australia may be biased by differences in population. A retrospective analysis was conducted from data of two large Australian twin studies (n = 1,835) having undertaken ophthalmic examination, namely, Twins Eye Study in Tasmania (TEST) and the Brisbane Adolescent Twins Study (BATS). Ordinal logistic regression was used to compute odds ratios and predicted probabilities for each category of eye colour by state. Tasmanian residence was associated with lower odds of darker iris colour (odds ratio 0.77, 95% CI [0.63-0.95]) signifying that participants living in Tasmania (TAS) are less likely to have darker-coloured irides than those residing in Queensland (QLD). For in iduals living in Tasmania the predicted probability (TAS versus QLD) of having light blue eyes was greater (16.7 versus 13.3 per cent), approximately the same for green eyes and less for brown/dark brown-coloured eyes (6.2 versus 7.9 per cent). We found a general trend of in iduals living in the southern states (TAS/VIC) of Australia having lighter-coloured irides compared to those living in the north (QLD). This finding has potential implications for all epidemiological research conducted to explore differences in UV-associated disease frequency in Australia, as population heterogeneity may confound the estimates obtained.
Publisher: Elsevier BV
Date: 2009
Publisher: IEEE
Date: 11-2013
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 11-10-2012
Publisher: Springer Science and Business Media LLC
Date: 26-11-2011
DOI: 10.1038/EYE.2010.180
Publisher: Wiley
Date: 16-12-2011
DOI: 10.1111/J.1442-9071.2010.02429.X
Abstract: To describe the methodology and baseline data of a population-based study designed to determine the prevalence of glaucoma and to study the risk factors for glaucoma development in a Nepali population. Population-based cross-sectional study. Subjects 40 years and above residing in Bhaktapur District. Power calculations suggest that a s le size of 4758 is required. Thirty clusters were randomly selected from the 2 municipalities and 16 Village Development Committees of Bhaktapur District in Nepal. A door-to-door census was conducted in the selected clusters to identify citizens 40 years of age and older. Demographic details were collected and a structured interview, regarding awareness for cataract and glaucoma was taken. All in iduals fulfilling the eligibility criteria were recruited and referred to the Tilganga Institute of Ophthalmology in Kathmandu for a detailed clinical examination including glaucoma diagnostic procedures. Peripheral blood s les were taken to facilitate future genetic analysis. Prevalence of glaucoma, risk factors and genetic screening. A total of 4800 people were selected. The mean age of participants was 55.4 ± 12.3 years (range: 40-99) and 51.8% were female. In total, 64.8% of our cohort was aged less than 59 years and 60.5% were illiterate. Among the various ethnic races, 69.7% belonged to the Newar ethnic group. This study will determine the prevalence of glaucoma and allow for an increased understanding of the risk factors for glaucoma development in this region.
Publisher: Elsevier BV
Date: 10-2021
Publisher: Springer Science and Business Media LLC
Date: 10-02-2013
DOI: 10.1038/NG.2554
Publisher: BMJ
Date: 07-08-2012
Publisher: American Medical Association (AMA)
Date: 09-2021
Publisher: Elsevier BV
Date: 12-2013
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.AJO.2006.12.038
Abstract: We identified families with autosomal dominant optic atrophy (ADOA), determined the number and type of OPA1 mutations, and investigated the phenotypic variation and penetrance in ADOA Australian pedigrees. Cross-sectional genetics study. Probands were identified on the basis of characteristic clinical features of ADOA. We screened the OPA1 gene using single-strand conformational polymorphism, heteroduplex analysis (SSCP/HA), or by direct sequencing. Penetrance for pedigrees in which a mutation of OPA1 had been identified was calculated initially using all recruited in iduals, and subanalysis was performed using only those families for which there was total recruitment of siblings. A total of 406 patients from 17 pedigrees were recruited, and OPA1 mutations were identified in 11/17 (65%) of these. The mean age at clinical examination was 38.2 +/- 19.9 years (median age, 35 years range, four to 83 years). The median best-corrected visual acuity in OPA1-mutation carriers was 20/70 (range, 20/16 to hand movements [HM]). The penetrance in Australian ADOA pedigrees in the families with complete sibling recruitment was 82.5%. On the other hand, overall penetrance for all in iduals harboring an OPA1 mutation was 88%. OPA1 mutations were identified in 11/17 (65%) of the ADOA pedigrees in this study. The penetrance in our cohort was lower than originally described (82.5% vs 98%) but higher than some recent studies since the availability of genotyping. It is anticipated that this figure would be even lower as more asymptomatic in iduals are identified. There are likely to be other genetic and environmental modifiers influencing disease penetrance.
Publisher: Springer Science and Business Media LLC
Date: 16-04-2018
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.AJO.2016.03.008
Abstract: To characterize and quantify Bruch membrane opening (BMO)-based optic nerve head (ONH) parameters in a large, young and healthy, predominantly white population. Cross-sectional study and reliability analysis. The ONH of 1344 predominantly white subjects were imaged with spectral-domain optical coherence tomography (SD-OCT). A customized script, coded in Matlab, was used to manually segment and measure multiple BMO-based parameters of the ONH. Measurements were compared to those obtained with confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph HRT). Regression analysis was performed to assess the relationship between BMO parameters and other ocular and demographic variables. Mean BMO disc and neuroretinal rim (NRR) areas ranged from 0.94 to 4.06 mm(2) (mean 1.77 ± 0.38 mm(2)) and 0.94 to 3.99 mm(2) (mean 1.56 ± 0.31 mm(2)), respectively. When compared to the equivalent HRT measurements, SD-OCT-derived measures differed significantly for all comparable ONH parameters (P < .001). The limits of agreement computed from Bland-Altman plots comparing SD-OCT and HRT measurements showed suboptimal agreement between the techniques. Linear regression analysis demonstrated an effect of ethnicity, axial length, and refractive error on BMO-based parameters. We have quantified BMO-based parameters in a large cohort of young adults using SD-OCT. These data will be informative in constructing normative profiles for clinical and research purposes in glaucoma diagnosis and management.
Publisher: Asia Pacific Academy of Ophthalmology
Date: 2016
Publisher: Elsevier BV
Date: 04-2020
Publisher: Wiley
Date: 19-03-2014
DOI: 10.1111/AOS.12388
Abstract: To investigate the age range for which cycloplegia provides additional information compared with non-cycloplegic refraction in teenagers and young adults. Data for 1295 subjects (704 female 591 male) from the Twins Eye Study in Tasmania (TEST) and the Brisbane Adolescent Twin Study (mean age: 19.65 ± 3.56, range: 13-26 years) were included. For all participants, cycloplegia was induced by instillation of either one drop of 1% cyclopentolate (13-14 years) or one drop of 1% tropicamide (15-26 years). Pre- and postcycloplegic refractive errors for both eyes were measured using a Humphrey-598 automated refractor and spherical equivalents of refractive error were calculated. Generalized Estimating Equations (GEE) were used to model the spherical equivalent refraction (SER) for each eye against age (by year) and axial length (in the given eye). The mean group difference between pre- and postcycloplegic SER (post minus pre) was 0.17 ± 0.52 D and 0.12 ± 0.51 D for the right and left eyes, respectively, indicating that postcycloplegic refraction was generally more hyperopic/less myopic. The mean difference between pre- and postcycloplegic SER decreased from 0.36 ± 0.41 D in the 13-year-olds to 0.06 ± 0.50 D in people aged 25 years. After adjusting for family-relatedness, the difference between pre- and postcycloplegia SER was significant in all age groups up until the age of 20 years. Non-cycloplegic autorefraction can result in group mean SER differences of greater myopia than cycloplegic autorefraction and occurs in teenagers (13-19 years of age), but not in adults 20-26 years. These data suggest that cycloplegia is not required in population estimates of refractive error for young adults once they reach approximately 20 years of age.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2017
DOI: 10.1038/NG.3875
Publisher: Elsevier BV
Date: 11-2021
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.
Publisher: American Chemical Society (ACS)
Date: 15-02-2022
Abstract: Conventional methods of neuronal differentiation in human induced pluripotent stem cells (iPSCs) are tedious and complicated, involving multistage protocols with complex cocktails of growth factors and small molecules. Artificial extracellular matrices with a defined surface topography and chemistry represent a promising venue to improve neuronal differentiation
Publisher: Cold Spring Harbor Laboratory
Date: 17-02-2019
DOI: 10.1101/552588
Abstract: The libraries generated by high-throughput single cell RNA-sequencing platforms such as the Chromium from 10X Genomics require considerable amounts of sequencing, typically due to the large number of cells. The ability to use this data to address biological questions is directly impacted by the quality of the sequence data. Here we have compared the performance of the Illumina NextSeq 500 and NovaSeq 6000 against the BGI MGISEQ-2000 platform using identical Single Cell 3’ libraries consisting of over 70,000 cells. Our results demonstrate a highly comparable performance between the NovaSeq 6000 and MGISEQ-2000 in sequencing quality, and cell, UMI, and gene detection. However, compared with the NextSeq 500, the MGISEQ-2000 platform performs consistently better, identifying more cells, genes, and UMIs at equalised read depth. We were able to call an additional 1,065,659 SNPs from sequence data generated by the BGI platform, enabling an additional 14% of cells to be assigned to the correct donor from a multiplexed library. However, both the NextSeq 500 and MGISEQ-2000 detected similar frequencies of gRNAs from a pooled CRISPR single cell screen. Our study provides a benchmark for high capacity sequencing platforms applied to high-throughput single cell RNA-seq libraries.
Publisher: Wiley
Date: 06-10-2023
DOI: 10.1111/AOS.15775
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
DOI: 10.1161/HYPERTENSIONAHA.108.125914
Abstract: Recent studies reported an association between smaller birth size and narrower retinal vascular caliber, but it remains unclear whether this association is attributed to confounding by shared environment or genetic factors. At a mean age of 9.3 years, 266 twins (49 monozygotic and 84 dizygotic pairs) in the Twins Eye Study in Tasmania underwent an ophthalmic examination including retinal photography. Retinal vascular caliber was measured using a validated protocol. The majority of these twins were also in the Tasmanian Infant Health Study, which prospectively collected data on birth parameters and antenatal maternal factors. We conducted the main analysis using linear mixed models, accounting for birth set clustering. Both the within-pair (−9.73 95% CI: −14.68 to −4.77 μm per 5-cm decrease in birth length) and between-pair associations (−7.15 95% CI: −11.54 to −3.01) with retinal arteriolar caliber were significant and of similar magnitude (difference in effect, P =0.61), after adjusting for age, sex, maternal smoking, mean arterial blood pressure, and other confounders. These associations remained within dizygotic and monozygotic pairs. Analyses of head circumference and retinal arteriolar caliber were similar to those of birth length (within-pair regression coefficient: −2.41 95% CI: −5.09 to 0.28 between-pair regression coefficient: −2.60 95% CI: −5.00 to −0.19). For birth weight, only a between-pair association was evident (−7.28 95% CI: −13.07 to −1.48). This study demonstrates a consistent association between smaller birth size and narrower retinal arterioles in twins. The independent effect of shorter birth length on retinal arteriolar caliber supports a role for twin-specific supply line factors affecting fetal growth on vascular structure.
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.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2016
Publisher: Elsevier BV
Date: 06-2022
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2018
DOI: 10.1101/425223
Abstract: The retina is a highly specialized neural tissue that senses light and initiates image processing. Although the functional organisation of specific cells within the retina has been well-studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile cell types in the human retina, we performed single cell RNA-sequencing on 20,009 cells obtained post-mortem from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct clusters representing all known retinal cells: rod photoreceptors, cone photoreceptors, Müller glia cells, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, retinal astrocytes and microglia. Notably, our data captured molecular profiles for healthy and early degenerating rod photoreceptors, and revealed a novel role of MALAT1 in putative rod degeneration. We also demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to our understanding of retinal biology and disease.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2017
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.
Publisher: The Company of Biologists
Date: 12-2022
DOI: 10.1242/DMM.049651
Abstract: CLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3, with most affected in iduals carrying at least one allele with a 966 bp deletion. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human induced pluripotent stem cells (iPSCs) of a compound heterozygous patient (CLN3 Δ 966 bp and E295K). We differentiated these isogenic iPSCs, and iPSCs from an unrelated healthy control donor, to neurons and identified disease-related changes relating to protein synthesis, trafficking and degradation, and in neuronal activity, which were not apparent in CLN3-corrected or healthy control neurons. CLN3 neurons showed numerous membrane-bound vacuoles containing erse storage material and hyperglycosylation of the lysosomal LAMP1 protein. Proteomic analysis showed increase in lysosomal-related proteins and many ribosomal subunit proteins in CLN3 neurons, accompanied by downregulation of proteins related to axon guidance and endocytosis. CLN3 neurons also had lower electrophysical activity as recorded using microelectrode arrays. These data implicate inter-related pathways in protein homeostasis and neurite arborization as contributing to CLN3 disease, and which could be potential targets for therapy.
Publisher: Cold Spring Harbor Laboratory
Date: 29-01-2021
DOI: 10.1101/2021.01.29.428701
Abstract: Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-β-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-β1 and other pro-inflammatory cytokines. TAK1 is also a key mediator of inflammation, innate immune responses, apoptosis and tissue homeostasis and plays an important role in physiological angiogenesis. Its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. We investigated the regulatory role of TAK1 in pathological angiogenesis in the retina. Transcriptome analysis of human retina featuring retinal neovascularization revealed enrichment of known TAK1-mediated signaling pathways. Selective inhibition of TAK1 activation by 5Z-7-oxozeaenol attenuated aberrant retinal angiogenesis in rats following oxygen-induced retinopathy. Transcriptome profiling revealed that TAK1 activation in human microvascular endothelial cells under TNFα stimulation led to increase the gene expression related to cytokines and leukocyte-endothelial interaction, mainly through nuclear factor kappa B (NFκB) signaling pathways. These results reveal that inhibition of TAK1 signaling may have therapeutic value for the treatment of pathological angiogenesis in the retina.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-10-2022
Publisher: MDPI AG
Date: 04-08-2020
DOI: 10.20944/PREPRINTS202008.0091.V1
Abstract: The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer& rsquo s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch cl . We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.
Publisher: Elsevier BV
Date: 08-2022
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.AJO.2006.02.041
Abstract: To investigate in Australian patients with glaucoma and normal controls the prevalence and associated phenotype of the WDR36 D658G mutation, which has previously been suggested to be a disease-causing mutation in pedigrees with primary open-angle glaucoma (POAG). Case-control study. Two hundred forty-nine in iduals with POAG and 217 age-matched control subjects were recruited through the Glaucoma Inheritance Study in Tasmania, Australia. Genomic DNA was lified by polymerase chain reaction by intronic primers. The presence of the D658G variant was detected by BglI restriction enzyme digestion. The D658G variant was identified in four POAG cases (1.6%) and four control subjects (1.8%) (chi(2) = 0.04, P = .84). No control subject with the variant had a family history of glaucoma. The WDR36 D658G is a neutral variant in the Australian population. Further populations should be carefully assessed for this variant before concluding that WDR36 is a glaucoma gene.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 09-02-2016
DOI: 10.1167/TVST.5.1.3
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.PRETEYERES.2022.101110
Abstract: Genetic medicine is offering hope as new therapies are emerging for many previously untreatable diseases. The eye is at the forefront of these advances, as exemplified by the approval of Luxturna® by the United States Food and Drug Administration (US FDA) in 2017 for the treatment of one form of Leber Congenital Amaurosis (LCA), an inherited blindness. Luxturna® was also the first in vivo human gene therapy to gain US FDA approval. Numerous gene therapy clinical trials are ongoing for other eye diseases, and novel delivery systems, discovery of new drug targets and emerging technologies are currently driving the field forward. Targeting RNA, in particular, is an attractive therapeutic strategy for genetic disease that may have safety advantages over alternative approaches by avoiding permanent changes in the genome. In this regard, antisense oligonucleotides (ASO) and RNA interference (RNAi) are the currently popular strategies for developing RNA-targeted therapeutics. Enthusiasm has been further fuelled by the emergence of clustered regularly interspersed short palindromic repeats (CRISPR)-CRISPR associated (Cas) systems that allow targeted manipulation of nucleic acids. RNA-targeting CRISPR-Cas systems now provide a novel way to develop RNA-targeted therapeutics and may provide superior efficiency and specificity to existing technologies. In addition, RNA base editing technologies using CRISPR-Cas and other modalities also enable precise alteration of single nucleotides. In this review, we showcase advances made by RNA-targeting systems for ocular disease, discuss applications of ASO and RNAi technologies, highlight emerging CRISPR-Cas systems and consider the implications of RNA-targeting therapeutics in the development of future drugs to treat eye disease.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 14-09-2018
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2014
DOI: 10.1101/007724
Abstract: A major bottleneck in biological discovery is now emerging at the computational level. Cloud computing offers a dynamic means whereby small and medium-sized laboratories can rapidly adjust their computational capacity. We benchmarked two established cloud computing services, Amazon Web Services Elastic MapReduce (EMR) on Amazon EC2 instances and Google Compute Engine (GCE), using publicly available genomic datasets (E.coli CC102 strain and a Han Chinese male genome) and a standard bioinformatic pipeline on a Hadoop-based platform. Wall-clock time for complete assembly differed by 52.9% (95%CI: 27.5-78.2) for E.coli and 53.5% (95%CI: 34.4-72.6) for human genome, with GCE being more efficient than EMR. The cost of running this experiment on EMR and GCE differed significantly, with the costs on EMR being 257.3% (95%CI: 211.5-303.1) and 173.9% (95%CI: 134.6-213.1) more expensive for E.coli and human assemblies respectively. Thus, GCE was found to outperform EMR both in terms of cost and wall-clock time. Our findings confirm that cloud computing is an efficient and potentially cost-effective alternative for analysis of large genomic datasets. In addition to releasing our cost-effectiveness comparison, we present available ready-to-use scripts for establishing Hadoop instances with Ganglia monitoring on EC2 or GCE.
Publisher: Wiley
Date: 28-01-2015
DOI: 10.1002/GEPI.21886
Publisher: Springer Science and Business Media LLC
Date: 06-01-2013
DOI: 10.1038/NG.2506
Publisher: Hindawi Limited
Date: 19-10-2022
DOI: 10.1002/HUMU.24482
Abstract: The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-38704-1
Abstract: The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and different conditions. Human induced pluripotent stem cells are uniquely suited to study these context-dependent effects but cell lines from hundreds or thousands of in iduals are required. Village cultures, where multiple induced pluripotent stem lines are cultured and differentiated in a single dish, provide an elegant solution for scaling induced pluripotent stem experiments to the necessary s le sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned to an induced pluripotent stem line using single-cell sequencing and illustrating that the genetic, epigenetic or induced pluripotent stem line-specific effects explain a large percentage of gene expression variation for many genes. We demonstrate that village methods can effectively detect induced pluripotent stem line-specific effects, including sensitive dynamics of cell states.
Publisher: Public Library of Science (PLoS)
Date: 18-10-2021
Publisher: Frontiers Media SA
Date: 03-05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 07-03-2019
DOI: 10.1101/570614
Abstract: A variety of experimental and computational methods have been developed to demultiplex s les from pooled in iduals in a single-cell RNA sequencing (scRNA-Seq) experiment which either require adding information (such as hashtag barcodes) or measuring information (such as genotypes) prior to pooling. We introduce scSplit which utilises genetic differences inferred from scRNA-Seq data alone to demultiplex pooled s les. scSplit also extracts a minimal set of high confidence presence/absence genotypes in each cluster which can be used to map clusters to original s les. Using a range of simulated, merged in idual-s le as well as pooled multi-in idual scRNA-Seq datasets, we show that scSplit is highly accurate and concordant with demuxlet predictions. Furthermore, scSplit predictions are highly consistent with the known truth in cell-hashing dataset. We also show that multiplexed-scRNA-Seq can be used to reduce batch effects caused by technical biases. scSplit is ideally suited to s les for which external genome-wide genotype data cannot be obtained (for ex le non-model organisms), or for which it is impossible to obtain unmixed s les directly, such as mixtures of genetically distinct tumour cells, or mixed infections. scSplit is available at: on-xu/scSplit
Publisher: MDPI AG
Date: 02-09-2020
DOI: 10.3390/CELLS9092018
Abstract: The study of neurodegenerative diseases using pluripotent stem cells requires new methods to assess neurodevelopment and neurodegeneration of specific neuronal subtypes. The cholinergic system, characterized by its use of the neurotransmitter acetylcholine, is one of the first to degenerate in Alzheimer’s disease and is also affected in frontotemporal dementia. We developed a differentiation protocol to generate basal forebrain-like cholinergic neurons (BFCNs) from induced pluripotent stem cells (iPSCs) aided by the use of small molecule inhibitors and growth factors. Ten iPSC lines were successfully differentiated into BFCNs using this protocol. The neuronal cultures were characterised through RNA and protein expression, and functional analysis of neurons was confirmed by whole-cell patch cl . We have developed a reliable protocol using only small molecule inhibitors and growth factors, while avoiding transfection or cell sorting methods, to achieve a BFCN culture that expresses the characteristic markers of cholinergic neurons.
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1016/J.OPHTHA.2007.08.013
Abstract: To estimate heritability and locate quantitative trait loci influencing axial length. Classic twin study of monozygotic and dizygotic twins reared together. Eight hundred ninety-three in iduals from 460 families were recruited through the Twin Eye Study in Tasmania and the Brisbane Adolescent Twin Study (BATS) and had ocular axial length measured. Structural equation modeling on the entire s le was used to estimate genetic and environmental components of variation in axial length. Analysis of existing microsatellite marker genomewide linkage scan data was performed on 318 in iduals from 142 BATS families. Ocular axial length. The heritability estimate for axial length, adjusted for age and sex, in the full s le was 0.81. The highest multipoint logarithm of the odds (LOD) score observed was 3.40 (genomewide P = 0.0004), on chromosome 5q (at 98 centimorgans [cM]). Additional regions with suggestive multipoint LOD scores were also identified on chromosome 6 (LOD scores, 2.13 at 76 cM and 2.05 at 83 cM), chromosome 10 (LOD score, 2.03 at 131 cM), and chromosome 14 (LOD score, 2.84 at 97 cM). Axial length, a major endophenotype for refractive error, is highly heritable and is likely to be influenced by one or more genes on the long arm of chromosome 5.
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
Publisher: Wiley
Date: 16-12-2013
DOI: 10.1111/J.1755-3768.2011.02314.X
Abstract: To investigate the association between conjunctival ultraviolet autofluorescence (UVAF), a biomarker of ocular ultraviolet radiation (UVR) exposure, and prevalent pterygium. We conducted a cross-sectional study on Norfolk Island, South Pacific. All permanent residents aged ≥15 were invited to participate. Participants completed a sun exposure questionnaire and underwent autorefraction and slit l biomicroscope examination. Area of conjunctival UVAF (sum of temporal/nasal area in right and left eyes) was determined using computerized methods. Multivariate logistic and linear regression models were used to estimate the associations with pterygia and UVAF, respectively. Of 641 participants, 70 people (10.9%) had pterygium in one or both eyes, and prevalence was higher in males (15.0% versus 7.7%, p = 0.003). Significant independent associations with pterygium in any eye were UVAF (per 10 mm(2)) [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.16-1.28, p = 0.002], tanning skin phenotype (OR 2.17, 1.20-3.92, p = 0.010) and spending more than three-quarters of the day outside (OR 2.22, 1.20-4.09, p = 0.011). Increasing quartile of UVAF was associated with increased risk of pterygium following adjustment of age, sex and time outdoors (p(Trend) = 0.002). Independent associations with increasing UVAF (per 10 mm(2)) were decreasing age, time outdoors, skin type and male gender (all p < 0.001). UVAF area correlated well with the duration of outdoor activity (p(Trend) < 0.001). Pterygium occurs in approximately one-tenth of Norfolk Islanders. Increasing conjunctival UVAF is associated with prevalent pterygia, confirming earlier epidemiological, laboratory and ray-tracing studies that pterygia are associated with UVR. Protection from the sun should be encouraged to reduce the prevalence of pterygium in the community.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0447-2
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Research Square Platform LLC
Date: 12-09-2023
Publisher: PeerJ
Date: 24-09-2018
DOI: 10.7717/PEERJ.5664
Abstract: The institutional affiliations and associated collaborative networks that scientists foster during their research careers are salient in the production of high-quality science. The phenomenon of multiple institutional affiliations and its relationship to research output remains relatively unexplored in the literature. We examined 27,612 scientific articles, modelling the normalized citation counts received against the number of authors and affiliations held. In agreement with previous research, we found that teamwork is an important factor in high impact papers, with average citations received increasing concordant with the number of co-authors listed. For articles with more than five co-authors, we noted an increase in average citations received when authors with more than one institutional affiliation contributed to the research. Multiple author affiliations may play a positive role in the production of high-impact science. This increased researcher mobility should be viewed by institutional boards as meritorious in the pursuit of scientific discovery.
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.
Publisher: Cold Spring Harbor Laboratory
Date: 26-03-2017
DOI: 10.1101/120659
Abstract: Cybrid technology was used to replace Leber hereditary optic neuropathy (LHON) causing mitochondrial DNA (mtDNA) mutations from patient-specific fibroblasts with wildtype mtDNA, and mutation-free induced pluripotent stem cells (iPSCs) were generated subsequently. Retinal ganglion cell (RGC) differentiation demonstrates increased cell death in LHON-RGCs and can be rescued in cybrid corrected RGCs.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2018
Publisher: Public Library of Science (PLoS)
Date: 22-06-2011
Publisher: Informa UK Limited
Date: 19-01-2017
DOI: 10.1080/09286586.2016.1255975
Abstract: To outline and detail the importance of conditional probability in clinical decision making and discuss the various diagnostic measures eye care practitioners should be aware of in order to improve the scope of their clinical practice. We conducted a review of the importance of conditional probability in diagnostic testing for the eye care practitioner. Eye care practitioners use diagnostic tests on a daily basis to assist in clinical decision making and optimizing patient care and management. These tests provide probabilistic information that can enable the clinician to increase (or decrease) their level of certainty about the presence of a particular condition. While an understanding of the characteristics of diagnostic tests are essential to facilitate proper interpretation of test results and disease risk, many practitioners either confuse or misinterpret these measures. In the interests of their patients, practitioners should be aware of the basic concepts associated with diagnostic testing and the simple mathematical rule that underpins them. Importantly, the practitioner needs to recognize that the prevalence of a disease in the population greatly determines the clinical value of a diagnostic test.
Publisher: Springer Science and Business Media LLC
Date: 09-2021
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.
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.PHARMTHERA.2017.02.026
Abstract: The revolution of induced pluripotent stem cell (iPSC) technology provides a platform for development of cell therapy, disease modeling and drug discovery. Recent technological advances now allow us to reprogram a patient's somatic cells into induced pluripotent stem cells (iPSCs). Together with methods to differentiate these iPSCs into disease-relevant cell types, we are now able to model disease in vitro using iPSCs. Importantly, this represents a robust in vitro platform using patient-specific cells, providing opportunity for personalized precision medicine. Here we provide a review of advances using iPSC for drug development, and discuss the potential and limitations of iPSCs for drug discovery in neurodegenerative and ocular diseases. Emerging technologies that can facilitate the search for new drugs by assessment using in vitro disease models will also be discussed, including organoid differentiation, organ-on-chip, direct reprogramming and humanized animal models.
Publisher: Oxford University Press (OUP)
Date: 25-08-2022
DOI: 10.1093/BIOINFORMATICS/BTAC582
Abstract: Single cell RNA-Sequencing (scRNA-seq) has rapidly gained popularity over the last few years for profiling the transcriptomes of thousands to millions of single cells. This technology is now being used to analyse experiments with complex designs including biological replication. One question that can be asked from single cell experiments, which has been difficult to directly address with bulk RNA-seq data, is whether the cell type proportions are different between two or more experimental conditions. As well as gene expression changes, the relative depletion or enrichment of a particular cell type can be the functional consequence of disease or treatment. However, cell type proportion estimates from scRNA-seq data are variable and statistical methods that can correctly account for different sources of variability are needed to confidently identify statistically significant shifts in cell type composition between experimental conditions. We have developed propeller, a robust and flexible method that leverages biological replication to find statistically significant differences in cell type proportions between groups. Using simulated cell type proportions data, we show that propeller performs well under a variety of scenarios. We applied propeller to test for significant changes in cell type proportions related to human heart development, ageing and COVID-19 disease severity. The propeller method is publicly available in the open source speckle R package (hipsonlab/speckle). All the analysis code for the article is available at the associated analysis website: phipsonlab.github.io ropeller-paper-analysis/. The speckle package, analysis scripts and datasets have been deposited at 0.5281/zenodo.7009042. Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.STEM.2016.04.011
Abstract: Ongoing breakthroughs with CRISPR/Cas-based editing could potentially revolutionize modern medicine, but there are many questions to resolve about the ethical implications for its therapeutic application. We conducted a worldwide online survey of over 12,000 people recruited via social media to gauge attitudes toward this technology and discuss our findings here.
Publisher: Springer International Publishing
Date: 2017
Publisher: Public Library of Science (PLoS)
Date: 13-05-2010
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.
Publisher: American Society for Clinical Investigation
Date: 06-06-2016
DOI: 10.1172/JCI85830
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.
Publisher: American Medical Association (AMA)
Date: 2019
Publisher: Elsevier BV
Date: 2021
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.AJO.2005.08.073
Abstract: To describe the phenotype of an in idual homozygous for the common Gln368STOP myocilin mutation and to discuss the other family members. Cascade screening was performed for Australian families that had been identified as having the myocilin Gln368STOP mutation. Recruited subjects underwent comprehensive clinical examination and mutation analysis for the Gln368STOP myocilin mutation by direct sequencing. One 49-year-old woman was found to be homozygous for the mutation. Her maximal recorded intraocular pressure was 17 mm Hg. Bilateral optic disk examination revealed small, healthy optic discs. Automated perimetry testing was normal. Neither the in idual homozygous for the Gln368STOP myocilin mutation nor her younger heterozygous siblings displayed any signs suggestive of glaucoma. One of the two heterozygous parents did manifest glaucoma. Although there is the possibility of the homozygous in idual developing glaucoma in the future, she does not manifest a phenotype that is more severe than usual.
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.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2019
DOI: 10.1038/S41588-019-0446-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 27-03-2013
Abstract: Recently, several studies have investigated genetic associations between Cytochrome P450 (CYP1B1), Endothelial nitric oxide synthase (eNOS), and Neurotrophin-4 (NTF4) with primary angle-closure glaucoma (PACG) in various ethnic groups. We investigated the association of these candidate genes with PACG in s les from Australia and Nepal. A total of 235 patients with PACG (106 Nepalese and 129 Australian) and 492 controls (204 Nepalese and 288 Australian) was included. Tag single nucleotide polymorphisms (SNPs) were selected to cover the majority of common variation within the candidate genes and genotyped in DNA extracted from peripheral whole blood. Allele and haplotype analyses were conducted in PLINK. Bonferroni correction was applied for the total number of SNPs in this study (P = 0.05/15 = 0.003). In the Australian cohort, one eNOS SNP rs3793342 showed significance association with PACG after Bonferroni correction (P value of 0.003, odds ratio [OR] 0.5, 95% confidence interval [CI] 0.3-0.8). After adjusting the results for sex and age, SNPs rs3793342 and rs7830 showed significance after Bonferroni correction (P value of 0.001 and 0.003, respectively). The eNOS haplotype of all 7 typed SNPs showed significant association with a global P value of 0.019, with the CGCAATC haplotype giving a specific P value of 0.008 and OR of 1.5 (95% CI 0.9-2.4). In the Nepalese cohort, SNPs in CYP1B1 and NTF4 genes showed borderline association with PACG, but did not survive Bonferroni correction. Our data support the involvement of common variations in eNOS with PACG pathogenesis. Differences were observed in the two populations studied, and additional replication studies in other populations are necessary to confirm these associations.
Publisher: BMJ
Date: 27-06-2012
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-04-2022
Abstract: The human immune system displays substantial variation between in iduals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interin idual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interin idual variation in the immune system.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1186/S12886-022-02325-X
Abstract: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus. This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. The mean final BCVA and CMT improved in both the insulin ( N = 137 p 0.001 p 0.001, respectively) and the OHA group ( N = 61 p = 0.199 p 0.001, respectively). The two treatment groups were comparable for final BCVA ( p = 0.263), BCVA change ( p = 0.184), final CMT ( p = 0.741), CMT change ( p = 0.458), and the cumulative injections received ( p = 0.594). The results were comparable between the two groups when stratified by baseline vision ( p 0.05) and baseline HbA1c ( p 0.05). Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.
Publisher: Wiley
Date: 11-2016
DOI: 10.1111/CEO.12837
Publisher: American Society for Clinical Investigation
Date: 06-11-2017
DOI: 10.1172/JCI95545
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Oxford University Press (OUP)
Date: 06-06-2017
DOI: 10.1093/IJE/DYX068
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 06-2007
DOI: 10.1167/IOVS.06-1470
Abstract: Numerous genetic diseases and environmental stimuli affect optic nerve morphology. The purpose of this study was to identify the principal heritable components of visible optic nerve head structures in a population-based s le of twins. Fifteen optic nerve specialists viewed stereoscopic optic nerve head photographs (Stereo Viewer-II Pentax Corp., Tokyo, Japan) from 50 randomly selected monozygotic or dizygotic twin pairs. Before viewing, each expert was questioned about which optic nerve head traits they believed were inherited. After viewing a standardized teaching set, the experts indicated which twin pairs they thought were monozygotic. Participants were then questioned about how their decisions were reached. A rank-ordered Rasch analysis was used to determine the relative weighting and value applied to specific optic nerve head traits. The proportion of twin pairs for which zygosity was correctly identified ranged from 74% to 90% (median, 82%) across the panel. Experts who correctly identified the zygosity in more than 85% of cases placed most weighting on shape and size of the optic disc and cup, whereas experts with the lowest scores placed greater weighting on the optic nerve head vasculature in reaching their decisions. In determining the genetic components of the optic nerve head, the results of this study suggest that the shape and size of the optic disc and cup are more heritable and should receive a greater priority for quantification than should vascular features.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2011
DOI: 10.1038/EYE.2011.83
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.OPHTHA.2019.04.041
Abstract: Obstructive sleep apnea (OSA) is linked to increased glaucoma risk in middle-aged and older adults. However, little is known about associations between OSA and glaucoma-related optic disc parameters in young adults. We explored associations between overnight polysomnography-derived measures of OSA and the optic disc in young adults. Cross-sectional cohort study. Eight hundred forty-eight adults 19 to 22 years of age. Participants underwent an ophthalmic examination that included OCT imaging of the optic disc and measurements of intraocular pressure, axial length, and refractive error. Participants then underwent an overnight polysomnography study that obtained measurements of apnea-hypopnea index (AHI), peripheral oxygen saturation level, and number of cortical arousals from sleep. Based on the AHI results, participants were grouped into no OSA (AHI < 5 events/hour), mild OSA (AHI ≥ 5 and <15 events/hour), moderate OSA (AHI ≥ 15 and <30 events/hour), or severe OSA (AHI ≥ 30 events/hour). Neuroretinal rim area, horizontal and vertical widths, and peripapillary retinal nerve fiber layer (RNFL) thickness. The median AHI result across the study cohort was 2.2 events per hour (interquartile range, 1.0-4.4 events/hour). Based on the AHI results, 178 participants (21.0%) demonstrated OSA: 150 with mild OSA, 26 with moderate OSA, and 2 with severe OSA. In the unadjusted analyses, participants with OSA on average showed thinner peripapillary RNFL at the inferotemporal (P = 0.026) and superotemporal (P = 0.008) segments compared with those without OSA. Additionally, higher AHI results were associated with thinner RNFL superotemporally (P = 0.007). These findings remained significant after adjusting for gender, body mass index, ethnicity, and potential ocular confounders. There were no significant differences in optic disc measures between groups of OSA severity. Obstructive sleep apnea may be associated with preclinical thinning of the peripapillary RNFL in young adults. This suggests that an increased glaucoma risk already may be present in in iduals with OSA since young adulthood. Long-term follow-up of this cohort will allow further optic disc changes in relationship to polysomnography parameters to be documented and associations with future glaucoma diagnosis to be explored.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 05-2014
DOI: 10.1167/TVST.3.3.7
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.
Publisher: BMJ
Date: 09-09-2015
DOI: 10.1136/BJOPHTHALMOL-2014-305498
Abstract: Previous studies have demonstrated a small but significant transient increase in intraocular pressure (IOP) in in iduals wearing certain types of swimming goggles. These findings suggested that wearing goggles could represent a significant risk factor for developing and/or worsening of glaucoma in people who swim regularly. The aim of this study was to determine if glaucoma prevalence is increased among adult swimmers. A comprehensive ocular examination was performed on 231 members of local swimming clubs and 118 non-swimmers. IOP was measured using iCARE tonometry and visual field testing was performed using Humphrey SITA fast 24-2. Retinal nerve fibre layer thickness was assessed using spectral domain optical coherence tomography. Based on measurements of IOP and visual fields, we did not detect any new cases of glaucoma in our cohort of frequent swimmers. Similarly, we found no difference in the thickness of the retinal nerve fibre layer between swimmers and non-swimmers the mean right global thickness (GT) was 94.0 μm (IQR 88.0, 100.3) vs 93.0 μm (IQR 89.0, 101.0), respectively (p=0.976), and the median left GT was 93.7 μm (IQR 88.0, 101) in both groups (p=0.799). These findings suggest that frequently wearing swim goggles does not lead to an increased risk of glaucoma over time in adults.
Publisher: Cold Spring Harbor Laboratory
Date: 28-11-2021
DOI: 10.1101/2021.11.28.470236
Abstract: Single cell RNA Sequencing (scRNA-seq) has rapidly gained popularity over the last few years for profiling the transcriptomes of thousands to millions of single cells. This technology is now being used to analyse experiments with complex designs including biological replication. One question that can be asked from single cell experiments, which has been difficult to directly address with bulk RNA-seq data, is whether the cell type proportions are different between two or more experimental conditions. As well as gene expression changes, the relative depletion or enrichment of a particular cell type can be the functional consequence of disease or treatment. However, cell type proportions estimates from scRNA-seq data are variable and statistical methods that can correctly account for different sources of variability are needed to confidently identify statistically significant shifts in cell type composition between experimental conditions. We have developed propeller , a robust and flexible method that leverages biological replication to find statistically significant differences in cell type proportions between groups. Using simulated cell type proportions data we show that propeller performs well under a variety of scenarios. We applied propeller to test for significant changes in proportions of cell types related to human heart development, ageing and COVID-19 disease severity. The propeller method is publicly available in the open source speckle R package ( hipsonlab/speckle ). All the analysis code for the paper is available at hipsonlab ropeller-paper-analysis/ , and the associated analysis website is available at phipsonlab.github.io ropeller-paper-analysis/ . Alicia Oshlack: Alicia.Oshlack@petermac.org Belinda Phipson: phipson.b@wehi.edu.au Yes.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
DOI: 10.1161/HYPERTENSIONAHA.109.132902
Abstract: Research into the genetic effects and specific genes associated with retinal vascular caliber, a risk marker of cardiovascular diseases, may provide new insights into the genetic contribution of early microvascular disease. A combined 374 monozygotic and 536 dizygotic twin pairs and 322 siblings from the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study underwent complete ophthalmic examinations, including retinal photography, and bilateral retinal vascular caliber was measured. Structural equation modeling was used to estimate the heritability. Genome-wide linkage analysis was conducted on 836 in iduals from 381 Brisbane Adolescent Twin Study families, with adjustments for age, sex, and other covariates. The heritabilities for the retinal arteriolar caliber were 59.4% (95% CI: 53.2% to 64.7%) and 56.5% (95% CI: 50.1% to 61.9%) in the Twins Eye Study in Tasmania and the Brisbane Adolescent Twin Study, respectively, and for venular caliber they were 61.7% (95% CI: 55.6% to 67.0%) and 64.2% (95% CI: 58.7% to 68.8%), respectively, after adjusting for age, sex, and body mass index. Two multipoint peaks detected on chromosomes 3p12.3 and 8p23.1 for retinal arteriolar caliber had suggestive linkage, with the highest multipoint peak logarithm of odds score of 2.24 on chromosome 8p23.1 (genome-wide P =7.0×10 −4 ). Two suggestive logarithm of odds scores for venular caliber were identified on chromosomes 2p14 and 9q21.13. The largest multipoint logarithm of odds score was 2.69 on chromosome 2p14 (genome-wide P =2.0×10 −4 ). In this large twin population, genetic factors appear to play a significant role in the variation of retinal vascular caliber. Several putative loci were identified for the retinal vascular caliber.
Publisher: Asia Pacific Academy of Ophthalmology
Date: 2019
DOI: 10.22608/APO.2018329
Publisher: Springer Science and Business Media LLC
Date: 16-11-2018
DOI: 10.1038/S10038-017-0374-Y
Abstract: Primary open-angle glaucoma (POAG) is influenced by both genetic and environmental factors. Despite significant progress in identifying genetic variants associated with POAG, there remains a substantial amount of unexplained heritability. Study design features that may enhance knowledge of the genetic architecture include focusing on multiple quantitative traits related to ocular disorders (i.e. endophenotypes), targeting genetic variants that directly influence gene expression (i.e. cis-eQTLs) and utilising genetically isolated populations to reduce genetic and environmental noise and thus enhance association signals. In this study we performed heritability and blood-based eQTL association analysis of five key POAG endophenotypes in 330 in iduals from the Norfolk Island (NI) isolate. Results showed evidence of heritability for all five traits, with H
Publisher: Oxford University Press (OUP)
Date: 16-11-2008
DOI: 10.1093/HMG/DDM342
Abstract: Pseudoexfoliation syndrome is a generalized disorder of the extracellular matrix, characterized by the pathological accumulation of abnormal fibrillar material in the anterior segment of the eye predisposing to glaucomatous optic neuropathy. We investigated the role of lysyl oxidase-like 1(LOXL1) sequence variation in a Caucasian Australian population-based cohort of 2508 in iduals, 86 (3.4%) of whom were diagnosed with pseudoexfoliation syndrome. Two non-synonymous variants in exon 1 of LOXL1 (Arg141Leu Gly153Asp) were found to be strongly associated with pseudoexfoliation. Two copies of the high risk haplotype at these single-nucleotide polymorphisms conferred a risk of 7.20 (95%CI: 3.04-20.75) compared with no copies of the high risk haplotype. Each of the disease-associated alleles is by far commoner in the normal population, and examination of cross-species homology reveals that the two disease-associated coding variants belong to the ancestral version of the gene. LOXL1 was found to be expressed by reverse transcription-polymerase chain reaction in all ocular tissues examined except retina. The presence of LOXL1 protein in ocular tissues of interest was demonstrated by western blotting. Specific bands of approximately 130 and 80 kDa, representing polymerized protein forms, were detected in the cornea, iris, ciliary body, lens capsule and optic nerve. The 42 kDa mature form of LOXL1 was detected in the iris and ciliary body. Our Caucasian population has a 9-fold lower lifetime incidence of pseudoexfoliation syndrome compared with Nordic populations despite having similar allelic architecture at the LOXL1 locus. This strongly suggests that as yet unidentified genetic or environmental factors independent of LOXL1 strongly influence the phenotypic expression of the syndrome.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.OPHTHA.2019.03.016
Abstract: To investigate which clinical measures influence whether an in idual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL). Prospective, longitudinal cohort study. Two hundred seventy-one eyes from 207 in iduals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 in iduals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance. In iduals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with in iduals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis. Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL. Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg 95% confidence interval [CI], 2.37-5.43 mmHg P < 0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm 95% CI, 4.38-9.77 μm P < 0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03 95% CI, 1.26-7.28 P = 0.01). Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S13059-019-1852-7
Abstract: A variety of methods have been developed to demultiplex pooled s les in a single cell RNA sequencing (scRNA-seq) experiment which either require hashtag barcodes or s le genotypes prior to pooling. We introduce scSplit which utilizes genetic differences inferred from scRNA-seq data alone to demultiplex pooled s les. scSplit also enables mapping clusters to original s les. Using simulated, merged, and pooled multi-in idual datasets, we show that scSplit prediction is highly concordant with demuxlet predictions and is highly consistent with the known truth in cell-hashing dataset. scSplit is ideally suited to s les without external genotype information and is available at: on-xu/scSplit
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-08-2018
Publisher: Public Library of Science (PLoS)
Date: 06-03-2017
Publisher: Oxford University Press (OUP)
Date: 14-02-2018
DOI: 10.1093/HMG/DDY053
Publisher: Wiley
Date: 04-2001
DOI: 10.1046/J.1442-9071.2001.D01-5.X
Abstract: To assess the visual outcomes and quality of life after cataract surgery in Aborig nal people and compare them with a case-matched population of non-Aborginal people living in remote and rural areas in the Top End of the Northern Territory. Patients living in remote areas of the Top End of the Northern Territory who underwent cataract surgery between 1994 and 1999 were identified from records at the three major hospitals in the region. Eighty-three patients were included in the study. Each patient underwent a complete ocular assessment and then was administered a standardized, field-tested, 12-item questionnaire concerning visual function. This was analyzed and the results of the Aboriginal and matched non-Aboriginal populations compared. Sixty one Aboriginal and 22 non-Aboriginal people from a total of 295 patients who underwent cataract surgery were included in the study. The two study groups were closely matched by sex, age at the time of surgery, time of follow up from surgery and the number who had undergone bilateral surgeryThe median preoperative visual acuity for the Aboriginal group was 6/60 against 6/24 of the non-Aboriginal group. After surgery, at the time of follow up, 26% of eyes in Aboriginal patients did not correct to 6/12 or better with pinhole approximation. Posterior capsule opacities were the most common principal postoperative cause for a deterioration of visual acuity in both groups. Postoperatve trauma was a common cause for a low best-corrected visual acuity n the Aboriginal group but not in the non-Aboriginal group. The majority (75.5%) of Aboriginal patients were satisfied with their operated eyes. Patients who were dissatisfied all had a visual acuity worse than 6/36. Aborigina patients reported worse visual function than did those in the non-Aboriginal group. Cataract surgery has a beneficial effect on the visual acuity and quality of life of Aboriginal and non-Aboriginal people. As compared to their non-Aboriginal counterparts, most Aboriginal people underwent surgery when they were legally blind, had a lower level of attained postoperative visual acuity and a high incidence of uncorrected refractive errors and posterior capsular opacification requiring laser capsulotomy. The positive mpact of cataract surgery on the lives of the majority of Aboriginal patients is highlighted, as is the need for continued postoperative follow up.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 23-09-2019
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 03-03-2023
DOI: 10.1167/IOVS.64.3.11
Publisher: Oxford University Press (OUP)
Date: 04-05-2016
DOI: 10.1093/JLB/LSW018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2014
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 28-06-2016
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.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-2010
DOI: 10.1167/IOVS.09-4786
Publisher: Springer Science and Business Media LLC
Date: 13-12-2022
Publisher: Public Library of Science (PLoS)
Date: 23-09-2014
Publisher: Springer Science and Business Media LLC
Date: 27-02-2018
Publisher: Springer New York
Date: 30-11-2018
DOI: 10.1007/978-1-4939-7522-8_9
Abstract: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) is used by some bacteria and most archaea to protect against viral phage intrusion and has recently been adapted to allow for efficient editing of the mammalian genome. Whilst CRISPR/Cas-based technology has been used to modify genes in mammalian cells in vitro, delivery of CRISPR/Cas system into mammalian tissue and/or organs is more difficult and often requires additional vectors. With the use of adeno-associated virus (AAV) gene delivery system, active CRISPR/Cas enzyme can be maintained for an extended period of time and enable efficient editing of genome in the retina in vivo. Herein we outline the method to edit the genome in mouse retina using a dual AAV vector -mediated CRISPR/Cas9 system.
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.
Publisher: Impact Journals, LLC
Date: 30-05-2017
Publisher: Wiley
Date: 29-10-2012
Publisher: BMJ
Date: 24-02-2009
Abstract: With an ageing population showing an increasing prevalence of glaucoma, there is a pressing demand for continuous intraocular pressure (IOP) measurements which could surpass clinic-based measurements such as routine applanation tonometry. Glaucoma patients have fluctuations in IOP, and it has been proposed that these fluctuations are relevant to glaucoma progression. In addition, interin idual and intrain idual variation in corneal thickness and rigidity can lead to significant and poorly quantitated errors in applanation-based methods of estimating IOP. Microelectrical mechanical systems and complementary metal oxide semiconductor-based technology has enabled the development of smart miniaturised devices by augmenting the computational ability of microelectronics with capabilities of microsensors and microactuators. This review addresses various sensor technologies and both invasive and non-invasive approaches to the measurement of IOP. Advances in wireless communication (telemetry) between the implanted sensors and the external readout device are reviewed. In addition, biocompatibility of implantable sensors is discussed.
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.
Publisher: Wiley
Date: 18-08-2011
DOI: 10.1111/J.1442-9071.2011.02626.X
Abstract: Ophthalmic population-based studies have been used to establish the frequency of eye disease and the associated environmental and genetic factors that cause vision impairment and blindness. Most of these studies have concentrated on the diseases of ageing: cataract, age-related macular degeneration, glaucoma and diabetic retinopathy. Other studies have identified eye diseases in children but few studies of young adult eye disease exist. We conducted a systematic review of the ophthalmic literature to identify potential population-based eye studies and then note the age of participants in the studies. We then summarized the disease specific to young adults to show there is a need for further research to identify eye disease in this important and often-neglected group in the community. Eighty-four large population-based studies have been conducted worldwide: 9 in North America, 2 in South America, 17 in Africa, 35 in Asia, 11 in Australia and the Pacific, 6 in Europe, 4 in the Middle East and 1 that covered 3 continents. No studies specifically examined young adults. Twenty-six per cent of studies included young adults as part of all ages examined but none of these examined a large number of young adults.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2018
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 29-06-2016
Abstract: Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein (Cas) has recently been adapted to enable efficient editing of the mammalian genome, opening novel avenues for therapeutic intervention of inherited diseases. In seeking to disrupt yellow fluorescent protein (YFP) in a Thy1-YFP transgenic mouse, we assessed the feasibility of utilizing the adeno-associated virus 2 (AAV2) to deliver CRISPR/Cas for gene modification of retinal cells in vivo. Single guide RNA (sgRNA) plasmids were designed to target YFP, and after in vitro validation, selected guides were cloned into a dual AAV system. One AAV2 construct was used to deliver Streptococcus pyogenes Cas9 (SpCas9), and the other delivered sgRNA against YFP or LacZ (control) in the presence of mCherry. Five weeks after intravitreal injection, retinal function was determined using electroretinography, and CRISPR/Cas-mediated gene modifications were quantified in retinal flat mounts. Adeno-associated virus 2-mediated in vivo delivery of SpCas9 with sgRNA targeting YFP significantly reduced the number of YFP fluorescent cells of the inner retina of our transgenic mouse model. Overall, we found an 84.0% (95% confidence interval [CI]: 81.8-86.9) reduction of YFP-positive cells in YFP-sgRNA-infected retinal cells compared to eyes treated with LacZ-sgRNA. Electroretinography profiling found no significant alteration in retinal function following AAV2-mediated delivery of CRISPR/Cas components compared to contralateral untreated eyes. Thy1-YFP transgenic mice were used as a rapid quantifiable means to assess the efficacy of CRISPR/Cas-based retinal gene modification in vivo. We demonstrate that genomic modification of cells in the adult retina can be readily achieved by viral-mediated delivery of CRISPR/Cas.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.OPHTHA.2010.09.002
Abstract: Optic nerve morphology is affected by genetic and acquired disease. Glaucoma is the most common optic neuropathy autosomal-dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON) are the most prevalent hereditary optic neuropathies. These 3 entities can exhibit similar topographical changes at the optic nerve head. Both ADOA and LHON have been reported to be misdiagnosed as glaucoma. Our aim was to determine whether glaucoma subspecialists and neuro-ophthalmologists can distinguish these diagnoses on optic disc assessment alone. Observational study. Twenty-three optic nerve experts. We randomized and masked 60 high-resolution stereoscopic optic disc photographs (15 ADOA images, 15 LHON, 15 glaucoma, and 15 normal controls). Experts were asked to assess the discs on 12 conventional topographic features and assign a presumptive diagnosis. Intra- and interanalysis was performed using the index of qualitative variation and absolute deviation. Can glaucoma specialists and neuro-ophthalmologists distinguish among the disease entities by optic nerve head phenotype. The correct diagnosis was identified in 85%, 75%, 27%, and 16% of the normal, glaucoma, ADOA, and LHON disc groups, respectively. The proportion of correct diagnoses within the ADOA and LHON groups was significantly lower than both normal and glaucomatous (P<0.001). Where glaucoma was chosen as the most likely diagnosis, 61% were glaucomatous, 34% were pathologic but nonglaucomatous discs, and 5% were normal. There was greater agreement for in idual parameters assessed within the normal disc set when compared with pathologic discs (P<0.05). The only parameter to have a significantly greater agreement within the glaucomatous disc set when compared with ADOA or LHON disc sets was pallor, whereby experts agreed on is absence in the glaucomatous discs but were not in agreement on its presence or its absence in the ADOA and LHON discs (P<0.01). Optic neuropathies can result in similar topographic changes at the optic disc, particularly in late-stage disease, making it difficult to differentiate ADOA and LHON from glaucoma based on disc assessment alone. Other clinical parameters such as acuity, color vision, history of visual loss, and family history are required to make an accurate diagnosis.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Cold Spring Harbor Laboratory
Date: 02-02-2023
DOI: 10.1101/2023.02.01.526555
Abstract: The exact pathogenesis of primary open-angle glaucoma (POAG) is poorly understood. Genome-wide association studies (GWAS) have recently uncovered many loci associated with variation in intraocular pressure (IOP) a crucial risk factor for POAG. Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs), the regulatory cells of IOP. Sixty-two genes at fifty-five loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a five-channel fluorescent cell staining protocol. A convolutional neural network (CNN) was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations. Cells where RALGPS1 had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, SD 0.030), followed by LTBP2 (AUC 0.846, SD 0.029) and BCAS3 (AUC 0.845, SD 0.020). Of seven multi-gene loci, five had statistically significant differences in AUC (p .05) between genes, allowing for pathological gene prioritisation. The mitochondrial channel most frequently showed the greatest degree of morphological variation (33.9% of cell lines). We demonstrate a robust method for functionally interrogating genome-wide association signals using high-throughput microscopy and AI. Genetic variations inducing marked morphological variation can be readily identified, allowing for the gene-based dissection of loci associated with complex traits.
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.
Publisher: Cold Spring Harbor Laboratory
Date: 14-11-2019
DOI: 10.1101/842328
Abstract: Human pluripotent stem cell (hPSC)-derived progenies are immature versions of cells, presenting a potential limitation to the accurate modelling of disease associated with maturity or age. Hence, it is important to characterise how closely cells used in culture resemble their native counterparts. In order to select appropriate points in time for RPE cultures to reflect native counterparts, we characterised the transcriptomic profiles of hPSC-derived retinal pigment epithelium (RPE) cells from 1- and 12-month cultures. We differentiated the human embryonic stem cell line H9 into RPE cells, performed single cell RNA-sequencing of a total of 16,576 cells, and analysed the resulting data to assess the molecular changes of RPE cells across these two culture time points. Our results indicate the stability of the RPE transcriptomic signature, with no evidence of an epithelial – mesenchymal transition, and with maturing populations of RPE observed with time in culture. Assessment of gene ontology pathways revealed that as cultures age, RPE cells upregulate expression of genes involved in metal binding and antioxidant functions. This might reflect an increased ability to handle oxidative stress as cells mature. Comparison with native human RPE data confirmed a maturing transcriptional profile of RPE cells in culture. These results suggest that in vitro long-term culture of RPE cells allow the modelling of specific phenotypes observed in native mature tissue. Our work highlights the transcriptional landscape of hPSC-derived RPE as they age in culture, which provides a reference for native and patient-s les to be benchmarked against.
Publisher: Wiley
Date: 27-04-2015
DOI: 10.1111/CEO.12508
Abstract: The sequencing of the human genome has seen the emergence of the direct-to-consumer (DTC) genetic-testing market, which allows in iduals to obtain information about their genetic profile and its many health and lifestyle implications. Genetics play an important role in the development of many eye diseases, however, little information is available describing the influence of the DTC industry in ophthalmology. In this review, we examined DTC companies providing genetic test products for eye disease. Of all eye conditions, the majority of DTC companies provided susceptibility testing or risk assessment for age-related macular degeneration (AMD). For the 15 companies noted to offer products, we found considerable variation in the cost, scope and clarity of informational content of DTC genetic testing for ophthalmic conditions. The clinical utility of these tests remains in question, and the American Academy of Ophthalmology recommendations against routine testing for many conditions probably still apply.
Publisher: Cold Spring Harbor Laboratory
Date: 22-12-2020
DOI: 10.1101/2020.12.21.20248288
Abstract: The COVID-19 pandemic caused by SARS-CoV-2 has infected millions worldwide and there is an urgent need to increase our diagnostic capacity to identify infected cases. Although RT-qPCR remains the gold standard for SARS-CoV-2 detection, this method requires specialised equipment in a diagnostic laboratory and has a long turn-around time to process the s les. To address this, several groups have recently reported development of loop-mediated isothermal lification (LAMP) as a simple, low cost and rapid method for SARS-CoV-2 detection. Herein we present a comparative analysis of three LAMP-based assays that target different regions of the SARS-CoV-2: ORF1ab RdRP, ORF1ab nsp3 and Gene N. We perform a detailed assessment of their sensitivity, kinetics and false positive rates for SARS-CoV-2 diagnostics in LAMP or RT-LAMP reactions, using colorimetric or fluorescent detection. Our results independently validate that all three assays can detect SARS-CoV-2 in 30 minutes, with robust accuracy at detecting as little as 1000 RNA copies and the results can be visualised simply by color changes. We also note the shortcomings of these LAMP-based assays, including variable results with shorter reaction time or lower load of SARS-CoV-2, and false positive results in some experimental conditions. Overall for RT-LAMP detection, the ORF1ab RdRP and ORF1ab nsp3 assays have higher sensitivity and faster kinetics for detection, whereas the Gene N assay exhibits no false positives in 30 minutes reaction time. This study provides validation of the performance of LAMP-based assays for SARS-CoV-2 detection, which have important implications in development of point-of-care diagnostic for SARS-CoV-2.
Publisher: Public Library of Science (PLoS)
Date: 10-08-2011
Publisher: Impact Journals, LLC
Date: 29-04-2017
Publisher: Cold Spring Harbor Laboratory
Date: 12-2020
DOI: 10.1101/2020.11.30.405654
Abstract: Apolipoprotein E (APOE) is the most important susceptibility gene for late onset of Alzheimer’s disease, with the presence of APOE-ε4 associated with increased risk of developing Alzheimer’s disease. Here, we reprogrammed human fibroblasts from in iduals with different APOE-ε genotypes into induced pluripotent stem cells, and generated isogenic lines with different APOE profiles. We then differentiated these into cerebral organoids for six months and assessed the suitability of this in vitro system to measure APOE, β amyloid, and Tau phosphorylation levels. We identified intra- and inter-variabilities in the organoids’ cell composition. Using the CRISPR-edited APOE isogenic lines, we observed more homogenous cerebral organoids, and similar levels of APOE, β amyloid, and Tau between the isogenic lines, with the exception of one site of Tau phosphorylation which was higher in the APOE-ε4/ε4 organoids. These data describe that pathological hallmarks of AD are observed in cerebral organoids, and that their variation is mainly independent of the APOE-ε status of the cells, but associated with the high variability of cerebral organoid differentiation. It demonstrates that the batch-to-batch and cell-line-to-cell-line variabilities need to be considered when using cerebral organoids.
Publisher: American Medical Association (AMA)
Date: 02-2020
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Wiley
Date: 13-02-2020
DOI: 10.1111/CEO.13724
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
DOI: 10.1016/J.JCRS.2013.07.055
Abstract: To compare the monochromatic aberrations in a large cohort of 20-year-old Australians with differing levels of visual acuity and explore the relationship between these aberrations and refractive error. Lions Eye Institute, Perth, Western Australia, Australia. Cross-sectional analysis of a population-based cohort. Monochromatic aberrations were measured using a Zywave II wavefront aberrometer with natural pupils in a dark room. The logMAR corrected distance visual acuity (CDVA) was measured monocularly under normal illumination. Cycloplegic autorefraction was also performed. The study enrolled 2039 eyes of 1040 participants. Data from 1007 right eyes were analyzed. The median CDVA and spherical equivalent were -0.06 logMAR (interquartile range [IQR], -0.10 to 0.00) and +0.25 diopters (D) (IQR, -0.38 to 0.63), respectively. The median 6.0 mm higher-order aberration (HOA) was 0.58 μm (IQR, 0.44 to 0.79). Coma-like aberrations and 3rd-, 4th-, and 5th-order HOAs were significantly different between subjects with a CDVA of -0.10 logMAR or better and those with a CDVA worse than -0.10 logMAR. Fourth-order aberrations Z(4,-4) (P=.024) and Z(4,-2) (P=.029) and 2nd-order aberration Z(2,0) (P<.001) differed significantly between myopic eyes, emmetropic eyes, and hyperopic eyes. Subjects with higher myopia had slightly higher total HOAs. The HOAs in this population were marginally higher than previously reported values. The findings confirm there is a difference in monochromatic aberrations between different vision and refractive groups. Results in this study will benefit decision-making processes in the clinical setting.
Publisher: Wiley
Date: 26-10-2016
DOI: 10.1002/GEPI.21936
Publisher: American Chemical Society (ACS)
Date: 11-10-2022
DOI: 10.1021/ACSSYNBIO.2C00460
Abstract: Directed evolution uses cycles of gene ersification and selection to generate proteins with novel properties. While traditionally directed evolution is performed in prokaryotic systems, recently a mammalian directed evolution system (viral evolution of genetically actuating sequences, or "VEGAS") has been described. Here we report that the VEGAS system has major limitations that preclude its use for directed evolution. The deconstructed Sindbis virus (SINV) genome that comprises the VEGAS system could no longer promote Sindbis structural gene (SSG)-dependent viral replication. Moreover, viral particles generated using the VEGAS system rapidly lost the target directed evolution transgene, and instead, "cheater" particles, primarily containing RNA encoding SINV structural components, arose. By sequencing, we found that this contamination came from RNA provided during initial SINV packaging, not RNA derived from the VEGAS system. Of note, both the structural RNA and target transgenes used in the VEGAS system contain viral packaging sequences. The impact of SINV "cheater" particles could be potentially overcome in the context of a robust VEGAS circuit, but since SSG complementation is also defective in the VEGAS system, selection for authentic evolution products is not currently possible. Similar results have been obtained in independent laboratories. Taken together, these results show that the VEGAS system does not work as described and, without significant redesign, cannot be used for mammalian directed evolution c aigns.
Publisher: Springer Science and Business Media LLC
Date: 05-09-2008
DOI: 10.1007/S00439-008-0555-Z
Abstract: Keratoconus is a debilitating ocular disease characterised by progressive asymmetrical thinning of the cornea, the clear covering at the front of the eye. The resulting protrusion of the cornea results in severe refractive error, in the most severe cases requiring corneal grafting. It is a complex disease with a genetic component. Despite several reports of linked loci, major gene identification has been elusive. A genome-wide linkage scan in a large Australian pedigree with apparent autosomal dominant keratoconus was conducted using the Affymetrix 10K SNP chip and two regions of linkage identified. Functional candidate genes from within both linkage peaks were assessed for corneal expression and screened for mutations in affected family members. Equal evidence of linkage was detected to both 1p36.23-36.21 and 8q13.1-q21.11 with LOD scores of 1.9. Analysis of both loci concurrently suggests digenic linkage with two-locus LOD score of 3.4. All affected in iduals carry identical haplotypes at both loci. Carriers of either linked haplotype without the other do not have keratoconus. No mutations were identified in the following candidate genes expressed in the cornea: ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 or TCEB1. Although the pedigree appears to demonstrate simple autosomal dominant inheritance, the disorder is actually genetically complex. This pedigree may provide a link between inherited forms of keratoconus and sporadic cases.
Publisher: Elsevier BV
Date: 2018
DOI: 10.2139/SSRN.3188388
Publisher: Cold Spring Harbor Laboratory
Date: 05-01-2018
DOI: 10.1101/243683
Abstract: Safe delivery of CRISPR/Cas endonucleases remains one of the major barriers to the widespread application of in vivo genome editing including the anticipatory treatment of monogenic retinal diseases. We previously reported the utility of adeno-associated virus (AAV)-mediated CRISPR/Cas genome editing in the retina however, with this type of viral delivery system, active endonucleases will remain in the retina for an extended period, making genotoxicity a significant consideration in clinical applications. To address this issue, we have designed a self-destructing “kamikaze” CRISPR/Cas system that disrupts the Cas enzyme itself following expression. Four guide RNAs (sgRNAs) were designed to target Streptococcus pyogenes Cas9 (SpCas9), after in situ validation, the selected sgRNAs were cloned into a dual AAV vector. One construct was used to deliver SpCas9 and the other delivered sgRNAs directed against SpCas9 and the target locus (yellow fluorescent protein, YFP), in the presence of mCherry. Both constructs were packaged into AAV2 vector and intravitreally administered in C57BL/6 and Thy1-YFP transgenic mice. After 8 weeks the expression of SpCas9, the efficacy of YFP gene disruption was quantified. A reduction of SpCas9 mRNA was found in retinas treated with AAV2-mediated-YFP/SpCas9 targeting CRISPR/Cas compared to those treated with YFP targeting CRISPR/Cas alone. We also show that AAV2-mediated delivery of YFP/SpCas9 targeting CRISPR/Cas significantly reduced the number of YFP fluorescent cells among mCherry-expressing cells (~85.5% reduction compared to LacZ/SpCas9 targeting CRISPR/Cas) in transfected retina of Thy1-YFP transgenic mice. In conclusion, our data suggest that a self-destructive “kamikaze” CRISPR/Cas system can be used as a robust tool for refined genome editing in the retina, without compromising on-target efficiency.
Publisher: Frontiers Media SA
Date: 30-11-2018
Publisher: Springer Science and Business Media LLC
Date: 27-12-2022
DOI: 10.1186/S13059-022-02837-1
Abstract: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis ( N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2016
DOI: 10.1007/S10561-016-9563-8
Abstract: The ability to generate human induced pluripotent stem cells (iPSCs) has opened new avenues for human disease modelling and therapy. The aim of our study was to determine research participants' understanding of the information given when donating skin biopsies for the generation of patient-specific iPSCs. A customised 35-item questionnaire based on previous iPSC consent guidelines was sent to participants who had previously donated s les for iPSC research. The questionnaire asked pertinent demographic details, participants' motivation to take part in iPSC research and their attitudes towards related ethical issues. 234 participants were contacted with 141 (60.3 %) complete responses received. The median duration between recruitment and follow-up questioning was 313 days (range 10-573 days). The majority of participants (n = 129, 91.5 %) believed they understood what a stem cell was however, only 22 (16.1 %) correctly answered questions related to basic stem cell properties. We found no statistically significant difference in responses from participants with different levels of education, or those with a health sciences background. The poor understanding amongst participants of iPSC research is unlikely to be unique to our study and may impact future research if not improved. As such, there is a need to develop an easily understood yet comprehensive consent process to ensure ongoing ethical progress of iPSC biobanking.
Publisher: Wiley
Date: 16-03-2011
DOI: 10.1111/J.1442-9071.2010.02487.X
Abstract: Eye colour or, more accurately, iris colour is one of the most obvious physical characteristics of a person. European parents frequently ask the colour of their newborn's eyes, only to see the iris change dramatically during their child's first year of life. Genetic and epidemiological findings have uncovered further details about the basis for iris colour, which may have important implications for further research and treatment of some eye diseases and ocular characteristics. Surprisingly there is no widely recognized classification system for eye colour. An added difficulty when trying to devise an international system is that subtle differences in colour description exist between languages (e.g. hazel vs. auburn). We reviewed the recent and very early literature pertaining to eye colour classification. Recent genetic investigations of eye colour have tended to either use simple (three-category grading systems) or more complex digital colour grading. We present a nine-category grading system. Categories in this novel schema include: (i) light blue (ii) darker blue (iii) blue with brown peripupillary ring (iv) green (v) green with brown iris ring (vi) peripheral green central brown (vii) brown with some peripheral green (viii) brown and (ix) dark brown. Although different observers may categorize a person's eye colour differently, it is generally only by an adjacent category. We also describe a continuum of iris pigmentation from a small ring of brown around the pupil to almost complete brown with small peripheral flecks. Digital publishing and assessment of iris colour will result in more standardized classification of iris colour and investigation of its role in eye disease.
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.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 11-2010
DOI: 10.1167/IOVS.10-5527
Publisher: Informa UK Limited
Date: 10-01-2013
DOI: 10.3109/13816810.2012.755632
Abstract: The Raine Eye Health Study (REHS) was conceived to determine the prevalence of and risk factors for eye disease in young adults, and to characterize ocular biometric parameters in a young adult cohort. This article summarizes the rationale and study design of REHS and outlines the baseline prevalence of ophthalmic disease in this population. The Western Australian Pregnancy Cohort (Raine) Study originated as a randomized-controlled trial of 2900 women recruited from the state's largest maternity hospital. Their offspring (N = 2868) have been followed at birth, ages 1, 2, 3, 5, 8, 10, 14, 17 and 20 years of age in a prospective cohort study. DNA has been collected from participants for genome-wide association studies. At the 20-year follow-up participants completed a comprehensive eye assessment that included visual acuity, orthoptic assessment and cycloplegic autorefraction, as well as several ocular biometric variables and multiple ophthalmic photographs of the anterior and posterior segments. A total of 1344 participants (51.3% male) were assessed over a 24-month period. For the majority of examined participants (85.5%) both parents were Caucasian, 63.3% had completed school year 12 or equivalent, 5.5% had myopia (spherical equivalent ≤-3 diopters) and 15 participants (1.2%) had unilateral or bilateral pterygia. Keratoconus, cataract, keratitis and uveitis were rare. The REHS design and methodology allow comparison with other population-based studies of eye disease. The study established the prevalence of eye disorders in a large s le of predominantly Caucasian young Australian adults.
Publisher: Wiley
Date: 13-01-2015
DOI: 10.1111/AOS.12644
Abstract: Astigmatism is a common cause of refractive error and is known to vary in prevalence with age. Although the search for genes associated with spherical refractive errors (especially myopia) has met with limited success, current efforts to identify genetic variants implicated in astigmatism development have been less rewarding. We aimed to assess the association between astigmatism and age to identify appropriate age cut‐offs for maximizing power in genetic studies of astigmatism. We performed a cross‐sectional analysis of right eye astigmatism data from four Australian‐based eye studies comprising 3841 participants aged 5–90 years. Measurements were performed under cycloplegia using an autorefractor, and in iduals with a history of cataract, refractive surgery or corneal pathology were excluded from the analysis. In addition to the magnitude and type (against‐the‐rule, with‐the‐rule, and oblique) of astigmatism, we calculated the vector components (J 0 , J 45 ) and evaluated the association of these outcome measures with age. The magnitude of refractive astigmatism ( RA ) remained relatively stable [mean ± SD (−0.44 D ± 0.50)] until in iduals reached the age of 50, thereafter increasing in average magnitude by approximately 1.00 D for those subjects aged 90. In contrast, corneal astigmatism ( CA ) remained relatively stable from childhood until the age of 80 (−0.76 D ± 0.61). The prevalence of clinically significant RA (≥1.00 D) increased with age and was highest in those aged years [55.1% (47.2–62.7%)]. Age was significantly associated with RA in adults [odds ratio ( OR ) = 1.04 per 1 year, p 0.001]. A weaker relationship was observed between CA and age ( OR = 1.007 per 1 year, p = 0.02). We have confirmed the previously documented association between RA and age. Our results indicate that most of the observed change occurs after the age of 50, providing a recommended cut‐off for participants in genetic studies of this refractive condition.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2018
DOI: 10.1101/297077
Abstract: Congenital glaucoma is a significant cause of irreversible blindness. In some instances glaucoma is associated with developmental abnormalities of the ocular anterior segment, which can impair drainage of aqueous humor, leading to an increase in intraocular pressure. Genome sequencing was performed on a parent-proband congenital glaucoma trio, with exome sequencing of 79 additional in iduals with suspected primary congenital glaucoma. We describe a unique ocular anterior segment dysgenesis associated with congenital glaucoma in four in iduals from three unrelated families. In each case, disease was associated with compound heterozygous variants in CPAMD8 , a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation of key drainage structures and the development of high intraocular pressure and glaucoma. This study reveals a unique genetic cause of childhood glaucoma, and expands the phenotypic spectrum of CPAMD8 -associated ocular disease.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.SURVOPHTHAL.2010.07.003
Abstract: Heritability is the proportion of phenotypic variation in a population that is attributable to genetic variation among in iduals. Many ophthalmic disorders and biometric traits are known to have a genetic basis and consequently much work has been published in the literature estimating the heritability of various ocular parameters. We collated and summarized the findings of heritability studies conducted in the field of ophthalmology. We grouped the various studies broadly by phenotype as follows: refraction, primary open-angle glaucoma, age-related macular degeneration (AMD), cataract, diabetic retinopathy, and others. A total of 82 articles were retrieved from the literature relating to estimation of heritability for an ocular disease or biometric trait of these, 37 papers were concerned with glaucoma, 28 with refraction, 4 with AMD, 5 with diabetic retinopathy, and 4 with cataract. The highest reported heritability for an ophthalmic trait is 0.99 for the phenotype ≥ 20 small hard drusen, indicating that observed variation in this parameter is largely governed by genetic factors. Over 60% of the studies employed a twin study design and a similar percentage utilized variance components methods and structural equation modeling (SEM) to derive their heritability values. Using modern SEM techniques, heritability estimates derived from twin subjects were generally higher than those from family data. Many of the estimates are in the moderate to high range, but to date the majority of genetic variants accounting for these findings have not been uncovered, hence much work remains to be undertaken to elucidate fully their molecular etiology.
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2022
DOI: 10.1101/2022.04.28.489465
Abstract: CLN3 disease is a lysosomal storage disorder associated with fatal neurodegeneration that is caused by mutations in CLN3 . Most in iduals with CLN3 disease carry at least one allele with a 966 bp deletion in CLN3 which results in the deletion of exons 7 and 8. There is a need for more physiologically relevant human cell-based CLN3 disease models to better understand the cellular changes during the disease process. Using CRISPR/Cas9, we corrected the 966 bp deletion mutation in human induced pluripotent stem cells (iPSCs) of a compound heterozygous patient ( CLN3 Δ 966 bp and E295K). The isogenic deletion-corrected and unedited CLN3 patient iPSCs were used for disease modeling. iPSC-derived neurons carrying this particular CLN3 mutation (CLN3 neurons) had lower functional activity as recorded using microelectrode arrays for most of the culture period. Proteomics analysis showed downregulation of proteins related to axon guidance and endocytosis at day in vitro (DIV) 14 and 42 in CLN3 neurons. This was accompanied by an increase in lysosomal-related proteins in CLN3 neurons. Western blot analysis revealed hyperglycosylation of the lysosomal marker, Lysosome Associated Membrane Protein 1 (LAMP1) in CLN3 neurons at DIV 14, 28 and 42, which was not apparent in control neurons. Ultrastructural analysis of CLN3 neurons showed numerous membrane-bound vacuoles containing erse types of storage material, ranging from curvilinear deposits, multilamellar structures to osmiophilic deposits. Our findings suggest alterations in lysosomal function and neurodevelopment involving axon guidance and synaptic transmission in CLN3-deficient neuronal derivatives, which could be potential targets for therapy.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.OPHTHA.2012.11.029
Abstract: To determine the proportion of all Myocilin coding mutations responsible for advanced primary open-angle glaucoma (POAG) in early-age-at-onset in iduals and to investigate the prevalence of exon 3 Myocilin mutations in advanced POAG at any age at onset in a large Australasian cohort. Cross-sectional study using a national disease registry. One thousand sixty in iduals with advanced POAG (103 with age at onset of 40 years or younger) and 320 with nonadvanced POAG all recruited by the Australian and New Zealand Registry of Advanced Glaucoma. Participants were examined and referred by their eye practitioner, and Myocilin genetic testing was performed by direct sequencing. Cascade genetic testing was made available for relatives of participants found to carry a Myocilin mutation. Advanced glaucoma diagnosis based on strict visual field entry criteria. Prevalence and spectrum of Myocilin mutations in in iduals with advanced and nonadvanced POAG. This is the first study to report Myocilin mutations in an advanced POAG cohort. No pathogenic Myocilin mutations were identified in exons 1 and 2 in early-age-at-onset advanced POAG cases. Exon 3 Myocilin mutations were identified in 45 advanced POAG patients (4.2%), which is significantly higher (P = 0.02) compared with nonadvanced POAG patients (1.6%). A novel mutation (Trp373X) and a new variant of uncertain pathogenicity (Ala447Thr) also were reported. The prevalence of Myocilin mutations rose from 16% to 40% in selected advanced POAG subgroups based on different thresholds of maximum recorded intraocular pressure, age at diagnosis, and the presence and strength of positive family history. Twenty-six in iduals with Myocilin mutations were identified through cascade genetic testing of first-degree relatives of affected mutation carriers. The prevalence of Myocilin mutations in glaucoma cases with severe visual field loss is significantly greater than in nonadvanced glaucoma patients. Myocilin screening in phenotypically selected cases can have a much higher yield than in previous unselected series. Identifying in iduals who have Myocilin mutations provides an opportunity to screen at-risk clinically unaffected relatives and to reduce glaucoma blindness through early management and intervention. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Publisher: Oxford University Press (OUP)
Date: 11-02-2014
DOI: 10.1093/HMG/DDU050
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 04-2008
DOI: 10.1167/IOVS.07-1397
Abstract: To estimate the heritability of the iridotrabecular angle width measured by anterior segment optical coherence tomography (ASOCT) in a classic twin study. Twins aged 8 to 16 years were identified from the Guangzhou Twin Registry. ASOCT was used to obtain one horizontal scan, and the images were analyzed with custom software. Angle width was represented by the angle opening distance (AOD) at the 500-microm anterior-to-scleral spur, as well as the angle recess area (ARA) and trabecular-iris space area (TISA) located 750 microm anterior to the scleral spur. Zygosity was confirmed by genotyping with 16 polymorphic markers in all same-sex twin pairs. Heritability was assessed by structural variance component genetic modeling after adjustment for age and sex, with the Mx program. The mean age of the participants was 11.7 +/- 2.6 years in 305 monozygotic (MZ) and 11.8 +/- 2.4 years in 157 dizygotic (DZ) pairs. The intraclass correlation coefficients for the AOD, ARA, and TISA were 0.70, 0.75, and 0.72 in the MZ pairs and 0.34, 0.32, and 0.33 in the DZ pairs, respectively. A model with additive genetic (69.7% 95% CI: 63.9%-74.6%) and unique environmental effects (30.3% 95% CI: 25.4%-36.1%) was the most parsimonious for AOD. Similar results were identified for ARA and TISA. The variance in drainage angle width in Chinese children appears to be largely attributable to genetic effects, with a heritability of approximately 70%.
Publisher: Wiley
Date: 19-08-2021
DOI: 10.1111/CEO.13980
Abstract: The prevalence of myopia is increasing globally including in Europe and parts of Asia but Australian data are lacking. This study aim described the change in myopia prevalence in middle‐aged Australian adults over approximately a 20‐year period. Two contemporary Western Australian studies (conducted in mid‐late 2010s): the coastal‐regional Busselton Healthy Ageing Study (BHAS) and the urban Gen1 of the Raine Study (G1RS) were compared to two earlier studies (early‐mid 1990s) in Australia: the urban Blue Mountains Eye Study (BMES) and urban/regional Melbourne Visual Impairment Project (MVIP). Refractive error was measured by autorefraction, vertometry, or subjective refraction. Participants (49–70 years) of European descent without self‐reported/diagnosed cataract, corneal disease, or refractive or corneal surgery were included. After exclusions, data were available from 2217, 1760, 700, 2987 and 756 participants from BMES, urban MVIP, regional MVIP, BHAS, and G1RS, respectively. The mean age ranged from 57.1 ± 4.6 years in the G1RS to 60.1 ± 6.0 years in the BMES 44–48% of participants were male. When stratified by location, the contemporary urban G1RS cohort had a higher age‐standardised myopia prevalence than the urban MVIP and BMES cohorts (29.2%, 16.4%, and 23.9%, p 0.001). The contemporary coastal‐regional BHAS had a higher age‐standardised myopia prevalence than the regional MVIP cohort (19.4% vs. 13.8%, p = 0.001). We report an increase in myopia prevalence in older adults in Australia born after World War ll compared to cohorts born before, accounting for urban/regional location. The prevalence of myopia remains relatively low in middle‐aged Australian adults.
Publisher: Elsevier BV
Date: 03-2019
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.
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.
Publisher: Wiley
Date: 26-10-2020
DOI: 10.1111/CEO.13866
Publisher: Springer Science and Business Media LLC
Date: 02-2017
DOI: 10.1038/NATURE21039
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.
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.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 24-05-2013
Publisher: Springer Science and Business Media LLC
Date: 03-01-2021
Publisher: Springer Science and Business Media LLC
Date: 05-08-2016
DOI: 10.1007/S00417-016-3434-7
Abstract: Giant cell arteritis (GCA) is a systemic granulomatous vasculitis, primarily affecting medium-large arteries. It has a predilection for the aorta and its major branches, including the carotid and vertebral arteries. Ophthalmic artery involvement frequently leads to irreversible visual loss, and therefore GCA is one of the few true ophthalmic emergencies. GCA, although classified as a large vessel vasculitis, is known to affect smaller-sized vessels, resulting in a multiplicity of signs in the eye, some of which are often missed. We set out to highlight some of the less frequently observed clinical signs, which may provide clues to clinically diagnosing GCA in patients presenting with non-classical features and inconclusive inflammatory markers. We review the literature and describe the erse ocular features and some of the systemic findings that can be associated with GCA. Although the most common ocular manifestation of GCA is anterior ischaemic optic neuropathy, the clinical presentation of GCA can vary dramatically. In the absence of obvious ocular involvement, more subtle ophthalmic signs of anterior segment ischaemia, such as hypotony and anisocoria, may be present at the time of initial clinical examination. There are no specific biomarkers for disease to date therefore, pertinent history and clinical examination can guide towards diagnosis in the acute setting. The diagnostic process is not always straightforward, yet appropriate and prompt diagnosis is critical to enable timely intervention and prevent significant morbidity.
Publisher: Springer Science and Business Media LLC
Date: 08-05-2018
Publisher: Public Library of Science (PLoS)
Date: 03-05-2012
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.OPHTHA.2016.11.011
Abstract: To assess the difference in severity of disease in primary open-angle glaucoma (POAG) patients with a Myocilin (MYOC) disease-causing variant who presented through normal clinical pathways (Clinical cases) versus those who were examined following genetic testing (Genetic cases). Retrospective clinical and molecular study. Seventy-three MYOC mutation carriers identified through the Australian and New Zealand Registry of Advanced Glaucoma. In iduals were classified based on how they first presented to an ophthalmologist: Clinical cases were referred by their general practitioner or optometrist, and Genetic cases were referred following positive results from genetic testing for the previously identified familial MYOC variant (cascade genetic testing). All cases were then sub-classified into 4 groups (unaffected, glaucoma suspect, glaucoma, advanced glaucoma) according to the severity of disease at the time of their first examination by an ophthalmologist. Glaucoma clinical parameters and age at presentation. At their first examination, 83% of Genetic cases were unaffected and 17% were glaucoma suspect, whereas among Clinical cases 44% were glaucoma suspect, 28% had glaucoma, and 28% had advanced glaucoma. Genetic cases were significantly younger at presentation than Clinical cases (40.6±12.5 vs. 47.5±16.7 years P = 0.018). The mean highest intraocular pressure (32.2±9.7 vs. 17.6±3.6 mmHg P < 0.001), cup-to-disc ratio (0.65±0.27 vs. 0.48±0.13 P = 0.006), and mean deviation on visual field testing (-10.0±10.3 vs. -1.2±1.2 P < 0.001) were all significantly worse in Clinical cases compared with Genetic cases. In iduals with common MYOC p.Gln368Ter variant were further analyzed separately to account for the phenotypic variability of different disease-causing variants. All findings remained significant after adjusting for the common MYOC p.Gln368Ter variant. Our findings demonstrated that MYOC cascade genetic testing for POAG allows identification of at-risk in iduals at an early stage or even before signs of glaucoma are present. To our knowledge, this is the first study to demonstrate the clinical utility of predictive genetic testing for MYOC glaucoma.
Publisher: Informa UK Limited
Date: 2008
DOI: 10.1080/13816810802334341
Abstract: In recent years, noteworthy gains have been made in unravelling the genetic contribution to some complex ocular diseases, principally age-related macular degeneration. Yet, a relatively poor understanding of the genetic aetiology for many other heritable blinding diseases, such as glaucoma, keratoconus and myopia, remains. Genetic isolates, populations with varying degrees of geographical or cultural seclusion, provide an effective means for investigating the molecular mechanisms involved in human diseases. This is particularly true for rare diseases in which founded alleles can be rapidly driven to a high frequency due to restriction of gene flow in the population. Recent success in complex gene mapping has resulted from the widened linkage disequilibrium (LD) in the genome of genetically isolated populations. An improved understanding of the predisposing genetic risk factors allows for enhanced screening modalities and paves the foundations for the translation of genomic technology into the clinic. This review focuses on the role population isolates have had in the investigation of genes underlying complex eye diseases and discusses their likely usefulness given the expansion of large-scale case-control association studies.
Publisher: Wiley
Date: 19-06-2015
DOI: 10.1111/CEO.12541
Abstract: X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Clinical and molecular characterization of male and female in iduals affected with XLRS in a consanguineous family. Consanguineous Eastern European-Australian family Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed in iduals analysed. The two females were homozygous for the variant, and the males were hemizygous. Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans.
Publisher: Optica Publishing Group
Date: 14-05-2010
DOI: 10.1364/OE.18.011347
Publisher: American Medical Association (AMA)
Date: 08-2014
DOI: 10.1001/JAMAOPHTHALMOL.2014.946
Abstract: Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. To perform a clinical and genetic investigation of a large white family with autosomal dominant nanophthalmos. Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase-polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available in iduals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated in iduals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. Nanophthalmos status. Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white in iduals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/13816810600870843
Abstract: Primary infantile glaucoma (PIG) is predominantly inherited as a recessive disease, whereas anterior segment dysgenesis (ASD) is usually dominantly inherited. The purpose of this study was to determine the likelihood of a person who has infantile glaucoma to produce a child who also manifests the disease. A retrospective cross-sectional design was utilized. The pedigrees of probands from south-eastern Australia diagnosed with infantile glaucoma since 1980 were reviewed. Cases were sub ided into two groups according to the presence or absence of ASD. Exclusion criteria included incomplete pedigree phenotype information or aphakic glaucoma following congenital cataract surgery. Fisher's exact test was used to compare the parent-offspring phenotype transmission between ASD-associated infantile glaucoma and PIG. A total of 67 probands were identified however, three pedigrees were excluded due to incomplete phenotype information. Direct parent-offspring transmission of phenotype was statistically significantly more common in ASD-associated infantile glaucoma (2/8) than in PIG (1/56) pedigrees (p = 0.039). Although this study reveals that Australian patients with ASD-associated infantile glaucoma are at greater risk of having children with infantile glaucoma than patients with PIG, the number of ASD pedigrees with direct transmission of infantile glaucoma is lower than expected. Based on our population frequency analysis and the results of our study, the risk of PIG, if one parent is affected by PIG and the other is normal, is less than 2%.
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.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2022
DOI: 10.1038/S41586-022-05275-Y
Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge s le sizes 1 . Here, using data from a genome-wide association study of 5.4 million in iduals of erse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-s le estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller s le sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
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.
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.
Publisher: BMJ
Date: 07-2005
Publisher: BMJ
Date: 04-2016
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 05-2008
DOI: 10.1167/IOVS.07-1297
Abstract: A Tyr-to-His (Y402H) sequence variant in the factor H (FH) and factor H-like protein (FHL-1) gene is strongly associated with an increased susceptibility for age-related macular degeneration (AMD). The purpose of this study was to understand how the Y402H variant in FH/FHL-1 contributes to the pathogenesis of AMD and, in particular, whether interactions mediated by FH/FHL-1, including binding to C-reactive protein (CRP), group A streptococcal M protein (GAS M6), heparin, and retinal pigment epithelial cells (RPE), are affected. FH was purified from sera of patients homozygous for FH(Y402) or (H402), and recombinant FH fragments representing FHL-1 were generated. Proteins were analyzed for binding to CRP, GAS M6, heparin, and RPE cells. Binding of the FH and FH1 to seven polymorphic variants to CRP and M protein was reduced. The variant did not influence the interaction of FH with heparin but did reduce binding of FHL-1. Binding of the FH and FHL-1 polymorphic variant to RPE cells was not affected. The FH Y402H polymorphism associated with AMD causes a reduction in binding of FH and FHL-1 to CRP and M protein. Both variants show comparable binding to RPE cells, indicating that AMD is unlikely to manifest as a result of impaired host cell-surface recognition. The decreased interaction between FH and CRP, which is essential for the anti-inflammatory function of CRP, provides a possible pathophysiological explanation for the association of the Y402H variant with AMD.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.EXER.2010.06.014
Abstract: The morphologic appearance of the optic disc is of interest in glaucoma. In contrast to descriptive classification systems that are currently used, a quantitative approach to the analysis of optic disc morphology is required. Our goal was to determine the optimal method for quantifying optic cup shape by comparing traditional (ovality, form-factor and neuroretinal rim (NRR) width ratio) and geometric morphometric approaches. Left optic disc stereophotographs of 160 (80 normal and 80 glaucomatous (stratified by severity)) subjects were examined. The optic cup margins were stereoscopically delineated with a custom tracing system and saved as a series of discrete points. The geometric morphometric methods of elliptic Fourier analysis (EFA) and sliding semi-landmark analysis (SSLA) were used to eliminate variation unrelated to shape (e.g. size) and yield a series of shape variables. Differences in optic cup shape between normal and glaucoma groups were investigated. Discriminant functions were computed and the sensitivity and specificity of each technique determined. Receiver operator characteristic (ROC) curves were calculated for all methods and evaluated in their potential to discriminate between normal and glaucomatous eyes based on the shape variables. All geometric morphometric methods revealed differences between normal and glaucomatous eyes in optic cup shape, in addition to the traditional parameters of ovality, form-factor and NRR width ratio (p<0.0005). SSLA (minimum bending energy criterion--18 points) had the best sensitivity (83%) and area under the curve (AUC) (0.91). EFA (72 points) performed similarly well (74%, 0.89) as did the set of traditional shape-based variables (76%, 0.86). This study demonstrated that a geometric morphometric approach for discriminating between normal and glaucomatous eyes in optic cup shape is superior to that provided by traditional single parameter shape measures. Such analytical techniques could be incorporated into future automated optic disc screening modalities.
Publisher: Springer Science and Business Media LLC
Date: 11-01-2012
Publisher: Wiley
Date: 08-2014
DOI: 10.1002/UOG.13399
Abstract: Through comprehensive ophthalmic examination of adult offspring we sought to determine the impact of multiple prenatal ultrasound scans on ocular development. 2743 pregnant women recruited to the Western Australian Pregnancy (Raine) Cohort study during 1989-1991 were randomized to receive at King Edward Memorial Hospital, Western Australia either multiple prenatal ultrasound scans and Doppler flow studies (intensive group) or a single ultrasound scan at 18 weeks' gestation. Neonatal birth weight of the offspring and other physical measurements were collected prospectively. At age 20 years, participants underwent a comprehensive ophthalmic examination including measurement of ocular biometry and visual acuity. Complete data were available for 1134 adult offspring participants. The mothers of 563 of these had been randomized to receive multiple prenatal ultrasound scans. The mean age of participants at follow-up was 20.0 years. There was no statistically significant difference between the two groups with regard to ocular biometric or visual outcomes, except for slightly higher intraocular pressure identified in in iduals exposed to multiple ultrasound scans (P = 0.034). Although infants in the intensive-ultrasound arm were more likely to have birth weights in the lower quartiles, this was not reflected in adult eye development. Axial length, lens thickness, corneal curvature and thickness and optic cup to disc ratio (a risk factor for glaucomatous optic neuropathy) were not significantly influenced by the more frequent ultrasound protocol. Prior to this study, there was a paucity of safety data for ultrasound with regard to eye development. We found that frequent in-utero exposure to ultrasound, including B-mode imaging and the use of spectral Doppler mode from 18 weeks' gestation, had no significant impact on visual outcomes or ocular biometry.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 10-01-2022
DOI: 10.1101/2022.01.07.475305
Abstract: Common SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge s le sizes. Here we show, using GWAS data from 5.4 million in iduals of erse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-s le estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller s le sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 18-08-2023
DOI: 10.1167/TVST.12.8.14
Publisher: Wiley
Date: 03-2009
DOI: 10.1111/J.1442-9071.2009.02002.X
Abstract: Primary open angle glaucoma (POAG) is a complex heterogeneous disease. The aim of this study was to describe the POAG phenotype in in iduals who harbour the novel GLC1L disease-associated haplotype in a large pedigree where the Myocilin Gln368STOP mutation also segregates. The clinical findings from 24 subjects with POAG from the GTAS02 family recruited as part of the Glaucoma Inheritance Study of Tasmania (GIST) were compared relative to genotype status. The previously identified GLC1L disease haplotype encompasses a chromosomal region of 8.3 centimorgans bounded by the markers D3S3521 and D3S1289 on 3p21-22. In subjects with the GLC1L disease haplotype (with or without Gln368STOP), the POAG phenotype was characterized by a mean age at diagnosis of 54.3 years, and mean maximum recorded intraocular pressure (IOP) of 23.9 mmHg. The mean maximum recorded IOP was lower in subjects with the predicted disease haplotype and no Gln368STOP mutation, compared with subjects with the predicted disease haplotype and presence of the Gln368STOP mutation (P = 0.02). Presence of the Gln368STOP mutation was significantly more common in those with the predicted disease haplotype than those without (P = 0.04). In the four subjects carrying the GLC1L disease-associated haplotype without the Gln368STOP mutation, a normotensive glaucoma (mean maximum recorded IOP 15 mmHg, range 13-17 mmHg) was present. The GLC1L locus may be associated with glaucoma in the absence of elevated IOP. Discovery of the specific gene within the GLC1L locus on 3p21-22 would provide a useful addition to our ability to offer genetic testing and counselling to POAG in iduals and their families.
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.
Publisher: BMJ
Date: 08-2017
Publisher: Springer Science and Business Media LLC
Date: 19-07-2015
DOI: 10.1007/S00125-015-3697-2
Abstract: Diabetic retinopathy is a serious complication of diabetes mellitus and can lead to blindness. A genetic component, in addition to traditional risk factors, has been well described although strong genetic factors have not yet been identified. Here, we aimed to identify novel genetic risk factors for sight-threatening diabetic retinopathy using a genome-wide association study. Retinopathy was assessed in white Australians with type 2 diabetes mellitus. Genome-wide association analysis was conducted for comparison of cases of sight-threatening diabetic retinopathy (n = 336) with diabetic controls with no retinopathy (n = 508). Top ranking single nucleotide polymorphisms were typed in a type 2 diabetes replication cohort, a type 1 diabetes cohort and an Indian type 2 cohort. A mouse model of proliferative retinopathy was used to assess differential expression of the nearby candidate gene GRB2 by immunohistochemistry and quantitative western blot. The top ranked variant was rs3805931 with p = 2.66 × 10(-7), but no association was found in the replication cohort. Only rs9896052 (p = 6.55 × 10(-5)) was associated with sight-threatening diabetic retinopathy in both the type 2 (p = 0.035) and the type 1 (p = 0.041) replication cohorts, as well as in the Indian cohort (p = 0.016). The study-wide meta-analysis reached genome-wide significance (p = 4.15 × 10(-8)). The GRB2 gene is located downstream of this variant and a mouse model of retinopathy showed increased GRB2 expression in the retina. Genetic variation near GRB2 on chromosome 17q25.1 is associated with sight-threatening diabetic retinopathy. Several genes in this region are promising candidates and in particular GRB2 is upregulated during retinal stress and neovascularisation.
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/13816810500374375
Abstract: The X chromosome is unique, both in terms of functional expression and evolutionary history. Population frequencies for a minority of conditions, such as mental retardation, are directly related to the X chromosome. To explore these ideas, we investigated the general role of the X chromosome in ocular genetics through bioinformatic analysis of the distribution of eye-related genes in the human genome. The proportion of eye-disease loci located on the X chromosome compared to those eye diseases with an autosomal locus was calculated. The resultant figure (3.47) is lower than that calculated for mental retardation (9.74). A comparison between the number of X chromosome genes expressed in the eye compared to the number of autosomal genes expressed in the eye also did not reveal significant differences. Of all genes expressed in the eye, 2.9% are thought to be located on the X chromosome, fewer than found for the larger autosomes (which range from 10.1% to 3.6%). The eye's functional genetic components appear to be dispersed throughout the human genome, possibly to ensure survival in the event of significant cytogenetic derangement.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 03-08-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-05-2021
Publisher: Wiley
Date: 30-10-2014
DOI: 10.1111/CEO.12449
Publisher: Public Library of Science (PLoS)
Date: 26-09-2012
Publisher: Cambridge University Press (CUP)
Date: 27-02-2013
DOI: 10.1017/THG.2013.5
Abstract: Twin studies are extremely useful for investigating hypotheses of genetic influence on a range of behavioral and physical traits in humans. Studies of physical traits, however, are usually limited to size-related biological characteristics because it is inherently difficult to quantify the morphological counterpart – shape. In recent years, the development of geometry-preserving analytical techniques built upon multivariate statistical methodologies has produced a new discipline in biological shape analysis known as geometric morphometrics. In this study of hand shape analysis, we introduce the reader already familiar with the field of twin research to the potential utility of geometric morphometrics and demonstrate the cross-discipline applicability of methods. We also investigate and compare the efficacy of the 2D:4D ratio, a commonly used marker of sexual dimorphism, to the fully multivariate approach of shape analysis in discriminating between male and female sex. Studies of biological shape variation utilizing geometric morphometric techniques may be completed with software freely available on the Internet and time invested to master the small learning curve in concepts and theory.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.661
Publisher: Springer Science and Business Media LLC
Date: 12-09-2010
DOI: 10.1038/NG.664
Publisher: Springer Science and Business Media LLC
Date: 25-07-2018
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 27-07-2016
DOI: 10.1111/CEO.12570
Abstract: P values associated with null hypothesis significance testing (NHST) are almost universal in the ophthalmic literature. A P value < 0.05 is traditionally considered 'significant'. This concept may deflect further thought about the veracity of the results. P values influence the publishability of the data and have flow-on effects for funding success and the direction of future research. Despite their importance, the problems inherent in P values have been recognized since their inception, and in more recent years have been increasingly highlighted in some scientific fields. In this review, we aim to bring the problems associated with P values and NHST to the attention of the ophthalmic research community. We do not offer a universal solution to the problem of determining the veracity of a scientific claim however, we demonstrate the need for caution in interpreting 'significant' P values by performing a Bayesian re-analysis of t-tests in the ophthalmic literature.
Publisher: Elsevier BV
Date: 07-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-04-2020
Publisher: Oxford University Press (OUP)
Date: 10-01-2017
DOI: 10.1093/HMG/DDW399
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 20-09-2019
Abstract: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3087
Publisher: Wiley
Date: 07-11-2015
DOI: 10.1111/CEO.12455
Abstract: Sun exposure is associated with several ophthalmic diseases, including pterygium which may develop in adolescence. This study reports the prevalence of pterygium and its associations in a large cohort of young Australian adults. Conjunctival ultraviolet autofluorescence, a biomarker of ocular sun exposure, has recently been characterized in some Australian populations. Cross-sectional population-based study. One thousand three hundred forty-four subjects aged 18-22 years in the Western Australian Pregnancy Cohort (Raine) Study. Standardized colour and ultraviolet autofluorescence photographs of the nasal and temporal conjunctiva were taken, and assessed for presence of pterygium and area of autofluorescence. Sun exposure and protective factors were assessed by structured questionnaire. Area of conjunctival ultraviolet autofluorescence in square millimetre (mm(2)) and presence of pterygium. Median total conjunctival autofluorescence was 44.2 mm(2) (interquartile range 20.2-69.8 mm(2)). Median conjunctival autofluorescence was higher in nasal than in temporal quadrants (23.8 mm(2) vs. 18.9 mm(2), P < 0.001), but did not differ according to age or gender. Higher body mass index was associated with lower levels of autofluorescence. Total autofluorescence increased with increasing time spent outdoors. Prevalence of pterygium was 1.2% (95% confidence interval 0.6-1.8%), and was associated with male gender (odds ratio 6.71, P = 0.012). Participants with pterygium had significantly more conjunctival autofluorescence than those without (median 73.4 mm(2) vs. 44.0 mm(2), P = 0.001). Conjunctival ultraviolet autofluorescence is associated with increased time spent outdoors, and increased prevalence of pterygium. The association of this biomarker with other ophthalmohelioses, including cataract, ocular surface squamous neoplasia and eyelid malignancy, has yet to be determined.
Publisher: Informa UK Limited
Date: 05-09-2022
DOI: 10.1080/09286586.2021.1968005
Abstract: In 1989-1991, pregnant women completed questionnaires on their current smoking and alcohol drinking patterns. Following the birth of their offspring, information on household smokers was obtained between the 1- and 13-year follow-ups. At the 20-year follow-up, these offspring underwent an eye examination including optical coherence tomography imaging of the RNFL. Participants (n = 1,287) were 19-22 years old at time of eye examination. Most participants (77%) had no
Publisher: Elsevier BV
Date: 07-2021
Publisher: Public Library of Science (PLoS)
Date: 23-08-2017
Publisher: Elsevier BV
Date: 03-2016
Publisher: Oxford University Press (OUP)
Date: 13-05-2020
Abstract: The libraries generated by high-throughput single cell RNA-sequencing (scRNA-seq) platforms such as the Chromium from 10× Genomics require considerable amounts of sequencing, typically due to the large number of cells. The ability to use these data to address biological questions is directly impacted by the quality of the sequence data. Here we have compared the performance of the Illumina NextSeq 500 and NovaSeq 6000 against the BGI MGISEQ-2000 platform using identical Single Cell 3′ libraries consisting of over 70 000 cells generated on the 10× Genomics Chromium platform. Our results demonstrate a highly comparable performance between the NovaSeq 6000 and MGISEQ-2000 in sequencing quality, and the detection of genes, cell barcodes, Unique Molecular Identifiers. The performance of the NextSeq 500 was also similarly comparable to the MGISEQ-2000 based on the same metrics. Data generated by both sequencing platforms yielded similar analytical outcomes for general single-cell analysis. The performance of the NextSeq 500 and MGISEQ-2000 were also comparable for the deconvolution of multiplexed cell pools via variant calling, and detection of guide RNA (gRNA) from a pooled CRISPR single-cell screen. Our study provides a benchmark for high-capacity sequencing platforms applied to high-throughput scRNA-seq libraries.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 16-04-2012
DOI: 10.1167/IOVS.11-8420
Abstract: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are the dimethylated isomeric derivatives of the amino acid L-arginine. ADMA is an endogenous inhibitor of nitric oxide synthase (NOS), while SDMA is a competitive inhibitor of cellular uptake of L-arginine, the substrate for NOS. As such, these metabolites are associated with endothelial dysfunction. As the nitric oxide pathway and endothelial dysfunction have been implicated in glaucoma, the aim of this study was to investigate serum ADMA, SDMA, and L-arginine levels in in iduals with advanced glaucoma compared with normal controls. In addition, we have investigated genetic variation in the DDAH1 and DDAH2 genes, encoding the enzymes responsible for degradation of ADMA, for association with ADMA level in glaucoma patients and controls. Two hundred eleven patients with advanced glaucoma and 295 normal controls were recruited. Liquid chromatography-tandem mass spectrometry was used to measure the serum ADMA, SDMA, and L-arginine levels of participants. Single nucleotide polymorphisms in the DDAH1 and DDAH2 genes reportedly associated with ADMA level were genotyped in all in iduals. A significant increase in both serum ADMA and SDMA concentration was detected in advanced glaucoma cases compared with controls (P ≤ 0.0001). No significant change was detected in serum L-arginine concentration. No association of polymorphisms in DDAH1 and DDAH2 with either ADMA level or glaucoma was detected. The serum levels of two dimethylarginines, ADMA and SDMA, are associated with advanced glaucoma. These data further implicate the nitric-oxide pathway in glaucoma pathogenesis.
Publisher: Wiley
Date: 19-08-2022
DOI: 10.1002/MGG3.2023
Abstract: Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well‐characterised cohort of 58 in iduals from 44 families with different types of corneal dystrophy. In iduals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.59
Publisher: American Medical Association (AMA)
Date: 06-2020
Publisher: BMJ
Date: 11-2006
Publisher: Oxford University Press (OUP)
Date: 10-2017
Abstract: Pediatric cataract is a leading cause of childhood blindness. This study aimed to determine the genetic cause of pediatric cataract in Australian families by screening known disease-associated genes using massively parallel sequencing technology. We sequenced 51 previously reported pediatric cataract genes in 33 affected in iduals with a family history (cases with previously known or published mutations were excluded) using the Ion Torrent Personal Genome Machine. Variants were prioritized for validation if they were predicted to alter the protein sequence and were absent or rare with minor allele frequency & % in public databases. Confirmed mutations were assessed for segregation with the phenotype in all available family members. All identified novel or previously reported cataract-causing mutations were screened in 326 unrelated Australian controls. We detected 11 novel mutations in GJA3, GJA8, CRYAA, CRYBB2, CRYGS, CRYGA, GCNT2, CRYGA, and MIP and three previously reported cataract-causing mutations in GJA8, CRYAA, and CRYBB2. The most commonly mutated genes were those coding for gap junctions and crystallin proteins. Including previous reports of pediatric cataract-associated mutations in our Australian cohort, known genes account for & % of familial pediatric cataract in Australia, indicating that still more causative genes remain to be identified.
Publisher: Elsevier BV
Date: 08-2018
Abstract: Pluripotent stem cells are an extremely powerful tool in modeling human diseases and hold much promise for personalized regenerative or cell replacement therapies. There is an increasing need for reproducible large-scale stem cell and differentiated progeny production, with minimal variation, rendering manual approaches impracticable. Here, we provide an overview of systems currently available for automated stem cell culture, and undertake a review of their capacities, capabilities, and relative limitations. With the merging of modern technology and stem cell biology, an increased demand and implementation of automated platforms for stem cell studies is anticipated.
Publisher: Mary Ann Liebert Inc
Date: 08-2022
Abstract: Retinal neovascularization is a severe complication of proliferative diabetic retinopathy (PDR). MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. In this study, we show that miR-143-3p is significantly downregulated in the retina of a rat model of oxygen-induced retinopathy (OIR) by miRNA-sequencing. Intravitreal injection of synthetic miR-143 mimics significantly ameliorate retinal neovascularization in OIR rats. miR-143 is identified to be highly expressed in the neural retina particularly in the ganglion cell layer and retinal vasculature. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodeling. The multiomics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating hypoxia-inducible factor-1 signaling. We predict hub genes regulated by miR-143 that may be involved in mediating endothelial cell function by cytoHubba. We also demonstrate that the retinal neovascular membranes in patients with PDR principally consist of endothelial cells by CIBERSORTx. We then identify 2 hub genes, thrombospondin 1 and plasminogen activator inhibitor, direct targets of miR-143, that significantly altered in the PDR patients. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2016
DOI: 10.1038/SREP30552
Abstract: Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro . In this study, we present a 45-day protocol that utilises magnetic activated cell sorting to generate enriched population of RGCs via stepwise retinal differentiation using hESCs. We performed an extensive characterization of these stem cell-derived RGCs by examining the gene and protein expressions of a panel of neural/RGC markers. Furthermore, whole transcriptome analysis demonstrated similarity of the hESC-derived RGCs to human adult RGCs. The enriched hESC-RGCs possess long axons, functional electrophysiological profiles and axonal transport of mitochondria, suggestive of maturity. In summary, this RGC differentiation protocol can generate an enriched population of functional RGCs from hESCs, allowing future studies on disease modeling of optic neuropathies and development of cell therapies.
Publisher: American Medical Association (AMA)
Date: 2007
DOI: 10.1001/ARCHOPHT.125.1.112
Abstract: To investigate whether structural differences of the optic nerve head are evident in young people who do not have manifest glaucoma but are known to carry myocilin mutations. A case-control design was adopted. Subjects from Australian pedigrees known to have either the Gln368STOP myocilin mutation (cutoff age, <40 years) or the Thr377Met myocilin mutation (cutoff age, <30 years) were examined for signs of glaucoma. Stereoscopic disc photographs were digitalized. Analysis of the optic disc area, optic cup area, and neuroretinal rim area was performed using digital stereoscopy with a Z-screen. Mutation analysis was conducted using direct sequencing. The t test, corrected for multiple comparison testing, was used in analysis. A total of 29 myocilin mutation-carrying (case) and 33 mutation-free (control) in iduals were reviewed. The mean +/- SD ages were 19.9 +/- 9.0 and 22.1 +/- 9.5 years in the mutation and mutation-free groups, respectively (P = .35). There was no significant difference in intraocular pressure between mutation carriers and noncarriers (P = .44). There were no statistically significant differences in the mean disc, neuroretinal rim, and cup areas between the groups. The mean +/- SD neuroretinal rim area was 1.24 +/- 0.24 mm(2) in the noncarrier group and 1.25 +/- 0.23 mm(2) in the mutation group (P = .46). No notch, nerve fiber layer defect, or neuroretinal rim hemorrhage was noted in any eye examined. Although confounded by penetrance and expressivity, no quantified structural difference in the optic nerve head was observed in in iduals who had a myocilin mutation prior to the diagnosis of glaucoma.
Publisher: Wiley
Date: 14-09-2016
Publisher: Springer Science and Business Media LLC
Date: 31-08-2014
DOI: 10.1038/NG.3079
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 02-07-2012
DOI: 10.1167/IOVS.11-8677
Abstract: We sought to determine whether conjunctival ultraviolet autofluorescence (UVAF), a biomarker of outdoor light exposure, is associated with myopia. We performed a cross-sectional study on Norfolk Island and recruited in iduals aged ≥ 15 years. Participants completed a sun-exposure questionnaire and underwent non-cycloplegic autorefraction. Conjunctival UVAF used a specially adapted electronic flash system fitted with UV-transmission filters (transmittance range 300-400 nm, peak 365 nm) as the excitation source. Temporal and nasal conjunctival UVAF was measured in both eyes using computerized photographic analysis with the sum referred to as "total UVAF." In 636 participants, prevalence of myopia decreased with an increasing quartile of total UVAF (P(trend) = 0.002). Median total UVAF was lower in subjects with myopia (spherical equivalent [SE] ≤ -1.0 diopter [D]) than participants without myopia: 16.6 mm(2) versus 28.6 mm(2), P = 0.001. In the multivariable model that adjusted for age, sex, smoking, cataract, height and weight, UVAF was independently associated with myopia (SE ≤ -1.0 D): odds ratio (OR) for total UVAF (per 10 mm(2)) was 0.81, 95% confidence interval (CI) 0.69 to 0.94, P = 0.007. UVAF was also significantly associated with myopia when analysis was restricted to subjects <50 years, and in moderate-severe myopia (SE ≤ -3.0 D). Prevalence of myopia decreased with increasing time outdoors (P(trend) = 0.03), but time outdoors was not associated with myopia on multivariable analysis. Study authors identified a protective association between increasing UVAF and myopia. The protective association of higher UVAF against myopia was stronger than that of increased levels of time spent outdoors as measured by this study's questionnaire. Future studies should investigate the association between UVAF and incident myopia, and its relationship to myopic progression.
Publisher: Cold Spring Harbor Laboratory
Date: 05-01-2018
DOI: 10.1101/243493
Abstract: Giant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies. GCA is a heterogenous disease, symptoms and signs are variable thereby making it challenging to diagnose and often delaying diagnosis. A temporal artery biopsy is the gold standard to test for GCA, and there are currently no specific biochemical markers to categorize or aid diagnosis of the disease. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA. We recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital (RVEEH), Melbourne, Australia, and aimed to collect blood s les at six time points: acute phase, 2–3 weeks, 6–8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting (MACS). RNA was extracted from all 195 collected s les for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, we identified two transcripts that remained differentially expressed after 12 months, namely SGTB , associated with neuronal apoptosis, and FCGR3A , which has been found in association with Takayasu arteritis (TA), another large vessel vasculitis. We detected genes that correlate with both symptoms and biochemical markers used in the acute setting for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes: a history of Polymyalgia Rheumatica, both visual disturbance and raised neutrophils at the time of presentation, bilateral blindness and death within 12 months. Altered IL32 gene expression could provide risk evaluation of GCA diagnosis at the time of presentation and give an indication of prognosis, which may influence management. This is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. These data significantly enhance the current knowledge of relevant biomarkers, their association with clinical prognostic markers, as well as potential candidates for detecting disease activity in whole blood s les. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide us in initiating appropriate patient management.
Publisher: Cambridge University Press (CUP)
Date: 02-2011
DOI: 10.1375/TWIN.14.1.42
Abstract: Aim: To describe the recruitment, ophthalmic examination methods and distribution of ocular biometry of participants in the Norfolk Island Eye Study, who were in iduals descended from the English Bounty mutineers and their Polynesian wives. Methods: All 1,275 permanent residents of Norfolk Island aged over 15 years were invited to participate, including 602 in iduals involved in a 2001 cardiovascular disease study. Participants completed a detailed questionnaire and underwent a comprehensive eye assessment including stereo disc and retinal photography, ocular coherence topography and conjunctival autofluorescence assessment. Additionally, blood or saliva was taken for DNA testing. Results: 781 participants aged over 15 years were seen (54% female), comprising 61% of the permanent Island population. 343 people (43.9%) could trace their family history to the Pitcairn Islanders (Norfolk Island Pitcairn Pedigree). Mean anterior chamber depth was 3.32mm, mean axial length (AL) was 23.5mm, and mean central corneal thickness was 546 microns. There were no statistically significant differences in these characteristics between persons with and without Pitcairn Island ancestry. Mean intra-ocular pressure was lower in people with Pitcairn Island ancestry: 15.89mmHg compared to those without Pitcairn Island ancestry 16.49mmHg ( P = .007). The mean keratometry value was lower in people with Pitcairn Island ancestry (43.22 vs. 43.52, P = .007). The corneas were flatter in people of Pitcairn ancestry but there was no corresponding difference in AL or refraction. Conclusion: Our study population is highly representative of the permanent population of Norfolk Island. Ocular biometry was similar to that of other white populations. Heritability estimates, linkage analysis and genome-wide studies will further elucidate the genetic determinants of chronic ocular diseases in this genetic isolate.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2015
Publisher: Cambridge University Press (CUP)
Date: 13-06-2012
DOI: 10.1017/THG.2012.22
Abstract: Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent (‘phoria’) and manifest (‘tropia’) strabismus using cover–uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) ( r = 0.65) compared to dizygotic (DZ) twin pairs ( r = 0.33), suggesting a genetic role ( p = .003). There was no significant difference in polychoric correlation between MZ ( r = 0.55) and DZ twin pairs ( r = 0.53) for exo-deviation ( p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50–0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
Publisher: Public Library of Science (PLoS)
Date: 25-01-2018
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.
Publisher: Wiley
Date: 28-10-2014
DOI: 10.1111/CEO.12239
Abstract: Diabetic retinopathy (DR) is a blinding disease of increasing prevalence that is caused by a complex interplay of genetic and environmental factors. Here we describe the patient recruitment methodology, case and control definitions, and clinical characteristics of a study s le to be used for genome-wide association analysis to detect genetic risk variants of DR. One thousand six hundred sixty-nine participants with either type 1 (T1) or type 2 (T2) diabetes mellitus (DM) aged 18 to 95 years were recruited in Australian hospital clinics. In iduals with T2DM had disease duration of at least 5 years and were taking oral hypoglycaemic medication, and/or insulin therapy. Participants underwent ophthalmic examination. Medical history and biochemistry results were collected. Venous blood was obtained for genetic analysis. Six hundred eighty-three diabetic cases (178 T1DM and 505 T2DM participants) with sight-threatening DR, defined as severe non-proliferative DR, proliferative DR or diabetic macular oedema were included in this analysis. Eight hundred twelve in iduals with DM but no DR or minimal non-proliferative DR were recruited as controls (191 with T1DM and 621 with T2DM). The presence of sight-threatening DR was significantly correlated with DM duration, hypertension, nephropathy, neuropathy, HbA1C and body mass index. Diabetic macular oedema was associated with T2DM (P < 0.001), whereas proliferative DR was associated with T1DM (P < 0.001). Adoption of a case-control study design involving extremes of the DR phenotype makes this a suitable cohort, for a well-powered genome-wide association study to detect genetic risk variants for DR.
Publisher: Wiley
Date: 28-01-2010
DOI: 10.1111/J.1755-3768.2009.01786.X
Abstract: This aim of this study was to compare the prevalence of various disease-associated and potentially modifiable risk factors between people with familial and sporadic forms of primary open angle glaucoma (OAG). A cross-sectional, retrospective study design was utilized. A detailed questionnaire enquiring about knowledge of family history, demographic data, current medications, and medical history of systemic disorders was administered. Where possible, living relatives were examined for signs of OAG. A total of 3,800 potential patients with OAG were identified, of whom 2062 were examined. One thousand twelve (59.5%) subjects were found to have familial OAG, and 688 (40.5%) subjects had no known or identified relative with OAG (sporadic glaucoma). One thousand forty-two unaffected family members examined. A past history of migraine was found more often with familial OAG (OR: 1.67 95% CI: 1.15-2.42). This effect was primarily driven by patients who had a first-degree relative also affected by OAG. Following adjustment for male gender and the age at review, the presence of atherosclerosis was also found to be more common in patients with familial glaucoma than in people with sporadic disease (OR: 1.42 95% CI: 1.05-1.92). No significant difference in the prevalence of hypertension, Raynaud's phenomenon, diabetes mellitus or thyroid disease was identified. Patients with a known relative affected by OAG were statistically significantly more likely to have a past history for migraine or presence of atherosclerosis compared to people with no known affected relative. An understanding of such differences and systemic comorbidities will be useful for further work investigating the underlying molecular mechanisms of this disease.
Publisher: Wiley
Date: 18-12-2019
DOI: 10.1111/CEO.13446
Publisher: Wiley
Date: 31-05-2005
DOI: 10.1111/J.1442-9071.2005.01018.X
Abstract: X-linked retinoschisis (XLRS), an X-linked recessive inherited degenerative retinopathy, is characterized by splitting in the nerve fibre layer and is caused by alterations in the RS1 gene. The aim of the present study was to review both the phenotypic features of XLRS and the mutation spectrum of the RS1 gene in an Australian cohort. Patients were recruited from ophthalmic and paediatric hospitals as well as private ophthalmic clinics across Australia. A cohort of 18 presumably unrelated families was identified. Twenty-two affected patients underwent clinical examination. Following DNA extraction all six exons of the RS1 gene were sequenced. The median age at diagnosis was 8 years (range 1-43 years) the median age at review was 14 years (range 5-63 years). The median best-corrected visual acuity upon review was 6/24 (range 6/6-1/36). Typical foveal schisis was found in 90.1% eyes examined (39/43) while peripheral schisis was present in 30% of eyes (13/43). The scotopic blue b-wave litude ranged between 2% and 82% of the mean normal litude. Five novel mutations (61G-->T, Gly21X 103C-->T, Gln35X 327-329del, Cys110del 527T-->C, Phe176Ser 573Gdel, Pro192fs) and six previously identified missense mutations (304C-->T, Arg102Trp 305G-->A, Arg102Gln 336G-->C, Trp112Cys 418G-->A, Gln140Arg 598C-->T, Arg200Cys 625C-->T, Arg209Cys) were found. The mutations present in codons 21 and 102 were each identified in two presumably unrelated pedigrees. One previously described point deletion (416Adel) was identified. Two pedigrees contained affected in iduals where exons 2 or 3, respectively, were unable to be lified, indicating the likely presence of a significant deletion. No mutation was found in the RS1 gene in two affected in iduals from different pedigrees. Population genetic studies of XLRS have not previously been conducted in Australia. The phenotype associated with these mutations varied. The identification of each pedigree's specific mutation allows future determination of female carrier status for genetic counselling purposes. Further study into the refinement of the XLRS phenotype as well as the degree of intrafamilial phenotypic variation is required.
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.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2014
DOI: 10.1038/GENE.2014.19
Abstract: Giant Cell Arteritis (GCA) is the most common vasculitis affecting the elderly. Archived formalin-fixed paraffin-embedded (FFPE) temporal artery biopsy (TAB) specimens potentially represent a valuable resource for large-scale genetic analysis of this disease. FFPE TAB s les were obtained from 12 patients with GCA. Extracted TAB DNA was assessed by real time PCR before restoration using the Illumina HD FFPE Restore Kit. Paired FFPE-blood s les were genotyped on the Illumina OmniExpress FFPE microarray. The FFPE s les that passed stringent quality control measures had a mean genotyping success of >97%. When compared with their matching peripheral blood DNA, the mean discordant heterozygote and homozygote single nucleotide polymorphisms calls were 0.0028 and 0.0003, respectively, which is within the accepted tolerance of reproducibility. This work demonstrates that it is possible to successfully obtain high-quality microarray-based genotypes FFPE TAB s les and that this data is similar to that obtained from peripheral blood.
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.
No related organisations have been discovered for Alex Hewitt.
Start Date: 07-2011
End Date: 12-2019
Amount: $21,000,000.00
Funder: Australian Research Council
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