ORCID Profile
0000-0003-4626-7248
Current Organisation
QIMR Berghofer Medical Research Institute
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Publisher: Elsevier BV
Date: 05-2020
Publisher: Elsevier BV
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Wiley
Date: 07-07-2021
DOI: 10.1002/AJMG.B.32866
Abstract: Suicide attempts (SA) among African Americans have increased at a greater rate than any other racial/ethnic group. Research in European ancestry populations has indicated that SA are genetically influenced however, less is known about the genetic contributors that underpin SA among African Americans. We examined whether genetic propensity for depression and risky behaviors (assessed via polygenic risk scores PRS) independently and jointly are associated with SA among urban, African Americans and whether sex differences exist in these relations. Participants (N = 1,157, 45.0% male) were originally recruited as part of two first grade universal school-based prevention trials. Participants reported in adolescence and young adulthood on whether they ever attempted suicide in their life. Depression and risky behaviors PRS were created based on large-scale genome-wide association studies conducted by Howard et al. (2019) and Karlson Línner et al. (2019), respectively. There was a significant interaction between the risky behavior PRS and depression PRS such that the combination of high risky behavior polygenic risk and low/moderate polygenic risk for depression was associated with greater risk for lifetime SA among the whole s le and African American males specifically. In addition, the risky behavior PRS was significantly positively associated with lifetime SA among African American males. These findings provide preliminary evidence regarding the importance of examining risky behavior and depression polygenic risk in relation to SA among African Americans, though replication of our findings in other African American s les is needed.
Publisher: Wiley
Date: 08-10-2014
DOI: 10.1111/GBB.12177
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2021
DOI: 10.1101/2021.07.12.21260397
Abstract: Major depression is one of the most disabling health conditions internationally. In recent years, new generation antidepressant medicines have become very widely prescribed. While these medicines are efficacious, side effects are common and frequently result in discontinuation of treatment. Compared with specific pharmacological properties of the different medications, the relevance of in idual vulnerability is understudied. We used data from the Australian Genetics of Depression Study to gain insights into the aetiology and genetic risk factors to antidepressant side effects. As expected, the most commonly reported longer-term side effects were reduced sexual function and weight gain. Importantly, participants reporting a specific side effect for one antidepressant were more likely to report the same side effect for other antidepressants, suggesting the presence of shared in idual or pharmacological factors. Depression Polygenic Risk Scores (PRS) were associated with side effects that overlapped with depressive symptoms, including suicidality and anxiety. Body Mass Index PRS were strongly associated with weight gain from all medications. PRS for headaches were associated with headaches from sertraline. Insomnia PRS showed some evidence of predicting insomnia from amitriptyline and escitalopram. Our results suggest a set of common factors underlying the risk for antidepressant side effects. These factors seem to be, at least in part, explained by genetic liability related to depression severity and the nature of the side effect. Future studies on the genetic aetiology of side effects will enable insights into their underlying mechanisms and the possibility of risk stratification and prophylaxis strategies.
Publisher: Cambridge University Press (CUP)
Date: 16-10-2023
DOI: 10.1017/THG.2023.41
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Oxford University Press (OUP)
Date: 17-08-2021
Abstract: Sleep is essential for both physical and mental health, and there is a growing interest in understanding how different factors shape in idual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel inferred causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data. We used summary-level statistics from genome-wide association studies and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 other phenotypes. We identify 84 inferred causal relationships. Among other findings, connective tissue disorders increase insomnia risk and reduce sleep duration depression-related traits increase insomnia and daytime dozing insomnia, napping, and snoring are affected by obesity and cardiometabolic traits and diseases and working with asbestos, thinner, or glues may increase insomnia risk, possibly through an increased risk of respiratory disease or socio-economic related factors. Overall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.
Publisher: Cold Spring Harbor Laboratory
Date: 23-04-2020
DOI: 10.1101/2020.04.20.20073247
Abstract: Observational studies have identified correlations between environmental and lifestyle factors and Parkinson’s disease (PD). However, the causal direction of many of these relationships remains unclear. To infer causal relationships between smoking and alcohol intake and PD. We use a two-s le Mendelian randomization (MR) experimental design to infer causal relationships between smoking ( initiation, age of initiation, heaviness , and cessation ) and alcohol ( drinks per week ) consumption as exposure variables and PD as the health outcome. We also conduct sensitivity analyses, including testing for pleiotropic effects MR-Egger and MR-PRESSO, and multivariable MR to jointly model the effects of drinking and smoking behavior on PD risk. Both alcohol intake (OR = 0.69 95% CI 0.56-0.86 p=0.001). and smoking cessation (comparing current vs. former smokers ) (IVW OR = 0.39 95% CI 0.22 to 0.69 p=0.001) were causally associated with a reduced risk of PD. In addition, our multivariable MR results provide additional assurance that the causal association between drinks per week and PD is unlikely due to confounding by smoking behavior. Our findings support the role of smoking as a protective factor against PD, but only when comparing current vs. former smokers . Increased alcohol intake also had a protective effect over PD risk, and the alcohol dehydrogenase 1B ( ADH1B ) locus is a candidate for further investigating the mechanisms underlying this association.
Publisher: Frontiers Media SA
Date: 26-08-2021
DOI: 10.3389/FGENE.2021.716236
Abstract: Hormone-dependent cancers (HDC) are among the leading causes of death worldwide among both men and women. Some of the established risk factors of HDC include unhealthy lifestyles, environmental factors, and genetic influences. Numerous studies have been conducted to understand gene–cancer associations. Transcriptome-wide association studies (TWAS) integrate data from genome-wide association studies (GWAS) and gene expression (expression quantitative trait loci – eQTL) to yield meaningful information on biological pathways associated with complex traits/diseases. Recently, TWAS have enabled the identification of novel associations between HDC risk and protein-coding genes. In the present study, we performed a TWAS analysis using the summary data-based Mendelian randomization (SMR)–heterogeneity in dependent instruments (HEIDI) method to identify microRNAs (miRNAs), a group of non-coding RNAs (ncRNAs) associated with HDC risk. We obtained eQTL and GWAS summary statistics from the ncRNA-eQTL database and the National Human Genome Research Institute–European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog. We identified 13 TWAS-significant miRNAs at cis regions (±1 Mb) associated with HDC risk (two, five, one, two, and three miRNAs for prostate, breast, ovarian, colorectal, and endometrial cancers, respectively). Among them, eight novel miRNAs were recognized in HDC risk. Eight protein-coding genes targeted by TWAS-identified miRNAs ( SIRT1 , SOX4 , RUNX2 , FOXA1 , ABL2 , SUB1 , HNRNPH1 , and WAC ) are associated with HDC functions and signaling pathways. Overall, identifying risk-associated miRNAs across a group of related cancers may help to understand cancer biology and provide novel insights into cancer genetic mechanisms. This customized approach can be applied to identify significant miRNAs in any trait/disease of interest.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2017
DOI: 10.1038/TP.2017.84
Publisher: Cold Spring Harbor Laboratory
Date: 24-05-2020
DOI: 10.1101/2020.05.23.20110841
Abstract: The bidirectional relationship between depression and chronic pain is well recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N=13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for ten different antidepressants. Chronic pain was associated with an increased risk of depression (OR=1.86 [1.37–2.54]), recent suicide attempt (OR=1.88[1.14–3.09]), higher use of tobacco (OR=1.05 [1.02–1.09]) and misuse of painkillers (e.g., opioids OR=1.31 [1.06–1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR=0.75[0.68–0.83]), escitalopram (OR=0.75[0.67–0.85]) and venlafaxine (OR=0.78[0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR=0.45[0.30–0.67]), escitalopram (OR=0.45[0.27–0.74]) and citalopram (OR=0.32[0.15–0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2021
DOI: 10.1038/S41598-021-93105-Y
Abstract: Previous observational studies have identified correlations between Parkinson’s disease (PD) risk and lifestyle factors. However, whether or not those associations are causal remains unclear. To infer causality between PD risk and smoking or alcohol intake, we conducted a two-s le Mendelian randomization study using genome-wide association study summary statistics from the GWAS & Sequencing Consortium of Alcohol and Nicotine use study (1.2 million participants) and the latest meta-analysis from the International Parkinson’s Disease Genomics Consortium (37,688 PD cases and 18,618 proxy-cases). We performed sensitivity analyses, including testing for pleiotropy with MR-Egger and MR-PRESSO, and multivariable MR modeling to account for the genetic effects of competing substance use traits on PD risk. Our results revealed causal associations of alcohol intake (OR 0.79 95% CI 0.65–0.96 p = 0.021) and smoking continuation (which compares current vs. former smokers ) (OR 0.64 95% CI 0.46–0.89 p = 0.008) with lower PD risk. Multivariable MR analyses showed that the causal association between drinks per week and PD is unlikely due to confounding by smoking behavior. Finally, frailty analyses suggested that the causal effects of both alcohol intake and smoking continuation on PD risk estimated from MR analysis are not explained by the presence of survival bias alone. Our findings support the role of smoking as a protective factor against PD, but only when comparing current vs. former smokers . Similarly, increased alcohol intake had a protective effect over PD risk, with the alcohol dehydrogenase 1B ( ADH1B ) locus as a potential candidate for further investigation of the mechanisms underlying this association.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1186/S10194-021-01284-W
Abstract: Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach. We leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method. We identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, ever feeling unenthusiastic / disinterested for a whole week , a phenotype related to the psychological well-being of in iduals, was a potential outcome of migraine. Overall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of in iduals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Wiley
Date: 14-07-2022
DOI: 10.1002/AJMG.B.32913
Abstract: Emergence of suicidal symptoms has been reported as a potential antidepressant adverse drug reaction. Identifying risk factors associated could increase our understanding of this phenomenon and stratify in iduals at higher risk. Logistic regressions were used to identify risk factors of self‐reported treatment‐attributed suicidal ideation (TASI). We then employed classifiers to test the predictive ability of the variables identified. A TASI GWAS, as well as SNP‐based heritability estimation, were performed. GWAS replication was sought from an independent study. Significant associations were found for age and comorbid conditions, including bipolar and personality disorders. Participants reporting TASI from one antidepressant were more likely to report TASI from other antidepressants. No genetic loci associated with TAS I ( p 5e‐8) were identified. Of 32 independent variants with suggestive association ( p 1e‐5), 27 lead SNPs were available in a replication dataset from the GENDEP study. Only one variant showed a consistent effect and nominal association in the independent replication s le. Classifiers were able to stratify non‐TASI from TASI participants (AUC = 0.77) and those reporting treatment‐attributed suicide attempts (AUC = 0.85). The pattern of TASI co‐occurrence across participants suggest nonspecific factors underlying its etiology. These findings provide insights into the underpinnings of TASI and serve as a proof‐of‐concept of the use of classifiers for risk stratification.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2016
DOI: 10.1038/MP.2016.9
Publisher: Oxford University Press (OUP)
Date: 22-02-2023
Abstract: Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg & 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.
Publisher: Humana Press
Date: 2013
DOI: 10.1007/978-1-62703-447-0_8
Abstract: Within this chapter we introduce the basic PLINK functions for reading in data, applying quality control, and running association analyses. Three worked ex les are provided to illustrate: data management and assessment of population substructure, association analysis of a quantitative trait, and qualitative or case-control association analyses.
Publisher: Center for Open Science
Date: 12-09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2023
DOI: 10.1101/2023.08.28.23294700
Abstract: Background Parkinson's Disease (PD) has a complex etiology, involving genetic and environmental factors. Most of our current understanding of the disease comes from studies in populations with mostly European ancestry, representing challenges in generalizing findings to other populations with different genetic, social, and environmental contexts. There are scarce studies focused in Latin American populations. The Mexican population is genetically erse because its admixture from Native American, European, and African ancestries, coupled with the unique environmental conditions, stressing the relevance of establishing genetic studies in this population. Thus, we have established the Mexican Parkinson's Research Network (MEX-PD), a consortium to research the clinical, genetical, environmental, and neurophysiological bases of the phenotypic ersity in Mexican PD patients. Objectives Describing how MEX-PD was established, the methods and instruments and presenting the first results. Methods Patients and controls were recruited from medical centers in 20 states of Mexico. Initial recruitment included neurological evaluation, cognitive assessment, and DNA collection. Results MEX-PD has registered 302 controls and 262 PD patients with a mean age of diagnosis of 61 years (SD=10.86). There were 19.8% PD patients identified with early onset. Levodopa was the most common pharmacological treatment. Conclusions MEX-PD contributes to understand PD nationally. The information gathered here will allow us to understand the prevalence of mental health, neurological symptoms, and cognitive function in the PD Mexican population and how genetical and environmental factors contributes to those outcomes. These will advocate for personalized treatments and improving quality of life in the Mexican population.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2020
DOI: 10.1038/S41598-020-66737-9
Abstract: Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt , suicide thoughts and non-suicidal self-harm (NSSH) in an independent target s le of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability ( h snp 2 ) estimates were ~10%, and both traits were highly genetically correlated ( LDSC r g 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour . Furthermore, in the target s le, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH , and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt . Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant.
Publisher: Springer Science and Business Media LLC
Date: 29-05-2020
DOI: 10.1038/S41398-020-0842-6
Abstract: A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of in iduals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.
Publisher: Oxford University Press (OUP)
Date: 08-04-2022
DOI: 10.1093/HMG/DDAC081
Abstract: Depression is one of the most common mental health disorders and one of the top causes of disability throughout the world. The present study sought to identify putative causal associations between depression and hundreds of complex human traits through a genome-wide screening of genetic data and a hypothesis-free approach. We leveraged genome-wide association studies summary statistics for depression and 1504 complex traits and investigated potential causal relationships using the latent causal variable method. We identified 559 traits genetically correlated with depression risk at FDR & 5%. Of these, 46 were putative causal genetic determinants of depression, including lifestyle factors, diseases of the nervous system, respiratory disorders, diseases of the musculoskeletal system, traits related to the health of the gastrointestinal system, obesity, vitamin D levels and the use of prescription medications, among others. No phenotypes were identified as potential outcomes of depression. Our results suggest that genetic liability to multiple complex traits may contribute to a higher risk for depression. In particular, we show a putative causal genetic effect of pain, obesity and inflammation on depression. These findings provide novel insights into the potential causal determinants of depression and should be interpreted as testable hypotheses for future studies to confirm, which may facilitate the design of new prevention strategies to reduce depression’s burden.
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: Cambridge University Press (CUP)
Date: 06-2021
DOI: 10.1017/THG.2021.27
Abstract: Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to in idual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian s le ( N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia ( p 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent s le, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to in idual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.
Publisher: BMJ
Date: 02-2022
DOI: 10.1136/BMJOPEN-2021-052032
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on in idual risk. The Australian Parkinson’s Genetics Study seeks to study genetic and patient-reported data from a large cohort of in iduals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression. In the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA s le via traditional post. 65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions. We plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.
Publisher: Cold Spring Harbor Laboratory
Date: 02-03-2021
DOI: 10.1101/2021.02.28.21251786
Abstract: Our group developed a transcriptome-based polygenic risk score (T-PRS) that uses common genetic variants to capture ‘depression-like’ shifts in cortical gene expression. Here, we mapped T-PRS onto diagnosis and symptom severity in major depressive disorder (MDD) cases and controls from the Psychiatric Genomics Consortium (PGC). To evaluate potential mechanisms, we further mapped T-PRS onto discrete measures of brain morphology and broad depression risk in healthy young adults. Genetic, self-report, and/or neuroimaging data were available in 29,340 PGC participants (59% women 12,923 MDD cases, 16,417 controls) and 482 participants in the Duke Neurogenetics Study (DNS: 53% women aged 19.8±1.2 years). T-PRS was computed from SNP data using PrediXcan to impute cortical expression levels of MDD-related genes from a previous post-mortem transcriptome meta-analysis. Sex-specific regressions were used to test effects of T-PRS on depression diagnosis, symptom severity, and Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index in the PGC and DNS s les, respectively. T-PRS did not predict depression diagnosis (OR=1.007, 95%CI=[0.997-1.018]) however, it correlated with symptom severity in men (rho=0.175, p=7.957×10 −4 ) in one large PGC cohort (N=762, 48% men). In DNS, T-PRS was associated with smaller amygdala volume in women (β=-0.186, t=-3.478, p=.001) and less prefrontal gyrification (max≤-2.970, p≤.006) in both sexes. In men, prefrontal gyrification mediated an indirect effect of T-PRS on broad depression risk (b=.005, p=.029), indexed using self-reported family history of depression. Depression-like shifts in cortical gene expression predict symptom severity in men and may contribute to disease vulnerability through their effect on cortical gyrification.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2015
Publisher: Wiley
Date: 06-02-2023
DOI: 10.1002/OBY.23669
Abstract: Sleep apnea and snoring have been associated with type 2 diabetes, with BMI playing a role in the pathway, but the directions of causality are unclear. This study examined the causal associations of sleep apnea and snoring with type 2 diabetes while assessing the role of BMI using multiple genetic methods. Five genetic methods were used: two‐s le bidirectional univariable Mendelian randomization (MR) inverse variance‐weighted (MR‐IVW) multivariable MR‐IVW network MR and latent causal variable method. Compared with univariable MR‐IVW, the odds ratio (95% CI) of type 2 diabetes for genetically predicted sleep apnea and snoring using the largest genome‐wide association study decreased dramatically, from 1.61 (95% CI: 1.16‐2.23) to 1.08 (95% CI: 0.59‐1.97) and from 1.98 (95% CI: 1.25‐3.13) to 1.09 (95% CI: 0.64‐1.86) after adjustment for BMI. Network MR showed that BMI accounts for 67% and 62% of the total effect of sleep apnea and snoring on type 2 diabetes, respectively. The latent causal variable suggested that sleep apnea and snoring have no direct causal effect on type 2 diabetes. These results first suggest that the associations of sleep apnea and snoring with type 2 diabetes were mainly driven by BMI. The possible indirect effects of sleep apnea and snoring on type 2 diabetes through BMI cannot be ruled out.
Publisher: Springer Science and Business Media LLC
Date: 15-03-2019
DOI: 10.1007/S10519-019-09954-X
Abstract: This study assessed the heritability of 25 hydroxyvitamin D
Publisher: Cold Spring Harbor Laboratory
Date: 10-05-2020
DOI: 10.1101/2020.05.06.20092643
Abstract: Sleep is essential for both physical and mental health. There is an increasing interest in understanding how different factors shape in idual variation in sleep duration, quality and patterns, or confer risk for sleep disorders. The present study aimed to identify novel causal relationships between sleep-related traits and other phenotypes, using a genetics-driven hypothesis-free approach not requiring longitudinal data. We used genetic data and the latent causal variable (LCV) method to screen the phenome and infer causal relationships between seven sleep-related traits (insomnia, daytime dozing, easiness of getting up in the morning, snoring, sleep duration, napping, and morningness) and 1,527 different phenotypes. We identify 84 significant causal relationships. Among other findings, poor health of musculoskeletal and connective tissue disorders increase insomnia risk and reduce sleep duration depression-related traits increase insomnia and daytime dozing insomnia, napping and snoring are affected by obesity and cardiometabolic traits and diseases and working with asbestos, thinner, or glues increases insomnia, potentially through an increased risk of respiratory disease. Overall, our results indicate that changes in sleep variables are predominantly the consequence, rather than the cause, of other underlying phenotypes and diseases. These insights could inform the design of future epidemiological and interventional studies in sleep medicine and research.
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2023
DOI: 10.1101/2023.02.18.23286098
Abstract: Astigmatism and myopia are two common ocular refractive errors that can impact daily life, including student learning and productivity. Current understanding suggests that the etiology of these conditions is the result of a complex interplay between genetic and environmental factors. Studies in populations of European ancestry have demonstrated a higher concordance of refractive errors in monozygotic (MZ) twins compared to dizygotic (DZ) twins. However, there is a lack of studies on genetically informative s les of multi-ethnic ancestry. This study aimed to estimate the genetic contribution to astigmatism and myopia in the Mexican population. A s le of 1399 families, including 243 twin pairs and 1156 single twins, completed a medical questionnaire about their own and their co-twins diagnosis of astigmatism and myopia. Concordance rates for astigmatism and myopia were estimated in Mexican twins, and heritability and genetic correlations were determined using a bivariate ACE Cholesky decomposition method. The results showed a concordance rate of 0.74 for MZ twins and 0.50 for DZ twins for astigmatism, and a higher concordance rate in MZ twins, 0.74, compared to DZ twins, 0.54 for myopia. Heritability estimates were 0.66 for astigmatism and 0.62 for myopia, with a cross-trait genetic correlation of rA=0.82 and a phenotypic correlation of rP=0.80. These results are consistent with previous findings in other populations, providing evidence for a similar genetic architecture of these conditions in the multi-ethnic Mexican population.
Publisher: Wiley
Date: 27-06-2022
DOI: 10.1002/JCB.30300
Abstract: Competing endogenous RNAs (ceRNAs) have become an emerging topic in cancer research due to their role in gene regulatory networks. To date, traditional ceRNA bioinformatic studies have investigated microRNAs as the only factor regulating gene expression. Growing evidence suggests that genomic (e.g., copy number alteration [CNA]), transcriptomic (e.g., transcription factors [TFs]), and epigenomic (e.g., DNA methylation [DM]) factors can influence ceRNA regulatory networks. Herein, we used the Least absolute shrinkage and selection operator regression, a machine learning approach, to integrate DM, CNA, and TFs data with RNA expression to infer ceRNA networks in cancer risk. The gene-regulating factors-mediated ceRNA networks were identified in four hormone-dependent (HD) cancer types: prostate, breast, colorectal, and endometrial. The shared ceRNAs across HD cancer types were further investigated using survival analysis, functional enrichment analysis, and protein-protein interaction network analysis. We found two (BUB1 and EXO1) and one (RRM2) survival-significant ceRNA(s) shared across breast-colorectal-endometrial and prostate-colorectal-endometrial combinations, respectively. Both BUB1 and BUB1B genes were identified as shared ceRNAs across more than two HD cancers of interest. These genes play a critical role in cell ision, spindle-assembly checkpoint signalling, and correct chromosome alignment. Furthermore, shared ceRNAs across multiple HD cancers have been involved in essential cancer pathways such as cell cycle, p53 signalling, and chromosome segregation. Identifying ceRNAs' roles across multiple related cancers will improve our understanding of their shared disease biology. Moreover, it contributes to the knowledge of RNA-mediated cancer pathogenesis.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 02-09-2016
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2020
DOI: 10.1101/2020.06.22.20103556
Abstract: Pneumonia is a respiratory condition with complex aetiology. Host genetic variation is thought to contribute to in idual differences in susceptibility and symptom manifestation. We analysed pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9,980 cases and 86,519 controls). We perform genome-wide association study (GWAS) meta-analysis, gene-based test, colocalisation, genetic correlation, latent causal variable and polygenic prediction in an independent Australian s le (N=5,595) to draw insights into the genetic aetiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead SNPs rs2009746 and rs76474922) to be associated with pneumonia(p e-8). Gene-based tests revealed eighteen genes in chromosomes 15,16 and 9, including IL127, PBX3, APOBR and smoking related genes CHRNA3/5 , associated with pneumonia. Evidence of HYKK and PBX3 involvement in pneumonia risk was supported by eQTL colocalisation analysis. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. Latent causal variable analysis suggests a strong genetic causal relationship cardiovascular health phenotypes and pneumonia risk. Polygenic risk scores (PRS) for pneumonia significantly predicted self-reported pneumonia history in an independent Australian s le, albeit with a small effect size (OR=1.11 95%CI=[1.04-1.19], p .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the association of genes in chromosome 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to in idual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
Publisher: Cold Spring Harbor Laboratory
Date: 21-09-2021
DOI: 10.1101/2021.09.15.21263562
Abstract: A major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia. Here, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments and (ii) by pooling data (N∼6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour. Our results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Scale for Suicidal Ideation (SSI), were highly correlated with each other (r=0.83), as were suicidal ideation items from common depression severity questionnaires. Our findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behaviour, but share a core factor with single suicidal ideation items found in depression severity questionnaires. Multi-site collaborations including cohorts that used distinct instruments for suicide risk assessment should be feasible provided that they harmonise across instruments or focus on specific constructs of suicidal thoughts or behaviours. Question: To inform future suicide research in multi-site international consortia, it is important to examine how different suicide measures relate to each other and whether they can be used interchangeably. Findings: Findings suggest detailed instruments (such as the Columbia Suicide Severity Rating Scale and Beck Scale for Suicidal Ideation) provide valuable information on suicidal thoughts and behaviour, and share a core factor with items on suicidal ideation from depression severity rating scale (such as the Hamilton Depression Rating Scale or the Beck Depression Inventory). Importance: Results from international collaborations can mitigate biases by harmonising distinct suicide risk assessment instruments. Next steps: Pooling data within international suicide research consortia may reveal novel clinical, biological and cognitive correlates of suicidal thoughts and/or behaviour.
Publisher: Informa UK Limited
Date: 10-2021
DOI: 10.2147/NDT.S331442
Publisher: Springer Science and Business Media LLC
Date: 21-10-2019
Publisher: SAGE Publications
Date: 16-07-2021
DOI: 10.1177/00048674211031491
Abstract: Chronic pain and depression are highly comorbid and difficult-to-treat disorders. We previously showed this comorbidity is associated with higher depression severity, lower antidepressant treatment effectiveness and poorer prognosis in the Australian Genetics of Depression Study. The current study aimed to assess whether a genetic liability to chronic pain is associated with antidepressant effectiveness over and above the effect of genetic factors for depression in a s le of 12,863 Australian Genetics of Depression Study participants. Polygenic risk scores were calculated using summary statistics from genome-wide association studies of multisite chronic pain and major depression. Cumulative linked regressions were employed to assess the association between polygenic risk scores and antidepressant treatment effectiveness across 10 different medications. Mixed-effects logistic regressions showed that in idual genetic propensity for chronic pain, but not major depression, was significantly associated with patient-reported chronic pain (Pain PRS OR = 1.17 [1.12, 1.22] MD PRS OR = 1.01 [0.98, 1.06]). Significant associations were also found between lower antidepressant effectiveness and genetic risk for chronic pain or for major depression. However, a fully adjusted model showed the effect of Pain PRS (adjOR = 0.93 [0.90, 0.96]) was independent of MD PRS (adjOR = 0.96 [0.93, 0.99]). Sensitivity analyses were performed to assess the robustness of these results. After adjusting for depression severity measures (i.e. age of onset number of depressive episodes interval between age at study participation and at depression onset), the associations between Pain PRS and patient-reported chronic pain with lower antidepressant effectiveness remained significant (0.95 [0.92, 0.98] and 0.84 [0.78, 0.90], respectively). These results suggest genetic risk for chronic pain accounted for poorer antidepressant effectiveness, independent of the genetic risk for major depression. Our results, along with independent converging evidence from other studies, point towards a difficult-to-treat depression subtype characterised by comorbid chronic pain. This finding warrants further investigation into the implications for biologically based nosology frameworks in pain medicine and psychiatry.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2022
DOI: 10.1038/S41467-022-28252-5
Abstract: Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial consequences. Here, we perform a GWAS meta-analysis comprising 20,165 in iduals with acne from nine independent European ancestry cohorts. We identify 29 novel genome-wide significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches, we identify putative causal genes at several acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including pustular psoriasis. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6% of the variance in acne liability in an independent cohort.
Publisher: Cambridge University Press (CUP)
Date: 03-06-2013
DOI: 10.1017/THG.2013.30
Abstract: Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs ( H19 -ICR, IGF2 -DMR, KvDMR, and NESPAS -ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high in idual variation and intra-domain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at in idual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to s le size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19 -ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS -ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1 , which are imprinted genes regulated by the NESPAS -ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with in idual methylation sites through family-based association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small s le size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent s les.
Publisher: Frontiers Media SA
Date: 18-08-2022
Abstract: Previous observational studies have found that lower levels of circulating polyunsaturated fatty acids (PUFAs) were associated with a higher risk of sleep apnea (SA). However, the causality of the association remains unclear. We used the two-s le Mendelian randomization (MR) study to assess the causal association of omega-3 and omega-6 fatty acids with SA. Single-nucleotide polymorphisms (SNPs) predicting the plasma level of PUFAs at the suggestive genome-wide significance level ( p & 5 × 10 –6 ) were selected as instrumental variables (IVs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) ( n = ∼8,000) Consortium. For outcomes, the summary-level statistics of SA were obtained from the latest genome-wide association study (GWAS), which combined five cohorts with a total number of 25,008 SA cases and 172,050 snoring cases (total = 523,366). We found no association of α-linolenic acid (ALA) [odds ratio (OR) = 1.09 per% changed, 95% confidence interval (CI) 0.67–1.78], eicosapentaenoic acid (EPA) (OR = 0.94, 95% CI 0.88–1.01), docosapentaenoic acid (DPA) (OR = 0.95, 95% CI 0.88–1.02), and docosahexaenoic acid (DHA) (OR = 0.99, 95% CI 0.96–1.02) with the risk of SA using inverse-variance weighted (IVW) method. Moreover, for omega-6 PUFAs, no association between linoleic acid (LA) (OR = 0.98, 95% CI 0.96–1.01), arachidonic acid (AA) (1.00, 95% CI 0.99–1.01), and adrenic acid (AdrA) (0.93, 95% CI 0.71–1.21) with the risk of SA was found. Similarly, no associations of PUFAs with SA were found in single-locus MR analysis. In the current study, we first found that there is no genetic evidence to support the causal role of omega-3 and omega-6 PUFAs in the risk of SA. From a public health perspective, our findings refute the notion that consumption of foods rich in PUFAs or the use of PUFAs supplementation can reduce the risk of SA.
Publisher: Wiley
Date: 18-02-2016
DOI: 10.1002/HBM.23136
Publisher: Elsevier BV
Date: 08-2021
Publisher: Research Square Platform LLC
Date: 19-04-2023
DOI: 10.21203/RS.3.RS-2755149/V1
Abstract: Background Age-related cataract is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation (UVR), and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Further research into the genetic basis of cataracts could provide valuable insights into the disease's etiology and lead to a better understanding of biological mechanisms that are associated with its development. Methods This study presents the largest genome-wide association study of cataracts to date, using data from 127,985 cases and 837,371 controls. We performed gene enrichment analysis to identify genes and biological pathways associated with cataracts. We integrated our results with gene expression reference datasets to identify genetic variants modifying risk for cataracts through changes in the expression of specific genes. We further explored drug-gene interactions to better understand the potential impact of pharmacological interventions on cataract development. Finally, we explored whether a causal relationship underlies the known comorbidity between type 1 diabetes and cataracts using a mendelian randomization framework, and the association between UV exposure and cataract risk in adults using a polygenic risk scoring approach. Findings Our study identified 85 independent genome-wide significant loci, 37 of which are novel. Gene-based association tests identified 126 genes associated with cataracts, hinting at a potential relationship between negative regulation of lipid biosynthesis and the development of cataracts. Four of the genes identified GNL3 , JAG1 , METTL21A , and CREB1 are involved in drug-gene interactions. Moreover, Mendelian Randomisation analysis identified a putative causal relationship between genetic predisposition to type 1 diabetes and an increased risk of cataracts. Lastly, we found evidence indicating that early-life exposure to UVR may have an impact on the later development of cataracts. Interpretation Our findings advance our understanding of the genetic basis of cataract and provide new insights into its etiology. We identified multiple genes and biological pathways associated with the condition, including associations with four genes from which drug repurposing could be proposed. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults and drug-genes interactions that has the potential of informing novel therapies.
Publisher: Royal College of Psychiatrists
Date: 09-02-2022
DOI: 10.1192/BJP.2022.7
Abstract: Despite efforts to predict suicide risk in children, the ability to reliably identify who will engage in suicide thoughts or behaviours has remained unsuccessful. We apply a novel machine-learning approach and examine whether children with suicide thoughts or behaviours could be differentiated from children without suicide thoughts or behaviours based on a combination of traditional (sociodemographic, physical health, social–environmental, clinical psychiatric) risk factors, but also more novel risk factors (cognitive, neuroimaging and genetic characteristics). The study included 5885 unrelated children (50% female, 67% White, 9–11 years of age) from the Adolescent Brain Cognitive Development (ABCD) study. We performed penalised logistic regression analysis to distinguish between: (a) children with current or past suicide thoughts or behaviours (b) children with a mental illness but no suicide thoughts or behaviours (clinical controls) and (c) healthy control children (no suicide thoughts or behaviours and no history of mental illness). The model was subsequently validated with data from seven independent sites involved in the ABCD study ( n = 1712). Our results showed that we were able to distinguish the suicide thoughts or behaviours group from healthy controls (area under the receiver operating characteristics curve: 0.80 child-report, 0.81 for parent-report) and clinical controls (0.71 child-report and 0.76–0.77 parent-report). However, we could not distinguish children with suicidal ideation from those who attempted suicide (AUROC: 0.55–0.58 child-report 0.49–0.53 parent-report). The factors that differentiated the suicide thoughts or behaviours group from the clinical control group included family conflict, prodromal psychosis symptoms, impulsivity, depression severity and history of mental health treatment. This work highlights that mostly clinical psychiatric factors were able to distinguish children with suicide thoughts or behaviours from children without suicide thoughts or behaviours. Future research is needed to determine if these variables prospectively predict subsequent suicidal behaviour.
Publisher: Cambridge University Press (CUP)
Date: 02-2021
DOI: 10.1017/THG.2021.4
Abstract: Several neuroimaging studies have reported associations between brain white matter microstructure and chronotype. However, it is unclear whether those phenotypic relationships are causal or underlined by genetic factors. In the present study, we use genetic data to examine the genetic overlap and infer causal relationships between chronotype and diffusion tensor imaging (DTI) measures. We identify 29 significant pairwise genetic correlations, of which 13 also show evidence for a causal association. Genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring in idual tracts, 10 genetic correlations were observed with mean diffusivity, 10 with axial diffusivity, 4 with radial diffusivity and 2 with mode of anisotropy. We found evidence for a possible causal association of eveningness with white matter microstructure measures in in idual tracts including the posterior limb and the retrolenticular part of the internal capsule the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata. Our findings contribute to the understanding of how genes influence circadian preference and brain white matter and provide a new avenue for investigating the role of chronotype in health and disease.
Publisher: Frontiers Media SA
Date: 12-01-2022
DOI: 10.3389/FNAGI.2021.807764
Abstract: The rate of progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) is estimated at & % per year, reaching up to 80–90% after 6 years. MCI is considered an indicator of early-stage AD. In this context, the diagnostic screening of MCI is crucial for detecting in iduals at high risk of AD before they progress and manifest further severe symptoms. Typically, MCI has been determined using neuropsychological assessment tools such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental Status Examination (MMSE). Unfortunately, other diagnostic methods are not available or are unable to identify MCI in its early stages. Therefore, identifying new biomarkers for MCI diagnosis and prognosis is a significant challenge. In this framework, miRNAs in serum, plasma, and other body fluids have emerged as a promising source of biomarkers for MCI and AD-related cognitive impairments. Interestingly, miRNAs can regulate several signaling pathways via multiple and erse targets in response to pathophysiological stimuli. This systematic review aims to describe the current state of the art regarding AD-related target genes modulated by differentially expressed miRNAs in peripheral fluids s les in MCI subjects to identify potential miRNA biomarkers in the early stages of AD. We found 30 articles that described five miRNA expression profiles from peripheral fluid in MCI subjects, showing possible candidates for miRNA biomarkers that may be followed up as fluid biomarkers or therapeutic targets of early-stage AD. However, additional research is needed to validate these miRNAs and characterize the precise neuropathological mechanisms.
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2020
DOI: 10.1101/2020.10.20.20216598
Abstract: In the present study, we sought to identify causal relationships between obesity and other complex traits and conditions using a data-driven hypothesis-free approach that uses genetic data to infer causal associations. We leveraged available summary-based genetic data from genome-wide association studies on 1,498 phenotypes and applied the latent causal variable method (LCV) between obesity and all traits. We identified 110 traits with significant causal associations with obesity. Notably, obesity influenced 26 phenotypes associated with cardiovascular diseases, 22 anthropometric measurements, nine with the musculoskeletal system, nine with behavioural or lifestyle factors including loneliness or isolation , six with respiratory diseases, five with body bioelectric impedances, four with psychiatric phenotypes, four related to the nervous system, four with disabilities or long-standing illness, three with the gastrointestinal system, three with use of analgesics, two with metabolic diseases, one with inflammatory response and one with the neurodevelopmental disorder ADHD , among others. Our results indicate that obesity causally affects a wide range of traits and comorbid diseases, thus providing an overview of the metabolic, physiological, and neuropsychiatric impact of obesity on human health.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2015
DOI: 10.1038/MP.2015.69
Publisher: Springer Science and Business Media LLC
Date: 20-03-2020
DOI: 10.1038/S41398-020-0705-1
Abstract: This review summarizes the last decade of work by the ENIGMA ( E nhancing N euro I maging G enetics through M eta A nalysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has ersified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across erse s les and associated genetic, environmental, demographic, cognitive, and psychosocial factors.
Publisher: Cambridge University Press (CUP)
Date: 06-2019
DOI: 10.1017/THG.2019.27
Abstract: The aim of the 25 and Up (25Up) study was to assess a wide range of psychological and behavioral risk factors behind mental illness in a large cohort of Australian twins and their non-twin siblings. Participants had already been studied longitudinally from the age of 12 and most recently in the 19Up study (mean age = 26.1 years, SD = 4.1, range = 20–39). This subsequent wave follows up these twins several years later in life (mean age = 29.7 years, SD = 2.2, range = 22–44). The resulting data set enables additional detailed investigations of genetic pathways underlying psychiatric illnesses in the Brisbane Longitudinal Twin Study (BLTS). Data were collected between 2016 and 2018 from 2540 twins and their non-twin siblings (59% female, including 341 monozygotic complete twin-pairs, 415 dizygotic complete pairs and 1028 non-twin siblings and singletons). Participants were from South-East Queensland, Australia, and the s le was of predominantly European ancestry. The 25Up study collected information on 20 different mental disorders, including depression, anxiety, substance use, psychosis, bipolar and attention-deficit hyper-activity disorder, as well as general demographic information such as occupation, education level, number of children, self-perceived IQ and household environment. In this article, we describe the prevalence, comorbidities and age of onset for all 20 examined disorders. The 25Up study also assessed general and physical health, including physical activity, sleep patterns, eating behaviors, baldness, acne, migraines and allergies, as well as psychosocial items such as suicidality, perceived stress, loneliness, aggression, sleep–wake cycle, sexual identity and preferences, technology and internet use, traumatic life events, gambling and cyberbullying. In addition, 25Up assessed female health traits such as morning sickness, breastfeeding and endometriosis. Furthermore, given that the 25Up study is an extension of previous BLTS studies, 86% of participants have already been genotyped. This rich resource will enable the assessment of epidemiological risk factors, as well as the heritability and genetic correlations of mental conditions.
Publisher: SAGE Publications
Date: 11-04-2022
DOI: 10.1177/00048674221091499
Abstract: Each year, around one million people die by suicide. Despite its recognition as a public health concern, large-scale research on causal determinants of suicide attempt risk is scarce. Here, we leverage results from a recent genome-wide association study (GWAS) of suicide attempt to perform a data-driven screening of traits causally associated with suicide attempt. We performed a hypothesis-generating phenome-wide screening of causal relationships between suicide attempt risk and 1520 traits, which have been systematically aggregated on the Complex-Traits Genomics Virtual Lab platform. We employed the latent causal variable (LCV) method, which uses results from GWAS to assess whether a causal relationship can explain a genetic correlation between two traits. If a trait causally influences another one, the genetic variants that increase risk for the causal trait will also increase the risk for the outcome inducing a genetic correlation. Nonetheless, a genetic correlation can also be observed when traits share common pathways. The LCV method can assess whether the pattern of genetic effects for two genetically correlated traits support a causal association rather than a shared aetiology. Our approach identified 62 traits that increased risk for suicide attempt. Risk factors identified can be broadly classified into (1) physical health disorders, including oesophagitis, fibromyalgia, hernia and cancer (2) mental health-related traits, such as depression, substance use disorders and anxiety and (3) lifestyle traits including being involved in combat or exposure to a war zone, and specific job categories such as being a truck driver or machine operator. Suicide attempt risk is likely explained by a combination of behavioural phenotypes and risk for both physical and psychiatric disorders. Our results also suggest that substance use behaviours and pain-related conditions are associated with an increased suicide attempt risk, elucidating important causal mechanisms that underpin this significant public health problem.
Publisher: Cambridge University Press (CUP)
Date: 02-09-2022
DOI: 10.1017/THG.2022.31
Abstract: Colorectal cancer is the third most common and second most deadly type of cancer worldwide, with approximately 1.9 million cases and 0.9 million deaths worldwide in 2020. Previous studies have shown that estrogen and testosterone hormones are associated with colorectal cancer risk and mortality. However, the potential effect of their precursor, dehydroepiandrosterone sulfate (DHEAS), on colorectal cancer risk has not been investigated. Therefore, evaluating DHEAS’s effect on colorectal cancer will expand our understanding of the hormonal contribution to colorectal cancer risk. In this study, we conducted a two-s le Mendelian randomization (MR) analysis to investigate the causal effect of DHEAS on colorectal cancer. We obtained DHEAS and colorectal cancer genomewide association study (GWAS) summary statistics from the Leipzig Health Atlas and the GWAS catalog and conducted MR analyses using the TwoS leMR R package. Our results suggest that higher DHEAS levels are causally associated with decreased colorectal cancer risk (odds ratio per unit increase in DHEAS levels z score = 0.70 95% confidence interval [0.51, 0.96]), which is in line with previous observations in a case–control study of colon cancer. The outcome of this study will be beneficial in developing plasma DHEAS-based biomarkers in colorectal cancer. Further studies should be conducted to interpret the DHEAS-colorectal cancer association among different ancestries and populations.
Publisher: Wiley
Date: 31-05-2018
DOI: 10.1111/ADD.14252
Publisher: Elsevier BV
Date: 02-2022
Publisher: American Psychiatric Association Publishing
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 09-11-2021
DOI: 10.1038/S43856-021-00046-8
Abstract: Major depression is one of the most disabling health conditions internationally. In recent years, new generation antidepressant medicines have become very widely prescribed. While these medicines are efficacious, side effects are common and frequently result in discontinuation of treatment. Compared with specific pharmacological properties of the different medications, the relevance of in idual vulnerability is understudied. We used data from the Australian Genetics of Depression Study to gain insights into the aetiology and genetic risk factors to antidepressant side effects. To this end, we employed structural equation modelling, polygenic risk scoring and regressions. Here we show that participants reporting a specific side effect for one antidepressant are more likely to report the same side effect for other antidepressants, suggesting the presence of shared in idual or pharmacological factors. Polygenic risk scores (PRS) for depression associated with side effects that overlapped with depressive symptoms, including suicidality and anxiety. Body Mass Index PRS are strongly associated with weight gain from all medications. PRS for headaches are associated with headaches from sertraline. Insomnia PRS show some evidence of predicting insomnia from amitriptyline and escitalopram. Our results suggest a set of common factors underlying the risk for antidepressant side effects. These factors seem to be partly explained by genetic liability related to depression severity and the nature of the side effect. Future studies on the genetic aetiology of side effects will enable insights into their underlying mechanisms and the possibility of risk stratification and prophylaxis strategies.
Publisher: Oxford University Press (OUP)
Date: 20-06-2022
Abstract: Migraine is a highly common and debilitating disorder that often affects in iduals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = −0.11, P = 1 × 10−3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippoc al and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in in iduals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2020
DOI: 10.1101/2020.09.29.20199893
Abstract: Sleep apnoea is characterised by periods of halted breathing during sleep. Despite its association with severe health conditions, the aetiology of sleep apnoea remains understudied, and previous genetic analyses have not identified many robustly associated genetic risk variants. We performed a genome-wide association study (GWAS) meta-analysis of sleep apnoea across five cohorts (N Total =523,366), followed by a multi-trait analysis of GWAS (MTAG) to boost power, leveraging the high genetic correlation between sleep apnoea and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional & joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (N Total =1,477,352 N cases =175,522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. Our MTAG analysis uncovered 49 significant independent loci associated with sleep apnoea risk. Twenty-nine variants were replicated in the 23andMe cohort. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. Our study uncovered multiple genetic loci associated with sleep apnoea risk, thus increasing our understanding of the aetiology of this condition and its relationship with other complex traits.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2021
Publisher: Springer Science and Business Media LLC
Date: 19-11-2021
DOI: 10.1038/S41598-021-01517-7
Abstract: Attention Deficit-Hyperactivity Disorder (ADHD) is a complex psychiatric and neurodevelopmental disorder that develops during childhood and spans into adulthood. ADHD’s aetiology is complex, and evidence about its cause and risk factors is limited. We leveraged genetic data from genome-wide association studies (GWAS) and performed latent causal variable analyses using a hypothesis-free approach to infer causal associations between 1387 complex traits and ADHD. We identified 37 inferred potential causal associations with ADHD risk. Our results reveal that genetic variants associated with iron deficiency anemia (ICD10) , obesity , type 2 diabetes, synovitis and tenosynovitis (ICD10) , polyarthritis (ICD10) , neck or shoulder pain , and substance use in adults display partial genetic causality on ADHD risk in children. Genetic variants associated with ADHD have a partial genetic causality increasing the risk for chronic obstructive pulmonary disease and carpal tunnel syndrome. Protective factors for ADHD risk included genetic variants associated with the likelihood of participating in socially supportive and interactive activities. Our results show that genetic liability to multiple complex traits influences a higher risk for ADHD, highlighting the potential role of cardiometabolic phenotypes and physical pain in ADHD’s aetiology. These findings have the potential to inform future clinical studies and development of interventions.
Publisher: Cold Spring Harbor Laboratory
Date: 23-09-2023
Publisher: Public Library of Science (PLoS)
Date: 07-11-2008
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: Springer Science and Business Media LLC
Date: 24-11-2022
DOI: 10.1007/S00406-022-01527-0
Abstract: S les can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva s le or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva s le. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva s le, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subs les. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of s les such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.
Publisher: American Psychological Association (APA)
Date: 03-2023
DOI: 10.1037/NEU0000850
Publisher: Cold Spring Harbor Laboratory
Date: 28-05-2020
DOI: 10.1101/2020.05.26.115568
Abstract: Chronic pain (CP) is a leading cause of disability worldwide with complex aetiologies that remain elusive. Here we addressed this issue by performing a GWAS on a large UK Biobank s le (N=188,352 cases & N=69,627 controls) which identified two independent loci associated with CP near ADAMTS6 and LEMD2 . Gene-based tests revealed additional CP-associated genes ( DCAKD, NMT1, MLN, IP6K3 ). Across 1328 complex traits, 548 (41%) were genetically correlated with CP, of which 175 (13%) showed genetic causal relationships using the latent causal variable approach and Mendelian randomization. In particular, major depressive disorder, anxiety, smoking, body fat & BMI were found to increase the risk of CP, whereas diet, walking for pleasure & higher educational attainment were associated with a reduced risk (i.e., protective effect). This data-driven hypothesis-free approach has uncovered several specific risk factors that warrant further examination in longitudinal trials to help deliver effective early screening & management strategies for CP.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2016
DOI: 10.1038/MP.2016.60
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
Publisher: Future Medicine Ltd
Date: 07-2022
Abstract: Antidepressant medications are frequently used as the first line of treatment for depression. However, their effectiveness is highly variable and influenced by genetic factors. Recently, pharmacogenetic studies, including candidate-gene, genome-wide association studies or polygenic risk scores, have attempted to uncover the genetic architecture of antidepressant response. Genetic variants in at least 27 genes are linked to antidepressant treatment response in both coding and non-coding genomic regions, but evidence is largely inconclusive due to the high polygenicity of the trait and limited cohort sizes in published studies. Future studies should increase the number and ersity of participants to yield sufficient statistical power to characterize the genetic underpinnings and biological mechanisms of treatment response, improve results generalizability and reduce racial health-related inequities.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2020
Publisher: Springer Science and Business Media LLC
Date: 14-02-2020
DOI: 10.1038/S41467-020-14625-1
Abstract: Although snoring is common in the general population, its aetiology has been largely understudied. Here we report a genetic study on snoring ( n ~ 408,000 snorers ~ 152,000) using data from the UK Biobank. We identify 42 genome-wide significant loci, with an SNP-based heritability estimate of ~10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism are observed. Gene-based associations identify 173 genes, including DLEU7 , MSRB3 and POC5 , highlighting genes expressed in the brain, cerebellum, lungs, blood and oesophagus. We use polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian s le ( n ~ 8000). Mendelian randomization analyses suggest a potential causal relationship between high BMI and snoring. Altogether, our results uncover insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond it being a cardinal symptom of OSA.
Publisher: Informa UK Limited
Date: 03-2023
DOI: 10.2147/CEOR.S395255
Publisher: American Psychiatric Association Publishing
Date: 10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2023
DOI: 10.1101/2023.03.08.23287006
Abstract: Stroke is the second leading cause of death and the third leading cause of long-term disability in the world. This study aimed to explore the novel putative causal genetic relationship of stroke with hundreds of complex traits by leveraging genetic data. We used genome-wide association studies (GWAS) data and the latent causal variable method to identify potential causal relationships between stroke and 1,504 complex traits of the UK biobank. We found that 262 traits were genetically correlated with stroke risk at a false discovery rate (FDR .05). Of those correlated traits, 28 showed robust evidence of partial genetic causality (GCP) with stroke (|GCP| 0.60 FDR 0.05). Our results showed that some conditions, including atrial fibrillation, pulmonary embolism, blood clots in the lung, platelet crit, self-reported deep venous thrombosis, weight gain after depression, and the use of some medications such as insulin, pioglitazone, and gliclazide were inferred to increase stroke risk. On the other hand, greater levels of testosterone, apolipoprotein A, SHBG, and HDL cholesterol decrease the risk of stroke. Also, our results suggest that genetic susceptibility to stroke raises the risk of neck and chest pain and loose teeth. Finally, our findings suggest that cardiac vascular disease, blood clot in lung, deep venous thrombosis, and certain anti-diabetic medications could have a causal role in increasing the risk of stroke, which could be used as novel testable hypotheses for future epidemiological studies.
Publisher: Public Library of Science (PLoS)
Date: 08-04-2022
DOI: 10.1371/JOURNAL.PONE.0266384
Abstract: This study examined whether polygenic risk scores (PRS) for lifetime cannabis and alcohol use were associated with misusing opioids, and whether sex differences existed in these relations in an urban, African-American s le. Data were drawn from three cohorts of participants ( N = 1,103 45% male) who were recruited in first grade as part of a series of elementary school-based, universal preventive intervention trials conducted in a Mid-Atlantic region of the U.S. In young adulthood, participants provided a DNA s le and reported on whether they had used heroin or misused prescription opioids in their lifetime. Three substance use PRS were computed based on prior GWAS: lifetime cannabis use from Pasman et al. (2018), heavy drinking indexed via maximum number of drinks from Gelernter et al. (2019), and alcohol consumption from Kranzler et al. (2019). Higher PRS for lifetime cannabis use, greater heavy drinking, and greater alcohol consumption were associated with heightened risk for misusing opioids among the whole s le. Significant sex by PRS interactions were also observed such that higher PRS for heavy drinking and alcohol consumption were associated with a greater likelihood of opioid misuse among males, but not females. Our findings further elucidate the genetic contributions to misusing opioids by showing that the genetics of cannabis and alcohol consumption are associated with lifetime opioid misuse among young adults, though replication of our findings is needed.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2022
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.JPAIN.2022.10.005
Abstract: The multiple comorbidities & dimensions of chronic pain present a formidable challenge in disentangling its aetiology. Here, we performed genome-wide association studies of 8 chronic pain types using UK Biobank data (N =4,037-79,089 cases N = 239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits. We report evidence of a shared genetic signature across chronic pain types as their genetic correlations and GCP directions were broadly consistent across an array of biopsychosocial traits. Across 5,942 significant genetic correlations, 570 trait pairs could be explained by a causal association (|GCP| >0.6 5% false discovery rate), including 82 traits affected by pain while 410 contributed to an increased risk of chronic pain (cf. 78 with a decreased risk) such as certain somatic pathologies (eg, musculoskeletal), psychiatric traits (eg, depression), socioeconomic factors (eg, occupation) and medical comorbidities (eg, cardiovascular disease). This data-driven phenome-wide association analysis has demonstrated a novel and efficient strategy for identifying genetically supported risk & protective traits to enhance the design of interventional trials targeting underlying causal factors and accelerate the development of more effective treatments with broader clinical utility. PERSPECTIVE: Through large-scale phenome-wide association analyses of >1,400 biopsychosocial traits, this article provides evidence for a shared genetic signature across 8 common chronic pain types. It lays the foundation for further translational studies focused on identifying causal genetic variants and pathophysiological pathways to develop novel diagnostic & therapeutic technologies and strategies.
Publisher: Wiley
Date: 12-06-2017
Abstract: Nanofabrication using a "bottom-up" approach of hybrid electrode materials into a well-defined architecture is essential for next-generation miniaturized energy storage devices. This paper describes the design and fabrication of reduced graphene oxide (rGO) olyoxometalate (POM)-based hybrid electrode materials and their successful exploitation for asymmetric supercapacitors. First, redox active nanoclusters of POMs [phosphomolybdic acid (PMo
Publisher: Springer Science and Business Media LLC
Date: 10-02-2023
DOI: 10.1038/S41598-023-29585-X
Abstract: Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of in idual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I–IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan–Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.
Publisher: Cambridge University Press (CUP)
Date: 06-2012
DOI: 10.1017/THG.2012.13
Abstract: The longitudinal fissure separates the human brain into two hemispheres that remain connected through the corpus callosum. The left and the right halves of the brain resemble each other, and almost every structure present in one side has an equivalent structure in the other. Despite this exceptional correspondence, the two hemispheres also display important anatomical differences and there is marked lateralization of certain cognitive and motor functions such as language and handedness. However, the mechanisms that underlie the establishment of these hemispheric specializations, as well as their physiological and behavioral implications, remain largely unknown. Thanks to recent advances in neuroimaging, a series of studies documenting variation in symmetry and asymmetry as a function of age, gender, brain region, and pathological state, have been published in the past decade. Here, we review evidence of normal and atypical cerebral asymmetry, and the factors that influence it at the macrostructural level. Given the prominent role that cerebral asymmetry plays in the organization of the brain, and its possible implication in neurodevelopmental and psychiatric conditions, further research in this area is anticipated.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2023
DOI: 10.1038/S41531-023-00515-Y
Abstract: Parkinson’s disease (PD) is a late-onset and genetically complex neurodegenerative disorder. Here we sought to identify genes and molecular pathways underlying the associations between PD and the volume of ten brain structures measured through magnetic resonance imaging (MRI) scans. We leveraged genome-wide genetic data from several cohorts, including the International Parkinson’s Disease Genomics Consortium (IPDG), the UK Biobank, the Adolescent Brain Cognitive Development (ABCD) study, the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), the Enhancing Neuroimaging Genetics through Meta-Analyses (ENIGMA), and 23andMe. We observed significant positive genetic correlations between PD and intracranial and subcortical brain volumes. Genome-wide association studies (GWAS) - pairwise analyses identified 210 genomic segments with shared aetiology between PD and at least one of these brain structures. Pathway enrichment results highlight potential links with chronic inflammation, the hypothalamic-pituitary-adrenal pathway, mitophagy, disrupted vesicle-trafficking, calcium-dependent, and autophagic pathways. Investigations for putative causal genetic effects suggest that a larger putamen volume could influence PD risk, independently of the potential causal genetic effects of intracranial volume (ICV) on PD. Our findings suggest that genetic variants influencing larger intracranial and subcortical brain volumes, possibly during earlier stages of life, influence the risk of developing PD later in life.
Publisher: Cold Spring Harbor Laboratory
Date: 21-07-2022
DOI: 10.1101/2022.07.20.500802
Abstract: Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in s les of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 studies with 88,316 MD cases and 902,757 controls to previously reported data from in iduals of European ancestry. This includes s les of African (36% of effective s le size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latinx participants (32%). The multi-ancestry GWAS identified 190 significantly associated loci, 53 of them novel. For previously reported loci from GWAS in European ancestry the power-adjusted transferability ratio was 0.6 in the Hispanic/Latinx group and 0.3 in each of the other groups. Fine-mapping benefited from additional s le ersity: the number of credible sets with ≤5 variants increased from 3 to 12. A transcriptome-wide association study identified 354 significantly associated genes, 205 of them novel. Mendelian Randomisation showed a bidirectional relationship with BMI exclusively in s les of European ancestry. This first multi-ancestry GWAS of MD demonstrates the importance of large erse s les for the identification of target genes and putative mechanisms.
Publisher: Oxford University Press (OUP)
Date: 16-12-2022
Abstract: Despite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk. We performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (NTotal = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (NTotal = 1 477 352 Ncases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method. Our SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions. Our study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 20-01-2022
DOI: 10.1167/IOVS.63.1.25
Publisher: MDPI AG
Date: 09-10-2021
Abstract: The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.
Publisher: Wiley
Date: 07-12-2018
DOI: 10.1002/AJMG.B.32699
Abstract: Genome-wide association studies have revolutionized our understanding of the genetic architecture of complex traits and diseases over the last decade. This knowledge is enabling clinicians, researchers, and direct-to-consumer genetics companies to conduct disease susceptibility testing based on powerful methods such as polygenic risk scoring. However, these technologies raise a set of complex ethical, legal, social, and policy considerations. Here we review and discuss a series of ethical dilemmas associated with susceptibility genetic testing for the two most common late-onset neurodegenerative diseases, Alzheimer's and Parkinson's disease, including testing in asymptomatic in iduals. Among others, these include informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. Importantly, appropriate counseling is a deciding factor for the ethical soundness of genetic testing, which poses a challenge for the regulation of these tests and the training of healthcare professionals. As genetic knowledge about these diseases continues growing and genetic testing becomes more widespread, it is increasingly important to raise awareness among researchers, medical practitioners, genetic counselors, and decision makers about the ethical, legal, and social issues associated with genetic testing for polygenic diseases.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2022
DOI: 10.1038/S41380-022-01734-0
Abstract: Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in s les ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a s le of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a s le of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC N = 519), clinical controls with a mood disorder but without STBs (CC N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic s le with various assessment instruments (HC = 606 CC = 419 Ideation = 289 HC = 253 CC = 432 Attempt=91). In the homogeneous C-SSRS s le, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323 FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous s les, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt however, more research is needed to understand the nature of its relationship to suicide risk.
Publisher: Cold Spring Harbor Laboratory
Date: 26-10-2021
DOI: 10.1101/2021.10.26.21265507
Abstract: S les can be prone to ascertainment and attrition biases.The Australian Genetics of Depression Study is a large publicly recruited cohort (n=20,689) established to increase the understanding of depression and antidepressant treatment response. As part of the recruitment, participants donated a saliva s le and were given the option to consent to linkage of prescription records for research purposes. This study investigates differences between participants who donated a saliva s le or agreed to linkage of their records compared to those who did not. We observed that older, male participants with a higher education were more likely to donate a saliva s le. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder and social anxiety disorder were associated with lower odds of donating a saliva s le whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was also associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia whereas there was no significant genetic effect for neuroticism. Overall, our results show moderate differences among these subs les. Most current epidemiological studies do not adjust, nor search, for attrition biases at the genetic level. The possibility to do so is a strength of s les such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.
Publisher: Cold Spring Harbor Laboratory
Date: 09-11-2020
DOI: 10.1101/2020.11.09.374199
Abstract: Previous neuroimaging studies have highlighted differences in white matter microstructure among in iduals with different chronotypes, but it is unclear whether those differences are due to genetic or environmental factors. Here we leverage summary statistics from recent large-scale genome-wide association studies (GWAS) of chronotype and diffusion tensor imaging (DTI) measures to examine the genetic overlap and infer causal relationships between these traits. We identified 29 significant pairwise genetic correlations, of which 13 also had evidence for a causal association. Negative genetic correlations were identified between chronotype and brain-wide mean, axial and radial diffusivities. When exploring in idual tracts, ten negative genetic correlations were observed with mean diffusivities, 10 with axial diffusivities, 4 with radial diffusivities and 2 with mode of anisotropy. We found evidence for a possible causal association of chronotype with white matter microstructure in in idual tracts including the posterior limb and retrolenticular part of the internal capsule the genu and splenium of the corpus callosum and the posterior, superior and anterior regions of the corona radiata. Our results suggest that eveningness is associated with variation in tract-specific white matter microstructure and, for an evening person, increases in axial and / or radial diffusivities may influence a higher mean diffusivity. These findings add to our understanding of circadian preference and its relationship with the brain, providing new perspectives on the genetic neurological underpinnings of chronotype’s role in health and disease. Sleep is essential for a healthy brain function, particularly for neural organization and brain structure development. In idual chronotype differences have been associated with depression, schizophrenia, diabetes and obesity, among other conditions. Investigating the shared genetic aetiology between chronotype and white matter microstructure is essential to understand the neurological basis of in idual variation in chronotype. In the present study, we show that tract-specific white matter microstructure is genetically correlated and causally associated with chronotype.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2022
DOI: 10.1038/S41397-022-00267-7
Abstract: Variation within the CYP2C19 gene has been linked to differential metabolism of selective serotonin reuptake inhibitors (SSRIs). Pharmacogenetic recommendations based on the effect of CYP2C19 variants have been made available and are used increasingly by clinical practitioners. Nonetheless, the underlying assumption linking differential metabolism to efficacy or adverse side effects remains understudied. Here, we aim to fill this gap by studying CYP2C19 polymorphisms and inferred metabolism and patient-reported antidepressant response in a s le of 9531 Australian adults who have taken SSRIs. Metaboliser status was inferred for participants based on CYP2C19 alleles. Primary analysis consisted of assessing differences in treatment efficacy and tolerability between normal (reference) and: ultrarapid , rapid , intermediate and poor metabolisers. Across medications, poor metabolisers reported a higher efficacy, whereas rapid metabolisers reported higher tolerability. When stratified by drug, associations between metaboliser status and efficacy did not survive multiple testing correction. Intermediate metabolisers were at greater odds of reporting any side effect for sertraline and higher number of side effects across medications and for sertraline. The effects between metaboliser status and treatment efficacy, tolerability and side effects were in the expected direction. Our power analysis suggests we would detect moderate to large effects, at least nominally. Reduced power may also be explained by heterogeneity in antidepressant dosages or concomitant medications, which we did not measure. The fact that we identify slower metabolisers to be at higher risk of side effects even without adjusting for clinical titration, and the nominally significant associations consistent with the expected metabolic effects provide new evidence for the link between CYP2C19 metabolism and SSRI response. Nonetheless, longitudinal and interventional designs such as randomized clinical trials that stratify by metaboliser status are necessary to establish the effects of CYP2C19 metabolism on SSRI treatment efficacy or adverse effects.
Publisher: Frontiers Media SA
Date: 16-10-2018
Publisher: Cold Spring Harbor Laboratory
Date: 07-04-2021
DOI: 10.1101/2021.04.02.21254825
Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on in idual risk. The Australian Parkinson’s Genetics Study (APGS) seeks to study genetic and patient-reported data from a large cohort of in iduals with PD in Australia to understand the sociodemographic, genetic, and environmental basis of PD susceptibility, symptoms and progression. In the pilot phase reported here, 1,819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme (PBS) records. The average age at the time of the questionnaire was 64 ± 6 years. We collected patient-reported PD information and socio-demographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred thirty-two participants (84.2%) met all inclusion criteria, and 1,499 provided a DNA s le via traditional post. 65% of participants were male, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions. We plan to recruit sex- and age-matched unaffected controls, genotype all participants, and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia. We used a time- and cost-effective recruitment method that enabled us to reach out to a random s le of in iduals who have been prescribed medications for Parkinson’s disease across all over Australia to invite them to participate in this study. The identities of letter recipients remained private and confidential and were not shared with the researchers. However, those recipients who were interested and willing to participate were directed to a website where they could sign up and provide informed consent. The source database only captures in iduals who have been prescribed medications to treat Parkinson’s disease in Australia and who are eligible for Medicare. Those without an official diagnosis, not receiving treatment, or not eligible for government subsidies are not included. We collected a wide range of patient-reported variables relevant to disease onset, diagnosis, symptoms, medical comorbidities, lifestyle, and family history in a large cohort of participants. However, some variables might not be as accurate as when measured by a specialist clinician. Given the 9% response rate to our single-letter invitation, there is a substantial risk of self-selection bias. Thus, patient characteristics for this cohort might differ from those of the typical population of in iduals with Parkinson’s disease in Australia.
Publisher: Cold Spring Harbor Laboratory
Date: 06-2020
DOI: 10.1101/2020.05.31.20118711
Abstract: Large-scale genome-wide association studies have uncovered genetic variants associated with depression however, most of this work has been limited to adults of European ancestry. We investigate the ability of depression polygenic risk scores (PRS) to predict both lifetime and past year major depressive disorder (MDD) diagnosis and the experience of a major depressive episode (MDE) in a s le of adolescents with admixed ancestry from Mexico City, and explore whether adverse life events moderate these relations. The study s le consisted of adolescents (N = 1,152) aged 12–17 from Mexico City who were interviewed and genotyped as part of a general population survey on adolescent mental health. PRS for depression were derived using summary statistics from a large-scale discovery genome-wide association study (GWAS) conducted on depressive symptoms that included over 800,000 in iduals of European ancestry (Howard et al., 2019). Higher depression PRS were associated with a higher likelihood of both past year MDD and MDE and lifetime MDE, accounting for 1.5%-2.5% of the variance in these outcomes. Adversity did not moderate the relationship between depression PRS and lifetime or past year MDD or MDE. This study is cross-sectional. As such, a few participants might have experience MDD/MDE after the interview. In addition, our s le comprised only Mexican youth and thus it may not generalize to other populations. Our results indicate that depression PRS derived from a European ancestry GWAS are associated with MDD and MDE risk among Mexican adolescents and have the potential to aid in the identification of youth who may be genetically prone to developing depressive symptoms.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 09-2022
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2021
DOI: 10.1101/2021.03.28.21254282
Abstract: Genome-wide association studies (GWAS) have independently identified hundreds of genomic regions associated with brain morphology and substance use. However, the genetic overlap between brain structure and substance use has not been characterized. Here we leverage GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using LD score regression. We also used genomic structural equation modeling to model a ‘substance use common genetic factor’ and examined its genetic overlap with brain structure. After accounting for multiple testing, we identified eight significant negative genetic correlations, including between alcoholic drinks per week and average cortical thickness and intracranial volume with the age of smoking initiation and five positive genetic correlations, including between insula surface area and lifetime cannabis use, and between the common factor with pericalcarine surface area. Our findings highlight a shared genetic etiology between variation in cortical brain morphology and substance use.
Publisher: Frontiers Media SA
Date: 12-04-2021
DOI: 10.3389/FPSYT.2021.643609
Abstract: The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study ( N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37–2.54]), recent suicide attempt (OR = 1.88 [1.14–3.09]), higher use of tobacco (OR = 1.05 [1.02–1.09]) and misuse of painkillers (e.g., opioids OR = 1.31 [1.06–1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68–0.83]), escitalopram (OR = 0.75 [0.67–0.85]) and venlafaxine (OR = 0.78 [0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30–0.67]), escitalopram (OR = 0.45 [0.27–0.74]) and citalopram (OR = 0.32 [0.15–0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
Publisher: Cold Spring Harbor Laboratory
Date: 12-09-2023
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: Springer Science and Business Media LLC
Date: 03-10-2020
Publisher: Cambridge University Press (CUP)
Date: 05-08-2016
DOI: 10.1017/THG.2016.60
Abstract: Investigations on the relationship between sweet taste perception and body mass index (BMI) have been inconclusive. Here, we report a longitudinal analysis using a genetically informative s le of 1,576 adolescent Australian twins to explore the relationship between BMI and sweet taste. First, we estimated the phenotypic correlations between perception scores for four different sweet compounds (glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame) and BMI. Then, we computed the association between adolescent taste perception and BMI in early adulthood (reported 9 years later). Finally, we used twin modeling and polygenic risk prediction analysis to investigate the genetic overlap between BMI and sweet taste perception. Our findings revealed that BMI in early adulthood was significantly associated with each of the sweet perception scores, with the strongest correlation observed in aspartame with r = 0.09 ( p = .007). However, only limited evidence of association was observed between sweet taste perception and BMI that was measured at the same time (in adolescence), with the strongest evidence of association observed for glucose with a correlation coefficient of r = 0.06 ( p = .029) and for aspartame with r = 0.06 ( p = .035). We found a significant ( p .05) genetic correlation between glucose and NHDC perception and BMI. Our analyses suggest that sweet taste perception in adolescence can be a potential indicator of BMI in early adulthood. This association is further supported by evidence of genetic overlap between the traits, suggesting that some BMI genes may be acting through biological pathways of taste perception.
Publisher: Oxford University Press (OUP)
Date: 05-01-2023
Abstract: Previously, observational studies have identified associations between sleep apnea (SA) and cardiovascular diseases (CVDs), whereas whether the associations are causal remain unclear. We used the bi-directional, two-s le Mendelian randomization (MR) study to assess the existence and direction of the causal relationship between SA or snoring and CVDs. Multivariable MR (MVMR) was used to assess the direct effect of SA on CVDs after adjusting for body mass index (BMI). Single-nucleotide polymorphisms (SNPs) associated with SA and snoring were obtained from the latest genome-wide association study, which combined five cohorts with a total number of 25 008 SA cases and 172 050 snoring cases (total = 523 366). Among the analytic s le of 523 366 in iduals (25 008 SA cases and 172 050 snoring cases), and after correcting for multiple testing, inverse-variance weighted (IVW) showed that SA and snoring increased the risk of hypertension [odds ratio (OR) = 1.03, 95% CI 1.02–1.05 and 1.05, 1.03–1.07], and coronary artery disease (CAD) (1.41,1.19–1.67 and 1.61,1.26–2.07) with all false-discovery rate (FDR) & 0.05, but such associations were decreased dramatically after adjusting for BMI using MVMR-IVW (0.06 & FDRBMI adjusted & 0.20). SA and snoring were not associated with atrial fibrillation (AF), heart failure (HF), or stroke. The presence of hypertension may increase the risk of SA (1.53, 1.04–2.25), but this association did not pass multiple comparisons (FDR & 0.05). Our results suggest that SA and snoring increased the risk of hypertension and CAD, and these associations may partly be driven by BMI. Conversely, no evidence of CVDs causally influencing SA or snoring was found.
Publisher: Wiley
Date: 26-06-2021
DOI: 10.1002/AJMG.B.32864
Abstract: Suicide is a major public health problem in Mexico and around the world. Genetic predisposition for major depressive disorder (MDD) has been associated with increased risk for suicidal behaviors (SB) in populations of European ancestry (EA). Here, we examine whether MDD polygenic risk scores (MDD PRS), derived from a genome-wide association study involving EA in iduals, predict SB, including ideation, planning, and attempt, among Mexican youth using a longitudinal design. At baseline, participants (N = 1,128, 12-17 years, 55% women) were interviewed and genotyped as part of a general population survey on adolescent mental health. Eight years later, they were recontacted for a follow up visit (N = 437, 20-25 years, 63% women). At both assessments, in iduals reported on their engagement in SB within the past year. MDD PRS were significantly positively associated with SB, particularly suicide ideation and planning during adolescence, accounting for ~4-5% of the variance in these outcomes. In contrast, associations between MDD PRS and SB during young adulthood did not reach statistical significance. Our results suggest that increased genetic liability for depression increased risk for SB, particularly during adolescence, expanding our knowledge of the genetic underpinnings of SB.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Miguel E. Rentería.