scholarly journals Insights into the genetic basis of retinal detachment

2019 ◽  
Vol 29 (4) ◽  
pp. 689-702 ◽  
Author(s):  
Thibaud S Boutin ◽  
David G Charteris ◽  
Aman Chandra ◽  
Susan Campbell ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Association Studies ◽  
Genetic Correlations ◽  
Self Report ◽  
Cataract Operation ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Data Set ◽  
Genome Wide

Abstract Retinal detachment (RD) is a serious and common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. In the UK Biobank data set, where RD was ascertained by self-report or hospital records, genetic correlations between RD and high myopia or cataract operation were, respectively, 0.46 (SE = 0.08) and 0.44 (SE = 0.07). These correlations are consistent with known epidemiological associations. Through meta-analysis of genome-wide association studies using UK Biobank RD cases (N = 3 977) and two cohorts, each comprising ~1 000 clinically ascertained rhegmatogenous RD patients, we uncovered 11 genome-wide significant association signals. These are near or within ZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1 and LOXL1. Replication in the 23andMe data set, where RD is self-reported by participants, firmly establishes six RD risk loci: FAT3, COL22A1, TYR, BMP3, ZC3H11B and PLCE1. Based on the genetic associations with eye traits described to date, the first two specifically impact risk of a RD, whereas the last four point to shared aetiologies with macular condition, myopia and glaucoma. Fine-mapping prioritized the lead common missense variant (TYR S192Y) as causal variant at the TYR locus and a small set of credible causal variants at the FAT3 locus. The larger study size presented here, enabled by resources linked to health records or self-report, provides novel insights into RD aetiology and underlying pathological pathways.

scholarly journals Insight into the genetic aetiology of retinal detachment by combining small clinical and large population-based datasets

2019 ◽  
Author(s):  
Thibaud S. Boutin ◽  
David G. Charteris ◽  
Aman Chandra ◽  
Susan Campbell ◽  
Caroline Hayward ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Genetic Risk ◽  
Association Studies ◽  
Population Based ◽  
Self Report ◽  
Cataract Operation ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Independent Population

AbstractIdiopathic retinal detachment is a serious common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. Genetic correlations between retinal detachment and high myopia or cataract operation were high, respectively 0.46 (SE=0.08) and 0.44 (SE=0.07), in the UK Biobank dataset and in line with known epidemiological associations. Meta-analysis of genome-wide association studies using UK Biobank retinal detachment cases (N=3977) and two cohorts, each comprising ∼1000 rhegmatogenous retinal detachment patients, uncovered 11 genome-wide significant association signals, near or withinZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1andLOXL1.Replication in the 23andMe dataset, where retinal detachment is self-reported by participants, firmly establishes association at six lociFAT3, COL22A1, TYR, BMP3, ZC3H11BandPLCE1.The former two seem to particularly impact on retinal detachment, the latter three shed light on shared aetiologies with cataract, myopia and glaucoma.Author SummaryRetinal detachments are common conditions that may lead to permanent severe sight reduction or blindness; they are a major cause of emergency eye surgery. The most common type of retinal detachment follows a break in the retina and is thought to be in part genetically determined but little is known about the contributing individual genetic risk variants. The condition prevalence increases with age and with common eye conditions such as myopia, cataract or glaucoma. We showed that the retinal detachment cases derived from self-report or hospitalisation records in the large UK Biobank dataset show very similar characteristics to samples of carefully clinically evaluated retinal detachment with break cases and therefore could be used to perform genetic analysis of the condition. Association studies require large sample of cases and by pooling Biobank and clinical cases, this study identifies 11 novel significant associations, six of which were further replicated in an independent population-based dataset (23andMe). Two of the replicated findings seem to specifically underline retinal detachment risk while three others highlight shared genetic risk with myopia, cataract and/or glaucoma, paving the way to better understanding of these conditions and of their overlap.

scholarly journals An atlas of genetic associations in UK Biobank

2017 ◽  
Author(s):  
Oriol Canela-Xandri ◽  
Konrad Rawlik ◽  
Albert Tenesa
Keyword(s):  
Complex Traits ◽  
Statistical Power ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Genome Wide ◽  
Related Individuals ◽  
Sufficient Statistical Power

ABSTRACTGenome-wide association studies have revealed many loci contributing to the variation of complex traits, yet the majority of loci that contribute to the heritability of complex traits remain elusive. Large study populations with sufficient statistical power are required to detect the small effect sizes of the yet unidentified genetic variants. However, the analysis of huge cohorts, like UK Biobank, is complicated by incidental structure present when collecting such large cohorts. For instance, UK Biobank comprises 107,162 third degree or closer related participants. Traditionally, GWAS have removed related individuals because they comprised an insignificant proportion of the overall sample size, however, removing related individuals in UK Biobank would entail a substantial loss of power. Furthermore, modelling such structure using linear mixed models is computationally expensive, which requires a computational infrastructure that may not be accessible to all researchers. Here we present an atlas of genetic associations for 118 non-binary and 599 binary traits of 408,455 related and unrelated UK Biobank participants of White-British descent. Results are compiled in a publicly accessible database that allows querying genome-wide association summary results for 623,944 genotyped and HapMap2 imputed SNPs, as well downloading whole GWAS summary statistics for over 30 million imputed SNPs from the Haplotype Reference Consortium panel. Our atlas of associations (GeneATLAS,http://geneatlas.roslin.ed.ac.uk) will help researchers to query UK Biobank results in an easy way without the need to incur in high computational costs.

scholarly journals Measuring genetic variation in the multi-ethnic Million Veteran Program (MVP)

2020 ◽  
Author(s):  
Haley Hunter-Zinck ◽  
Yunling Shi ◽  
Man Li ◽  
Bryan R. Gorman ◽  
Sun-Gou Ji ◽  
...  
Keyword(s):  
Quality Control ◽  
Association Studies ◽  
Current Data ◽  
Control Analysis ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
High Quality ◽  
Data Set ◽  
Entire Cohort ◽  
Genome Wide

AbstractThe Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect consented biosamples from at least one million Veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide genome-wide scan of the entire cohort, in parallel with whole genome sequencing, methylation, and other omics assays. Here, we present the design and performance of MVP 1.0 custom Axiom® array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality control analysis was developed and conducted on an initial tranche of 485,856 individuals leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high quality genotypes not only on common variants but also on rare variants. We confirmed the substantial ancestral diversity of MVP with nearly 30% non-European individuals, surpassing other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current data set has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

scholarly journals A year of COVID-19 GWAS results from the GRASP portal reveals potential SARS-CoV-2 modifiers

2021 ◽  
Author(s):  
Florian Thibord ◽  
Melissa V Chan ◽  
Ming-Huei Chen ◽  
Andrew D Johnson
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Therapeutic Strategies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Independent Dataset ◽  
Genome Wide ◽  
Data Release ◽  
Host Genetic

Host genetic variants influence the susceptibility and severity of several infectious diseases, and the discovery of novel genetic associations with Covid-19 phenotypes could help developing new therapeutic strategies to reduce its burden. Between May 2020 and February 2021, we used Covid-19 data released periodically by UK Biobank and performed over 400 Genome-Wide Association Studies (GWAS) of Covid-19 susceptibility (N=15,738 cases), hospitalization (N=1,916), severe outcomes (N=935) and death (N=828), stratified by ancestry and sex. In coherence with previous studies, we observed 2 independent signals at the chr3p21.31 locus (rs73062389-A, OR=1.22, P=7.64E-14 and rs13092887-A, OR=1.73, P=2.38E-8, in Europeans) modulating susceptibility and severity, respectively, and a signal influencing susceptibility at the ABO locus (rs9411378-A, OR=1.10, P =7.36E-10, in Europeans), which was more significant in men than in women (P=0.01). In addition, we detected 7 genome-wide significant signals in the last data release analyzed (on February 24th 2021), of which 4 were associated with susceptibility (SCRT2, LRMDA, chr15q24.2, MIR3681HG), 2 with hospitalization (ANKS1A, chr12p13.31) and 1 for severity (ADGRE1). Finally, we identified over 300 associations which increased in significance over time, and reached at least P<10-5 in the last data release analyzed. We replicated 2 of these signals in an independent dataset: a variant downstream of CCL3 (rs2011959) associated with severity in men, and a variant located in an ATP5PO intron (rs12482569) associated with hospitalization. These results, freely available on the GRASP portal, provide new insights on the host genetic architecture of Covid-19 phenotypes.

scholarly journals Genetic stratification of depression by neuroticism: revisiting a diagnostic tradition

2019 ◽  
Vol 50 (15) ◽  
pp. 2526-2535 ◽  
Author(s):  
Mark J. Adams ◽  
David M. Howard ◽  
Michelle Luciano ◽  
Toni-Kim Clarke ◽  
Gail Davies ◽  
...  
Keyword(s):  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Artery Disease ◽  
Specific Association ◽  
Genetic Stratification ◽  
Genomic Regions ◽  
Genetic Contributions

AbstractBackgroundMajor depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.MethodsWe analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.ResultsWe found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.ConclusionOur findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.

scholarly journals Genome-wide analyses of behavioural traits are subject to bias by misreports and longitudinal changes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angli Xue ◽  
Longda Jiang ◽  
Zhihong Zhu ◽  
Naomi R. Wray ◽  
Peter M. Visscher ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Longitudinal Changes ◽  
Genome Wide ◽  
The Uk ◽  
Almost All ◽  
Cardiovascular Traits

AbstractGenome-wide association studies (GWAS) have discovered numerous genetic variants associated with human behavioural traits. However, behavioural traits are subject to misreports and longitudinal changes (MLC) which can cause biases in GWAS and follow-up analyses. Here, we demonstrate that individuals with higher disease burden in the UK Biobank (n = 455,607) are more likely to misreport or reduce their alcohol consumption levels, and propose a correction procedure to mitigate the MLC-induced biases. The alcohol consumption GWAS signals removed by the MLC corrections are enriched in metabolic/cardiovascular traits. Almost all the previously reported negative estimates of genetic correlations between alcohol consumption and common diseases become positive/non-significant after the MLC corrections. We also observe MLC biases for smoking and physical activities in the UK Biobank. Our findings provide a plausible explanation of the controversy about the effects of alcohol consumption on health outcomes and a caution for future analyses of self-reported behavioural traits in biobank data.

scholarly journals Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits

2019 ◽  
Author(s):  
Rona J. Strawbridge ◽  
Joey Ward ◽  
Mark E.S. Bailey ◽  
Breda Cullen ◽  
Amy Ferguson ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Association Studies ◽  
Genetic Correlations ◽  
Intima Media Thickness ◽  
Genome Wide Association ◽  
Ultra Sound ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Media Thickness ◽  
Genome Wide

AbstractObjectivesAtherosclerosis is the underlying cause of most cardiovascular disease, but mechanisms underlying atherosclerosis are incompletely understood. Ultra-sound measurement of the carotid artery intima-media thickness (cIMT) can be used to measure vascular remodelling, which is indicative of atherosclerosis. Genome-wide association studies have identified a number of genetic loci associated with cIMT, but heterogeneity of measurements collected by many small cohorts have been a major limitation in these efforts. Here we conducted genome-wide association analyses in UK Biobank (N=22,179), the largest single study with consistent cIMT measurements.Approach and resultsWe used BOLT-LMM to run linear regression of cIMT in UK Biobank, adjusted for age, sex, genotyping platform and population structure. In white British participants, we identified 4 novel loci associated with cIMT and replicated most previously reported loci. In the first sex-specific analyses of cIMT, we identified a female-specific locus on Chromosome 5, associated with cIMT in women only and highlight VCAN as a good candidate gene at this locus. Genetic correlations with body-mass index and glucometabolic traits were also observed.ConclusionThese findings replicate previously reported associations, highlight novel biology and provide new directions for investigating the sex differences observed in cardiovascular disease presentation and progression.

scholarly journals Physician-confirmed and administrative definitions of stroke in UK Biobank reflect the same underlying genetic trait.

2021 ◽  
Author(s):  
Kristiina Rannikmae ◽  
Konrad Rawlik ◽  
Amy C Ferguson ◽  
Nikos Avramidis ◽  
Muchen Jiang ◽  
...  
Keyword(s):  
Primary Care ◽  
Association Studies ◽  
Genetic Correlations ◽  
Self Report ◽  
Hospital Death ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Trait ◽  
Stroke Case ◽  
Code Type

Background: Stroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation. Methods: We compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci. Results: Stroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg 0.81-1) and each other (rg 0.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definitions. Conclusions: Stroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date.

scholarly journals EPID-19. SHARED GENOMIC ARCHITECTURE OF GLIOMA AND NEURO-COGNITIVE AND NEURO-PSYCHIATRIC TRAITS REVEALED BY LD-SCORE REGRESSION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi78-vi78
Author(s):  
Kyle Walsh ◽  
Quinn Ostrom ◽  
Chenan Zhang ◽  
Jacob Edelson ◽  
Erica Shen ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
College Attendance ◽  
Case Control ◽  
Cognitive Test ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genomic Architecture ◽  
Genome Wide

Abstract BACKGROUND Genome-wide analyses estimate glioma heritability at 25%, yet known risk loci account for just one-third of this risk and suggest that sporadic glioma is a highly polygenic disease with hitherto unaccounted for genomic architecture. LD-score regression leverages results from genome-wide association studies (GWAS) and known patterns of linkage disequilibrium (LD) to estimate correlation between the genetic architecture of multiple phenotypes. We applied LD-score regression to identify associations with neuro-cognitive and neuro-psychiatric traits not amenable to study in prior glioma case-control analyses. METHODS GWAS summary statistics were obtained from the Glioma International Case-Control Consortium (GICC) meta-analysis (Melin, et al. 2017) and for 64 neuro-cognitive and neuro-psychiatric traits primarily from the UK Biobank. Included SNPs had quality scores ≥0.70 and minor allele frequency ≥0.01. Pairwise genetic correlations between traits were estimated using the LDSC package. P-values < 7.8x10-4 (i.e. 0.05/64) were considered significant. RESULTS Significant negative correlations were identified between the genetic architectures of glioma and bipolar disorder (Rg=-0.41, P=1.4x10-9) and schizophrenia (Rg=-0.29, P=7.1x10-9), consistent in both GBM and LGG. Significant positive correlations were identified with measures of educational attainment, including age at educational completion (Rg=0.11, P=2.0x10-4), obtaining a college degree (Rg=0.086, P=4.9x10-4), college attendance (Rg=0.086, P=5.9x10-4), and years of education (Rg=0.081, P=7.7x10-4). These associations were notably stronger with LGG. A number of additional nominal associations were observed, including with anorexia (anti-correlated) and performance on a pair-matching cognitive test (positively correlated). Importantly, LD-score regression did not identify an association between glioma risk in GICC data and Townsend deprivation index in UK Biobank data. CONCLUSIONS These results implicate a shared genetic basis for glioma and several psychiatric and cognitive traits. Further research is needed to understand these associations and to explore underlying mechanisms, including the mediating effects of neuro-inflammation, developmental differences in neural‒glial cell circuitry, and inter-individual variation in myelination.

scholarly journals Genome-wide analyses of behavioural traits biased by misreports and longitudinal changes

2020 ◽  
Author(s):  
Angli Xue ◽  
Longda Jiang ◽  
Zhihong Zhu ◽  
Naomi R. Wray ◽  
Peter M. Visscher ◽  
...  
Keyword(s):  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Longitudinal Changes ◽  
Genome Wide ◽  
The Uk ◽  
Almost All ◽  
Cardiovascular Traits

AbstractGenome-wide association studies (GWAS) have discovered numerous genetic variants associated with human behavioural traits. However, behavioural traits are subject to misreports and longitudinal changes (MLC) which can cause biases in GWAS and follow-up analyses. Here, we demonstrate that individuals with higher disease burden in the UK Biobank (n = 455,607) are more likely to misreport or reduce their alcohol consumption (AC) levels, and propose a correction procedure to mitigate the MLC-induced biases. The AC GWAS signals removed by the MLC corrections are enriched in metabolic/cardiovascular traits. Almost all the previously reported negative estimates of genetic correlations between AC and common diseases become positive/non-significant after the MLC corrections. We also observe MLC biases for smoking and physical activities in the UK Biobank. Our findings provide a plausible explanation of the controversy about the effects of AC on health outcomes and a caution for future analyses of self-reported behavioural traits in biobank data.

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