scholarly journals A tissue-level phenome-wide network map of colocalized genes and phenotypes in the UK Biobank

2021 ◽  
Author(s):  
Ghislain Rocheleau ◽  
Iain S Forrest ◽  
Áine Duffy ◽  
Shantanu Bafna ◽  
Amanda Dobbyn ◽  
...  
Keyword(s):  
Clustering Algorithm ◽  
Target Genes ◽  
Genome Wide Association Study ◽  
Wide Spectrum ◽  
Association Studies ◽  
Tissue Level ◽  
Bipartite Network ◽  
Uk Biobank ◽  
Tissue Specific ◽  
The Uk

Background: Phenome-wide association studies conducted in electronic health record (EHR)-linked biobanks have uncovered a large number of genomic loci associated with traits and diseases. However, interpretation of the complex relationships of associated genes and phenotypes is challenging. Results: We constructed a tissue-level phenome-wide network map of colocalized genes and phenotypes. First, we generated colocalized expression quantitative trait loci from 48 tissues of the Genotype-Tissue Expression project and from publicly available genome-wide association study summary statistics from the UK Biobank. We identified 9,151 colocalized genes for 1,411 phenotypes across 48 tissues. Then, we constructed a bipartite network using the colocalized signals to establish links between genes and phenotypes in each tissue. The majority of links are observed in a single tissue whereas only a few are present in all tissues. Finally, we applied the biLouvain clustering algorithm in each tissue-specific bipartite network to identify co-clusters of non-overlapping genes and phenotypes. The majority of co-clusters contains a small number of genes and phenotypes, and 88.6% of co-clusters are found in only one tissue. To demonstrate functionality of the phenome-wide map, we tested if these co-clusters were enriched with known biological and functional gene classes and observed several significant enrichments. Furthermore, we observed that tissue-specific co-clusters are enriched with reported drug side effects for the corresponding drug target genes in clinical trial data. Conclusions: The phenome-wide map provides links between genes, phenotypes and tissues across a wide spectrum of biological classes and can yield biological and clinical discoveries. The phenome-wide map is publicly available at https://rstudio-connect.hpc.mssm.edu/biPheMap/.

scholarly journals Frequent Daytime Napping is Detrimental to Human Health: A phenotype-wide Mendelian Randomization Study

2020 ◽  
Author(s):  
Lanlan Chen ◽  
Aowen Tian ◽  
Zhipeng Liu ◽  
Miaoran Zhang ◽  
Xingchen Pan ◽  
...  
Keyword(s):  
Health Outcomes ◽  
Human Health ◽  
Mendelian Randomization ◽  
Wide Spectrum ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Major Depressive ◽  
Genome Wide ◽  
The Uk

ABSTRACTBackgroundIt remains controversial whether daytime napping is beneficial for human health.ObjectiveTo examine the causal relationship between daytime napping and the risk for various human diseases.DesignPhenotype-wide Mendelian randomization study.SettingNon-UK Biobank cohorts reported in published genome-wide association studies (GWAS) provided the outcome phenotypes in the discovery stage. The UK Biobank cohort provided the outcome phenotypes in the validation stage.ParticipantsThe UK Biobank GWAS included 361,194 European-ancestry residents in the UK. Non-UKBB GWAS included various numbers of participants.ExposureSelf-reported daytime napping frequency.Main outcome measureA wide-spectrum of human health outcomes including obesity, major depressive disorder, and high cholesterol.MethodsWe examined the causal relationship between daytime napping frequency in the UK Biobank as exposure and a panel of 1,146 health outcomes reported in genome-wide association studies (GWAS), using a two-sample Mendelian randomization analysis. The significant findings were further validated in the UK Biobank health outcomes of 4,203 human traits and diseases. The causal effects were estimated using a fixed-effect inverse variance weighted model. MR-Egger intercept test was applied to detect horizontal pleiotropy, along with Cochran’s Q test to assess heterogeneity among the causal effects of IVs.FindingsThere were significant causal relationships between daytime napping frequency and a wide spectrum of human health outcomes. In particular, we validated that frequent daytime napping increased the risks of major depressive disorder, obesity and abnormal lipid profile.InterpretationThe current study showed that frequent daytime napping mainly had adverse impacts on physical and mental health. Cautions should be taken for health recommendations on daytime napping. Further studies are necessary to precisely define the best daytime napping strategies.

scholarly journals Genome-wide association study identifies 44 independent genomic loci for self-reported adult hearing difficulty in the UK Biobank cohort

2019 ◽  
Author(s):  
Helena RR. Wells ◽  
Maxim B. Freidin ◽  
Fatin N. Zainul Abidin ◽  
Antony Payton ◽  
Piers Dawes ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Age Related ◽  
Genome Wide ◽  
Hearing Difficulty ◽  
The Uk

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 651. ARHI is a multifactorial condition caused by both genetic and environmental factors, with estimates of heritability between 35% and 55%2–4. The genetic risk factors and underlying biological pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive. We performed genome-wide association studies (GWAS) for two self-reported hearing phenotypes, hearing difficulty (HDiff) and hearing aid use (HAid), using over 250,000 UK Biobank5 volunteers aged between 40-69 years. We identified 44 independent genome-wide significant loci (P<5E-08), 33 of which have not previously been associated with any form of hearing loss. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology and cognition. Immunohistochemistry for protein localisation in adult mouse cochlea indicate metabolic, sensory and neuronal functions for NID2, CLRN2 and ARHGEF28 identified in the GWAS. These results provide new insight into the genetic landscape underlying susceptibility to ARHI.

scholarly journals Genome-wide association study of liking of physical activity in the UK Biobank

2021 ◽  
Author(s):  
Yann C. Klimentidis ◽  
Michelle Newell ◽  
Matthijs D. van der Zee ◽  
Victoria L. Bland ◽  
Sebastian May-Wilson ◽  
...  
Keyword(s):  
Physical Activity ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Wide Range ◽  
The Uk

A lack of physical activity (PA) is one of the most pressing health issues facing society today. Our individual propensity for PA is partly influenced by genetic factors. Stated liking of various PA behaviors may capture additional dimensions of PA behavior that are not captured by other measures, and contribute to our understanding of the genetics of PA behavior. Here, in over 157,000 individuals from the UK Biobank, we sought to complement and extend previous findings on the genetics of PA behavior by performing genome-wide association studies of self-reported liking of several PA-related behaviors plus an additional derived trait of overall PA-liking. We identified a total of 19 unique genome-wide significant loci across all traits, only four of which overlap with loci previously identified for PA behavior. The PA-liking traits were genetically correlated with self-reported (rg: 0.38 to 0.80) and accelerometry-derived (rg: 0.26 to 0.49) PA measures, and with a wide range of health-related traits and dietary behaviors. Replication in the Netherlands Twin Register (NTR; n>7,300) and the TwinsUK (n>1,300) study revealed directionally consistent associations. Polygenic risk scores (PRS) were then trained in UKB for each PA-liking trait and for self-reported PA behavior. The PA-liking PRS significantly predicted the same liking trait in NTR. The PRS for liking of going to the gym predicted PA behavior in NTR (r2 = 0.40%) nearly as well as the one constructed based on self-reported PA behavior (r2 = 0.42%). Combining the two PRS into a single model increased the r2 to 0.59%, suggesting that although these PRS correlate with each other, they are also capturing distinct dimensions of PA behavior. In conclusion, we have identified the first loci associated with PA-liking, and extended and refined our understanding of the genetic basis of PA behavior.

scholarly journals Estimating the effective sample size in association studies of quantitative traits

2021 ◽  
Author(s):  
Andrey Ziyatdinov ◽  
Jihye Kim ◽  
Dmitry Prokopenko ◽  
Florian Privé ◽  
Fabien Laporte ◽  
...  
Keyword(s):  
Statistical Power ◽  
Quantitative Traits ◽  
Mixed Model ◽  
Association Studies ◽  
Effective Sample Size ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
The Uk

Abstract The effective sample size (ESS) is a metric used to summarize in a single term the amount of correlation in a sample. It is of particular interest when predicting the statistical power of genome-wide association studies (GWAS) based on linear mixed models. Here, we introduce an analytical form of the ESS for mixed-model GWAS of quantitative traits and relate it to empirical estimators recently proposed. Using our framework, we derived approximations of the ESS for analyses of related and unrelated samples and for both marginal genetic and gene-environment interaction tests. We conducted simulations to validate our approximations and to provide a quantitative perspective on the statistical power of various scenarios, including power loss due to family relatedness and power gains due to conditioning on the polygenic signal. Our analyses also demonstrate that the power of gene-environment interaction GWAS in related individuals strongly depends on the family structure and exposure distribution. Finally, we performed a series of mixed-model GWAS on data from the UK Biobank and confirmed the simulation results. We notably found that the expected power drop due to family relatedness in the UK Biobank is negligible.

scholarly journals Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

scholarly journals Genetic overlap between Alzheimer’s disease and depression mapped onto the brain

2021 ◽  
Author(s):  
Jennifer Monereo Sánchez ◽  
Miranda T. Schram ◽  
Oleksandr Frei ◽  
Kevin O’Connell ◽  
Alexey A. Shadrin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Brain Mri ◽  
Genetic Correlations ◽  
Gaussian Mixture ◽  
Brain Morphology ◽  
Uk Biobank ◽  
Genetic Overlap ◽  
The Uk

ABSTRACTBackgroundAlzheimer’s disease (AD) and depression are debilitating brain disorders that are often comorbid. Shared brain mechanisms have been implicated, yet findings are inconsistent, reflecting the complexity of the underlying pathophysiology. As both disorders are (partly) heritable, characterizing their genetic overlap may provide etiological clues. While previous studies have indicated negligible genetic correlations, this study aims to expose the genetic overlap that may remain hidden due to mixed directions of effects.MethodsWe applied Gaussian mixture modelling, through MiXeR, and conjunctional false discovery rate (cFDR) analysis, through pleioFDR, to genome-wide association study (GWAS) summary statistics of AD (n=79,145) and depression (n=450,619). The effects of identified overlapping loci on AD and depression were tested in 403,029 participants of the UK Biobank (mean age 57.21 52.0% female), and mapped onto brain morphology in 30,699 individuals with brain MRI data.ResultsMiXer estimated 98 causal genetic variants overlapping between the two disorders, with 0.44 concordant directions of effects. Through pleioFDR, we identified a SNP in the TMEM106B gene, which was significantly associated with AD (B=-0.002, p=9.1×10−4) and depression (B=0.007, p=3.2×10−9) in the UK Biobank. This SNP was also associated with several regions of the corpus callosum volume anterior (B>0.024, p<8.6×10−4), third ventricle volume ventricle (B=-0.025, p=5.0×10−6), and inferior temporal gyrus surface area (B=0.017, p=5.3×10−4).DiscussionOur results indicate there is substantial genetic overlap, with mixed directions of effects, between AD and depression. These findings illustrate the value of biostatistical tools that capture such overlap, providing insight into the genetic architectures of these disorders.

scholarly journals Reproducibility in the UK Biobank of Genome-Wide Significant Signals Discovered in Earlier Genome-wide Association Studies

2020 ◽  
Author(s):  
Jack W. O’Sullivan ◽  
John P. A. Ioannidis
Keyword(s):  
Effect Size ◽  
Association Studies ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Single Nucleotide ◽  
Genome Wide ◽  
The Uk ◽  
Open Question

AbstractWith the establishment of large biobanks, discovery of single nucleotide polymorphism (SNPs) that are associated with various phenotypes has been accelerated. An open question is whether SNPs identified with genome-wide significance in earlier genome-wide association studies (GWAS) are replicated also in later GWAS conducted in biobanks. To address this question, the authors examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, replication GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNPs (of which 6,289 had reached p<5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0% and it was lower for binary than for quantitative phenotypes (58.1% versus 94.8% respectively). There was a18.0% decrease in SNP effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNP effect size, phenotype trait (binary or quantitative), and discovery p-value, we built and validated a model that predicted SNP replication with area under the Receiver Operator Curve = 0.90. While non-replication may often reflect lack of power rather than genuine false-positive findings, these results provide insights about which discovered associations are likely to be seen again across subsequent GWAS.

scholarly journals Genome-Wide Association Meta-Analysis Supports Genes Involved in Valve and Cardiac Development to Associate With Mitral Valve Prolapse

2021 ◽  
Author(s):  
Mengyao Yu ◽  
Sergiy Kyryachenko ◽  
Stephanie Debette ◽  
Philippe Amouyel ◽  
Jean-Jacques Schott ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Additional Risk ◽  
Genome Wide ◽  
The Uk

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

2021 ◽  
Author(s):  
Christa Meisinger ◽  
Dennis Freuer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Atopic Dermatitis ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
The Other ◽  
Uk Biobank ◽  
Inflammatory Bowel ◽  
The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

LPA and APOE are associated with statin selection in the UK Biobank

2020 ◽  
Author(s):  
Adam Lavertu ◽  
Gregory McInnes ◽  
Yosuke Tanigawa ◽  
Russ B Altman ◽  
Manuel A. Rivas
Keyword(s):  
Statin Therapy ◽  
High Intensity ◽  
Drug Response ◽  
Association Studies ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Treatment Decisions ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
The Uk

AbstractGenetics plays a key role in drug response, affecting efficacy and toxicity. Pharmacogenomics aims to understand how genetic variation influences drug response and develop clinical guidelines to aid clinicians in personalized treatment decisions informed by genetics. Although pharmacogenomics has not been broadly adopted into clinical practice, genetics influences treatment decisions regardless. Physicians adjust patient care based on observed response to medication, which may occur as a result of genetic variants harbored by the patient. Here we seek to understand the genetics of drug selection in statin therapy, a class of drugs widely used for high cholesterol treatment. Genetics are known to play an important role in statin efficacy and toxicity, leading to significant changes in patient outcome. We performed genome-wide association studies (GWAS) on statin selection among 59,198 participants in the UK Biobank and found that variants known to influence statin efficacy are significantly associated with statin selection. Specifically, we find that carriers of variants in APOE and LPA that are known to decrease efficacy of treatment are more likely to be on atorvastatin, a stronger statin. Additionally, carriers of the APOE and LPA variants are more likely to be on a higher intensity dose (a dose that reduces low-density lipoprotein cholesterol by greater than 40%) of atorvastatin than non-carriers (APOE: p(high intensity) = 0.16, OR = 1.7, P = 1.64 × 10−4, LPA: p(high intensity) = 0.17, OR = 1.4, P = 1.14 × 10−2). These findings represent the largest genetic association study of statin selection and statin dose association to date and provide evidence for the role of LPA and APOE in statin response, furthering the possibility of personalized statin therapy.

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