scholarly journals Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank

2019 ◽  
Author(s):  
Huanwei Wang ◽  
Futao Zhang ◽  
Jian Zeng ◽  
Yang Wu ◽  
Kathryn E. Kemper ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Genetic Variants ◽  
Phenotypic Variability ◽  
Environmental Data ◽  
European Ancestry ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Genotype By Environment ◽  
A Genome ◽  
The Uk

AbstractGenotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank, and identified 75 significant vQTLs with P<2.0×10−9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.

scholarly journals Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw3538 ◽  
Author(s):  
Huanwei Wang ◽  
Futao Zhang ◽  
Jian Zeng ◽  
Yang Wu ◽  
Kathryn E. Kemper ◽  
...  
Keyword(s):  
Environmental Factors ◽  
Genetic Variants ◽  
Phenotypic Variability ◽  
Environmental Data ◽  
European Ancestry ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Genotype By Environment ◽  
A Genome ◽  
The Uk

Genotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank and identified 75 significant vQTLs with P < 2.0 × 10−9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.

scholarly journals Large-Scale, Genome-Wide Gene-Diet Interaction Testing for HbA1c Using Derived Dietary Patterns in the UK Biobank

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1280-1280
Author(s):  
Kenneth Westerman ◽  
Ye Chen ◽  
Han Chen ◽  
Jose Florez ◽  
Joanne Cole ◽  
...  
Keyword(s):  
Principal Components ◽  
Dietary Patterns ◽  
Genetic Variants ◽  
Interaction Analysis ◽  
European Ancestry ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Gene Level ◽  
The Uk

Abstract Objectives Gene-diet interaction analysis can inform the development of precision nutrition for diabetes by uncovering genetic variants whose effects on glycemic traits vary across dietary behaviors. However, due to noise in dietary datasets and the low statistical power inherent in interaction analysis, there is a lack of confident, well-replicated gene-diet interactions for glycemic traits. Emerging computationally-efficient software tools have made it feasible to conduct well-powered, genome-wide interaction analysis in hundreds of thousands of individuals. Here, our objective was to conduct a genome-wide gene-diet interaction analysis for glycated hemoglobin (HbA1c; a measure of hyperglycemia), leveraging the large sample size of the UK Biobank cohort and data-driven dietary patterns to discover genetic variants whose effect is modulated by diet. Methods Food frequency questionnaires were previously used to derive empirical dietary patterns using principal components analysis (FFQ-PCs) in the UK Biobank. FFQ-PCs were used in genome-wide interaction analysis for HbA1c levels in unrelated, non-diabetic individuals of European ancestry (N = 331,610), adjusting for age, sex, and 10 genetic principal components. P-values were calculated for both the interaction (P-int) and a joint test (significance of the variant-HbA1c association combining the main and interaction effects) and the MAGMA tool was used to calculate gene-level enrichment statistics. Results Preliminary results from the first two FFQ-PCs confirmed known genetic loci for HbA1c using the joint test, such as at G6PC2 and GCK. Though no interaction tests reached genome-wide significance, suggestive signals (P-int &lt; 1e-5) emerged at the variant level (including one near TPSD1, which codes for a tryptase and has been linked to red blood cell traits) and the gene level (such as for GTF3C2, which has previously been shown to interact with sleep in impacting lipid traits). Conclusions We have conducted the largest genome-wide study of gene-diet interactions for glycemic traits to-date and identified regions in the genome whose effect on HbA1c may be modulated by dietary intake, suggesting that this approach has the potential to reveal new insights into the genetics of glycemic traits and inform individualized dietary guidelines for diabetes prevention and management. Funding Sources NHLBI.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Vol 29 (8) ◽  
pp. 1396-1404 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Significant Locus ◽  
The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

scholarly journals Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank

BMJ ◽  
2019 ◽  
pp. l476 ◽  
Author(s):  
Shan Luo ◽  
Shiu Lun Au Yeung ◽  
Jie V Zhao ◽  
Stephen Burgess ◽  
C Mary Schooling
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Genetic Variants ◽  
Controlled Trial ◽  
European Ancestry ◽  
Gene Region ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
1000 Genomes ◽  
The Uk

Abstract Objective To determine whether endogenous testosterone has a causal role in thromboembolism, heart failure, and myocardial infarction. Design Two sample mendelian randomisation study using genetic variants as instrumental variables, randomly allocated at conception, to infer causality as additional randomised evidence. Setting Reduction by Dutasteride of Prostate Cancer Events (REDUCE) randomised controlled trial, UK Biobank, and CARDIoGRAMplusC4D 1000 Genomes based genome wide association study. Participants 3225 men of European ancestry aged 50-75 in REDUCE; 392 038 white British men and women aged 40-69 from the UK Biobank; and 171 875 participants of about 77% European descent, from CARDIoGRAMplusC4D 1000 Genomes based study for validation. Main outcome measures Thromboembolism, heart failure, and myocardial infarction based on self reports, hospital episodes, and death. Results Of the UK Biobank participants, 13 691 had thromboembolism (6208 men, 7483 women), 1688 had heart failure (1186, 502), and 12 882 had myocardial infarction (10 136, 2746). In men, endogenous testosterone genetically predicted by variants in the JMJD1C gene region was positively associated with thromboembolism (odds ratio per unit increase in log transformed testosterone (nmol/L) 2.09, 95% confidence interval 1.27 to 3.46) and heart failure (7.81, 2.56 to 23.8), but not myocardial infarction (1.17, 0.78 to 1.75). Associations were less obvious in women. In the validation study, genetically predicted testosterone (based on JMJD1C gene region variants) was positively associated with myocardial infarction (1.37, 1.03 to 1.82). No excess heterogeneity was observed among genetic variants in their associations with the outcomes. However, testosterone genetically predicted by potentially pleiotropic variants in the SHBG gene region had no association with the outcomes. Conclusions Endogenous testosterone was positively associated with thromboembolism, heart failure, and myocardial infarction in men. Rates of these conditions are higher in men than women. Endogenous testosterone can be controlled with existing treatments and could be a modifiable risk factor for thromboembolism and heart failure.

scholarly journals Interactions Between Sugar-Sweetened Beverage Consumption and Genetic Variants in the ChREBP Locus on Lipoprotein Concentrations in the UK Biobank: A Replication Study

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1255-1255
Author(s):  
Melanie Guirette ◽  
Danielle Haslam ◽  
Gina Peloso ◽  
Achilleas Pitsillides ◽  
Caren Smith ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Meta Analysis ◽  
Density Lipoprotein ◽  
High Linkage Disequilibrium ◽  
European Ancestry ◽  
Uk Biobank ◽  
Study Objective ◽  
Sugar Sweetened Beverage ◽  
Sweetened Beverage ◽  
The Uk

Abstract Objectives A meta-analysis of 11 CHARGE cohorts (N = 63,599) suggested that genetic variants within or near the CHREBP locus may modify the associations between sugar sweetened beverage (SSB) consumption and high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. The study objective was to replicate these findings in a large independent cohort. Methods Blood lipids and 24-hour recalls were available for 57,794 adults of European ancestry in the UK Biobank (2006-‘10). SSBs included “squash” and “fizzy” drinks derived from a single 24-hr recall. A total of 875 SNPs within or near the CHREBP locus were identified and included in this analysis. Associations between these SNPs and HDL-C and TG concentrations were quantified among participants who did not report SSB consumption (non-consumers, n = 45,866), reported ≥0.5 servings/day of SSB (consumers, n = 11,928), and a subset of consumers who reported ≥2 servings/day of SSB (high consumers, n = 3742). Interaction between SSB and selected SNPs on HDL-C and TG concentrations was evaluated by examining the difference in beta coefficients between strata. Results were considered statistically significant at a Bonferroni-corrected pinteract &lt; 0.0001 (0.05/499 effective tests). Results A significant interaction between SSB consumption and TBL2-rs71556729 on HDL-C concentration previously observed in the meta-analysis was replicated in UK Biobank. However, we observed a stronger interaction for a SNP in high linkage disequilibrium (R2 = 0.93) FZD9-rs34821369 (MAF = 0.03, pinteract = 8.2E-05) with TBL2-rs71556729 (MAF = 0.03, pinteract = 0.0004). Among only SSB consumers, each additional minor G allele at FZD9-rs34821369 was associated with mean HDL-C concentrations 1.63 mg/dL (SE = 0.53, P = 0.002) higher than those with the major T allele. Conclusions Our results suggest that adults with the minor allele at FZD9-rs34821369 may be protected against SSB-induced low HDL-C concentrations. These results are consistent the findings from a prior meta-analysis of 11 cohorts. Funding Sources NIH, AHA, USDA-ARS. This research has been conducted using the UK Biobank Resource (Application Number 35,835).

scholarly journals Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Jianchang Hu ◽  
Cai Li ◽  
Shiying Wang ◽  
Ting Li ◽  
Heping Zhang
Keyword(s):  
Genetic Variants ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Individual Risk ◽  
Uk Biobank ◽  
Risk Of Death ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
The Uk

Abstract Background The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. Methods In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. Results We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. Conclusions Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

scholarly journals Exploring polygenic-environment and residual-environment interactions for depressive symptoms within the UK Biobank

2021 ◽  
Author(s):  
Alexandra Claire Gillett ◽  
Bradley Jermy ◽  
S. Hong Lee ◽  
Oliver Pain ◽  
David M Howard ◽  
...  
Keyword(s):  
Depressive Symptoms ◽  
A Priori ◽  
Reaction Norm ◽  
Risk Scores ◽  
Environment Interaction ◽  
Uk Biobank ◽  
Negative Results ◽  
Residual Variation ◽  
A Genome ◽  
The Uk

Substantial advances have been made in identifying genetic contributions to depression, but little is known about how the effect of genes can be modulated by the environment, creating a gene-environment interaction. Using multivariate reaction norm models (MRNMs) within the UK Biobank (N=61294-91644), we investigate whether the polygenic and residual variation of depressive symptoms are modulated by 25 a-priori selected covariate traits: 12 environmental variables, 5 biomarkers and polygenic risk scores for 8 mental health disorders. MRNMs provide unbiased polygenic-covariate interaction estimates for a quantitative trait by controlling for outcome-covariate correlations and residual-covariate interactions. Of the 25 selected covariates, 11 significantly modulate depressive symptoms, but no single interaction explains a large proportion of phenotypic variation. Results are dominated by residual-covariate interactions, suggesting that covariate traits (including neuroticism, childhood trauma and BMI) typically interact with unmodelled variables, rather than a genome-wide polygenic score, to influence depressive symptoms. Only average sleep duration has a polygenic-covariate interaction explaining a demonstrably non-zero proportion of the variability in depressive symptoms. This effect is small, accounting for only 1.22% (95% CI [0.54,1.89]) of variation. The presence of an interaction highlights a specific focus for intervention, but the negative results here indicate a limited contribution from polygenic-environment interactions.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Chromosome 17 ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

ABSTRACTBackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P > 0.05).ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P < 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

scholarly journals The role of linoleic acid in asthma and inflammatory markers: a Mendelian randomization study

2019 ◽  
Vol 110 (3) ◽  
pp. 685-690 ◽  
Author(s):  
Jie V Zhao ◽  
C Mary Schooling
Keyword(s):  
Linoleic Acid ◽  
Blood Cell ◽  
White Blood Cell ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
European Ancestry ◽  
Uk Biobank ◽  
Reverse Causality ◽  
The Uk

ABSTRACT Background Asthma is a common respiratory disease, possibly caused by autoimmunity. Linoleic acid (LA), the main n–6 (ω-6) PUFA from widely used vegetable oils, is thought to suppress immune responses that might have benefits for asthma. However, this question has not been examined in randomized controlled trials. Objectives To obtain unconfounded estimates, we assessed how genetically predicted LA affected asthma using 2-sample Mendelian randomization. We also examined its role in white blood cell traits (eosinophil, neutrophil, and low monocyte counts) identified as potential causal factors in asthma. Methods We used 18 uncorrelated, genome-wide significant genetic variants to predict LA, which we applied to a large genetic case (n = 19,954)–control (n = 107,715) study of asthma, to the UK Biobank (408,961 people of European ancestry with 26,332 asthma cases), and for white blood cell traits to the UK Biobank. We also repeated the analysis on asthma using 29 replicated, functionally relevant genetic variants. In addition, we examined the role of asthma in LA to assess reverse causality. Results Genetically predicted LA was associated with lower risk of asthma (OR: 0.89 per SD increase in LA; 95% CI: 0.85, 0.93), with no association of asthma with LA. Genetically predicted LA was associated with lower eosinophil count (−0.03; 95% CI: −0.061, −0.004) and lower neutrophil count (−0.04; 95% CI: −0.057, −0.023). These estimates were robust to different selections of genetic variants and sensitivity analyses. Conclusions LA might protect against asthma possibly via white blood cell traits, with relevance to the identification of effective new interventions for asthma.

Contrasting Broad- and Clinically- defined Polygenic Indicators of Depression and Depression-related Phenotypes in Adults and Children

2020 ◽  
Author(s):  
John E. McGeary ◽  
Chelsie Benca-Bachman ◽  
Victoria Risner ◽  
Christopher G Beevers ◽  
Brandon Gibb ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Cognitive Reappraisal ◽  
Twin Studies ◽  
European Ancestry ◽  
Summary Statistics ◽  
Depression Severity ◽  
Uk Biobank ◽  
Polygenic Scores ◽  
Adults And Children ◽  
The Uk

Twin studies indicate that 30-40% of the disease liability for depression can be attributed to genetic differences. Here, we assess the explanatory ability of polygenic scores (PGS) based on broad- (PGSBD) and clinical- (PGSMDD) depression summary statistics from the UK Biobank using independent cohorts of adults (N=210; 100% European Ancestry) and children (N=728; 70% European Ancestry) who have been extensively phenotyped for depression and related neurocognitive phenotypes. PGS associations with depression severity and diagnosis were generally modest, and larger in adults than children. Polygenic prediction of depression-related phenotypes was mixed and varied by PGS. Higher PGSBD, in adults, was associated with a higher likelihood of having suicidal ideation, increased brooding and anhedonia, and lower levels of cognitive reappraisal; PGSMDD was positively associated with brooding and negatively related to cognitive reappraisal. Overall, PGS based on both broad and clinical depression phenotypes have modest utility in adult and child samples of depression.

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