scholarly journals Molecular genetic contributions to social deprivation and household income in UK Biobank (n = 112,151)

2016 ◽  
Author(s):  
William David Hill ◽  
Saskia P Hagenaars ◽  
Riccardo E Marioni ◽  
Sarah E Harris ◽  
David CM Liewald ◽  
...  
Keyword(s):  
Cognitive Ability ◽  
Household Income ◽  
Social Deprivation ◽  
Molecular Genetic ◽  
Mental Illnesses ◽  
Phenotypic Variance ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk

Individuals with lower socio-economic status (SES) are at increased risk of physical and mental illnesses and tend to die at an earlier age [1-3]. Explanations for the association between SES and health typically focus on factors that are environmental in origin [4]. However, common single nucleotide polymorphisms (SNPs) have been found collectively to explain around 18% (SE = 5%) of the phenotypic variance of an area-based social deprivation measure of SES [5]. Molecular genetic studies have also shown that physical and psychiatric diseases are at least partly heritable [6]. It is possible, therefore, that phenotypic associations between SES and health arise partly due to a shared genetic etiology. We conducted a genome-wide association study (GWAS) on social deprivation and on household income using the 112,151 participants of UK Biobank. We find that common SNPs explain 21% (SE = 0.5%) of the variation in social deprivation and 11% (SE = 0.7%) in household income. Two independent SNPs attained genome-wide significance for household income, rs187848990 on chromosome 2, and rs8100891 on chromosome 19. Genes in the regions of these SNPs have been associated with intellectual disabilities, schizophrenia, and synaptic plasticity. Extensive genetic correlations were found between both measures of socioeconomic status and illnesses, anthropometric variables, psychiatric disorders, and cognitive ability. These findings show that some SNPs associated with SES are involved in the brain and central nervous system. The genetic associations with SES are probably mediated via other partly-heritable variables, including cognitive ability, education, personality, and health.

scholarly journals Molecular Genetic Contributions to Social Deprivation and Household Income in UK Biobank

2016 ◽  
Vol 26 (22) ◽  
pp. 3083-3089 ◽  
Author(s):  
W. David Hill ◽  
Saskia P. Hagenaars ◽  
Riccardo E. Marioni ◽  
Sarah E. Harris ◽  
David C.M. Liewald ◽  
...  
Keyword(s):  
Household Income ◽  
Social Deprivation ◽  
Molecular Genetic ◽  
Uk Biobank ◽  
Genetic Contributions

scholarly journals Inherited Thrombophilias Are Associated with an Increased Risk of COVID-19 Associated Venous Thromboembolism: A Prospective Population-Based Cohort Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3214-3214
Author(s):  
Hannah P Stevens ◽  
Rodrigo Canovas ◽  
Karlheinz Peter ◽  
Huyen Tran ◽  
Zane Kaplan ◽  
...  
Keyword(s):  
Cohort Study ◽  
Venous Thromboembolism ◽  
Population Based ◽  
Uk Biobank ◽  
Factor V Leiden Mutation ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Icd 10 ◽  
The Impact

Abstract Background: COVID-19 is associated with high rates of venous thromboembolism (VTE). The impact of common inherited thrombophilias on the development of COVID-19-associated VTE (COVID-19 VTE) is not well understood. Objective: To determine if the presence of inherited thrombophilias modifies the risk of COVID-19 VTE or COVID-19 mortality. Methods: Prospective population-based cohort study evaluating adult participants of the UK Biobank diagnosed with COVID-19 between November 2019 and May 2021. Individuals were of European descent and aged between 45 and 69 at recruitment to UK Biobank. We evaluated six single nucleotide polymorphisms including rs6025 (Factor V Leiden mutation) and rs1799963 (Prothrombin mutation) in addition to two polygenic risk scores (PRS-VTE and PRS-ABO). A genome-wide association study was performed for associations with COVID-19 VTE. COVID-19 VTE was defined using International Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes for VTE following COVID-19 diagnosis. COVID-19 mortality was defined using ICD-10 codes for COVID-19 on the death certificate. Results: Demographic and clinical characteristics are shown in Table 1. Of the 13 712 COVID-19 positive individuals included in the analysis, the median age was 54 years and 52.5% were female. There were 197 (1.4%) cases of COVID-19 VTE and 890 (6.5%) died due to COVID-19. The rs6025 variant, synonymous with FVL, was associated with a 1.8-fold risk of COVID-19 VTE (95% CI 1.040-2.931) (Table 2). The risk of COVID-VTE was also increased with rs2066865 (OR 1.345; 95% CI 1.074-1.675) and the PRS-VTE (OR 1.262; 95% CI 1.081-1.468) (Table 2). COVID-19 VTE was associated with increased COVID-19 mortality (OR 2.731; 95% CI 1.885-3.901) but this study found no association between the studied inherited thrombophilias and COVID-19 mortality (Table 2). On genome-wide analysis, two novel SNPs, rs4975019 and rs2875853, located on chromosomes 4 and 16 respectively, were associated with an increased occurrence of COVID-19 VTE. Conclusions: These data demonstrate that several inherited thrombophilias increase the risk of COVID-19 VTE and suggest that two novel SNPs are associated with COVID-19 VTE. These results suggest that certain inherited thrombophilias may assist in characterising a subgroup of COVID-19 patients at higher risk of thrombotic events who require individualised antithrombotic therapy. Future prospective studies are required to evaluate inherited thrombophilias in this patient cohort. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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

2020 ◽  
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 ◽  
Increase Risk

AbstractBackgroundThe severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogenous. 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.MethodsIn this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1,778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS failed 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.ResultsWe 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-CoV2.ConclusionsEight genetic variants are identified to significantly increase risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely evidence and clues for better understanding the molecular pathogenesis of COVID-19 and genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

scholarly journals The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yu-Fang Pei ◽  
Yao-Zhong Liu ◽  
Xiao-Lin Yang ◽  
Hong Zhang ◽  
Gui-Juan Feng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lean Mass ◽  
Genetic Architecture ◽  
Polygenic Risk Score ◽  
Phenotypic Variance ◽  
Uk Biobank ◽  
Appendicular Lean Mass ◽  
Genome Wide ◽  
A Genome

Abstract Appendicular lean mass (ALM) is a heritable trait associated with loss of lean muscle mass and strength, or sarcopenia, but its genetic determinants are largely unknown. Here we conducted a genome-wide association study (GWAS) with 450,243 UK Biobank participants to uncover its genetic architecture. A total of 1059 conditionally independent variants from 799 loci were identified at the genome-wide significance level (p < 5 × 10−9), all of which were also significant at p < 5 × 10–5 in both sexes. These variants explained ~15.5% of the phenotypic variance, accounting for more than one quarter of the total ~50% GWAS-attributable heritability. There was no difference in genetic effect between sexes or among different age strata. Heritability was enriched in certain functional categories, such as conserved and coding regions, and in tissues related to the musculoskeletal system. Polygenic risk score prediction well distinguished participants with high and low ALM. The findings are important not only for lean mass but also for other complex diseases, such as type 2 diabetes, as ALM is shown to be a protective factor for type 2 diabetes.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

scholarly journals Analysis of genetic dominance in the UK Biobank

2021 ◽  
Author(s):  
Duncan S Palmer ◽  
Wei Zhou ◽  
Liam Abbott ◽  
Nik Baya ◽  
Claire Churchhouse ◽  
...  
Keyword(s):  
Complex Traits ◽  
Multiple Testing ◽  
Model Organisms ◽  
Systematic Evaluation ◽  
Hair Color ◽  
Phenotypic Variance ◽  
Additive Effects ◽  
Uk Biobank ◽  
Genome Wide ◽  
The Uk

In classical statistical genetic theory, a dominance effect is defined as the deviation from a purely additive genetic effect for a biallelic variant. Dominance effects are well documented in model organisms. However, evidence in humans is limited to a handful of traits, particularly those with strong single locus effects such as hair color. We carried out the largest systematic evaluation of dominance effects on phenotypic variance in the UK Biobank. We curated and tested over 1,000 phenotypes for dominance effects through GWAS scans, identifying 175 loci at genome-wide significance correcting for multiple testing (P < 4.7 × 10-11). Power to detect non-additive loci is much lower than power to detect additive effects for complex traits: based on the relative effect sizes at genome-wide significant additive loci, we estimate a factor of 20-30 increase in sample size will be necessary to capture clear evidence of dominance similar to those currently observed for additive effects. However, these localised dominance hits do not extend to a significant aggregate contribution to phenotypic variance genome-wide. By deriving a version of LD-score regression to detect dominance effects tagged by common variation genome-wide (minor allele frequency > 0.05), we found no strong evidence of a contribution to phenotypic variance when accounting for multiple testing. Across the 267 continuous and 793 binary traits the median contribution was 5.73 × 10-4, with unbiased point estimates ranging from -0.261 to 0.131. Finally, we introduce dominance fine-mapping to explore whether the more rapid decay of dominance LD can be leveraged to find causal variants. These results provide the most comprehensive assessment of dominance trait variation in humans to date.

scholarly journals Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

2017 ◽  
Author(s):  
Amit V. Khera ◽  
Mark Chaffin ◽  
Krishna G. Aragam ◽  
Connor A. Emdin ◽  
Derek Klarin ◽  
...  
Keyword(s):  
Coronary Disease ◽  
Fold Increase ◽  
Predictive Capacity ◽  
Cumulative Impact ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Artery Disease

AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

scholarly journals Comparative transcriptome analysis of mule uncovered several heterosis-related genes for improving muscular endurance and cognition

2019 ◽  
Author(s):  
Shan Gao
Keyword(s):  
Alternative Splicing ◽  
Molecular Genetic ◽  
Hybrid Vigor ◽  
Neuronal System ◽  
Future Studies ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Mechanisms ◽  
Productive Traits ◽  
Genome Wide Gene Expression

AbstractHeterosis has been widely exploited in animal and plant breeding to enhance the productive traits of hybrid progeny of two breeds or two species. Although, there were multiple models for explaining the hybrid vigor, such as dominance and over-dominance hypothesis, its underlying molecular genetic mechanisms remain equivocal. The aim of this study is through comparing the different expression genes (DEGs) and different alternative splicing (DAS) genes to explore the mechanism of heterosis. Here, we performed a genome-wide gene expression and alternative splicing analysis of two heterotic crosses between donkey and horse in three tissues. The results showed that the DAS genes influenced the heterosis-related phenotypes in a unique than DEGs and about 10% DEGs are DAS genes. In addition, over 69.7% DEGs and 87.2% DAS genes showed over-dominance or dominance, respectively. Furthermore, the “Muscle Contraction” and “Neuronal System” pathways were significantly enriched both for the DEGs and DAS genes in muscle. TNNC2 and RYR1 genes may contribute to mule’s great endurance while GRIA2 and GRIN1 genes may be related with mule’s cognition. Together, these DEGs and DAS genes provide the candidates for future studies of the genetic and molecular mechanism of heterosis in mule.

Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases

2021 ◽  
pp. ASN.2020111599
Author(s):  
Zhi Yu ◽  
Jin Jin ◽  
Adrienne Tin ◽  
Anna Köttgen ◽  
Bing Yu ◽  
...  
Keyword(s):  
Kidney Function ◽  
Kidney Diseases ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Plasma Proteome ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Genome Wide ◽  
A Genome

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

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