Dataset Information

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

ABSTRACT: Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency?

SUBMITTER: Emdin CA

PROVIDER: S-EPMC5915445 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Emdin Connor A CA Khera Amit V AV Chaffin Mark M Klarin Derek D Natarajan Pradeep P Aragam Krishna K Haas Mary M Bick Alexander A Zekavat Seyedeh M SM Nomura Akihiro A Ardissino Diego D Wilson James G JG Schunkert Heribert H McPherson Ruth R Watkins Hugh H Elosua Roberto R Bown Matthew J MJ Samani Nilesh J NJ Baber Usman U Erdmann Jeanette J Gupta Namrata N Danesh John J Chasman Daniel D Ridker Paul P Denny Joshua J Bastarache Lisa L Lichtman Judith H JH D'Onofrio Gail G Mattera Jennifer J Spertus John A JA Sheu Wayne H-H WH Taylor Kent D KD Psaty Bruce M BM Rich Stephen S SS Post Wendy W Rotter Jerome I JI Chen Yii-Der Ida YI Krumholz Harlan H Saleheen Danish D Gabriel Stacey S Kathiresan Sekar S

Nature communications 20180424 1

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additi ...[more]

PMID: 29691411

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Project description:Background/objectivesPhysical activity (PA) protects against a wide range of diseases. Habitual PA appears to be heritable, motivating the search for specific genetic variants that may inform efforts to promote PA and target the best type of PA for each individual.Subjects/methodsWe used data from the UK Biobank to perform the largest genome-wide association study of PA to date, using three measures based on self-report (nmax = 377,234) and two measures based on wrist-worn accelerometry data (nmax = 91,084). We examined genetic correlations of PA with other traits and diseases, as well as tissue-specific gene expression patterns. With data from the Atherosclerosis Risk in Communities (ARIC; n = 8,556) study, we performed a meta-analysis of our top hits for moderate-to-vigorous PA (MVPA).ResultsWe identified ten loci across all PA measures that were significant in both a basic and a fully adjusted model (p < 5 × 10-9). Upon meta-analysis of the nine top hits for MVPA with results from ARIC, eight were genome-wide significant. Interestingly, among these, the rs429358 variant in the APOE gene was the most strongly associated with MVPA, whereby the allele associated with higher Alzheimer's risk was associated with greater MVPA. However, we were not able to rule out possible selection bias underlying this result. Variants in CADM2, a gene previously implicated in obesity, risk-taking behavior and other traits, were found to be associated with habitual PA. We also identified three loci consistently associated (p < 5 × 10-5) with PA across both self-report and accelerometry, including CADM2. We found genetic correlations of PA with educational attainment, chronotype, psychiatric traits, and obesity-related traits. Tissue enrichment analyses implicate the brain and pituitary gland as locations where PA-associated loci may exert their actions.ConclusionsThese results provide new insight into the genetic basis of habitual PA, and the genetic links connecting PA with other traits and diseases.

Dataset Information

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Publications

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

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