Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 10, Issue 2, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.116.001643
Keywords
body mass index; epidemiology; genetics; Mendelian randomization analysis; venous thromboembolism
Funding
- French National Institute for Health and Medical Research
- French Ministry of Health
- French Medical Research Foundation
- French Agency for Research
- National Heart, Lung, and Blood Institute (United States)
- National Institute for Health Research (United States)
- National Human Genome Research Institute (United States)
- National Cancer Institute (United States)
- Donald W. Reynolds Foundation
- Fondation Leducq
- European Commission
- Netherlands Organisation for Scientific Research
- Netherlands Heart Foundation
- Dutch Cancer Foundation
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Canada
- British Heart Foundation
- ICAN Institute for Cardiometabolism and Nutrition
- National Heart, Lung, and Blood Institute of the National Institutes of Health [T32 HL007734]
- Rhodes Trust
- Massachusetts General Hospital (MGH)
- Donovan Family Foundation
- National Institutes of Health [R01HL127564]
- Medical Research Council [MC_qA137853] Funding Source: researchfish
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Background-UK Biobank is the world's largest repository for phenotypic and genotypic information for individuals of European ancestry. Here, we leverage UK Biobank to understand the inherited basis for venous thromboembolism (VTE), a leading cause of cardiovascular mortality. Methods and Results-We identified 3290 VTE cases and 116 868 controls through billing code-based phenotyping. We performed a genome-wide association study for VTE with approximate to 9 000 000 imputed single-nucleotide polymorphisms. We performed a phenome-wide association study for a genetic risk score of 10 VTE-associated variants. To assess whether obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a genetic risk score instrument composed of 68 body mass index-associated variants. The genome-wide association study for VTE replicated previous findings at the F5, F2, ABO, F11, and FGG loci. We identified 1 new locus-ZFPM2 rs4602861-at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07-1.15; P=4.9x10(-10)) and a new independent variant at the F2 locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06-1.13; P=7.60x10(-9)). In a phenome-wide association study, a 10 single-nucleotide polymorphism VTE genetic risk score was associated with coronary artery disease (odds ratio, 1.08; 95% confidence interval, 1.05-1.10 per unit increase in VTE odds; P=1.08x10(-9)). In a Mendelian randomization analysis, genetically elevated body mass index (a 1 SD increase) was associated with 57% higher risk of VTE (odds ratio, 1.57; 95% confidence interval, 1.08-1.97; P=0.003). Conclusions-For common diseases such as VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference.
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