Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor.
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Abstract | 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 ≈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=4.9×10-10) and a new independent variant at the F2 locus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06-1.13; P=7.60×10-9). 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=1.08×10-9). 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. |
Year of Publication | 2017
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Journal | Circ Cardiovasc Genet
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Volume | 10
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Issue | 2
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Date Published | 2017 Apr
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ISSN | 1942-3268
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DOI | 10.1161/CIRCGENETICS.116.001643
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PubMed ID | 28373160
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PubMed Central ID | PMC5395047
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Grant list | R01 HL127564 / HL / NHLBI NIH HHS / United States
T32 HL007734 / HL / NHLBI NIH HHS / United States
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