Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor

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.