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 (GWAS) for VTE with ~9,000,000 imputed SNPs. We performed a phenome-wide association study (PheWAS) for a genetic risk score (GRS) of 10 VTE associated variants. To assess if obesity is a causal factor for VTE, we performed Mendelian randomization analysis using a GRS instrument composed of 68 body mass index (BMI)-associated variants. The GWAS for VTE replicated previous findings at the F5, F2, ABO, F11, and FGG loci. We identified one new locus - ZFPM2 rs4602861 - at genome-wide significance [OR = 1.11 (95%CI: 1.07–1.15, P = 4.9×10−10)] and a new independent variant at the F2 locus [rs3136516, OR = 1.10 (95%CI: 1.06–1.13, P = 7.60×10−9)]. In a PheWAS, a 10 SNP VTE GRS was associated with coronary artery disease [OR = 1.08 (95%CI: 1.05–1.10 per unit increase in VTE odds, P = 1.08×10−9]. In a Mendelian randomization analysis, genetically-elevated BMI (a one standard deviation increase) was associated with 57% higher risk of VTE [OR = 1.57 (95%CI: 1.08–1.97, P = 0.003)].
Conclusions
For common diseases like VTE, biobanks provide potential to perform genetic discovery, explore the phenotypic consequences for disease-associated variants, and test causal inference.