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

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 (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.

A large‐scale exome array analysis of venous thromboembolism

“…Despite these successes, much of the heritability of VTE remains unexplained. A recent study based on 3,290 VTE cases and 116,868 controls from the UK Biobank estimated the heritability due to genotyped and imputed single-nucleotide polymorphisms (SNPs) to be~30% (Klarin, Emdin, Natarajan, Conrad, & Kathiresan, 2017), and twin studies have estimated VTE heritability to be as high as~50% (Heit et al, 2004). However, the UK Biobank study also noted that known variants only explain 5% of VTE heritability.…”

Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk

“…Candidate and genome-wide association studies (GWAS) have identified seven VTE-associated susceptibility genes ( ABO, F2, F5, F11, FGG, PROCR , and NME7 ) (Germain et al, 2011; Greliche et al, 2013; Heit et al, 2012; Tang et al, 2013; Tregouet et al, 2009). A large meta-analysis of GWAS identified two additional susceptibility genes on chromosomes 10 and 19 ( TSPAN15 and SLC44A2 ) (Germain et al, 2015), and recently, two GWAS newly identified F8 and ZFPM2 genes on X chromosome and chromosome 8, respectively (Hinds et al, 2016; Klarin et al, 2017). …”

Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

“…Interestingly, Klarin et al (2017 ) recently reported an association between the T allele of rs6993770 and decreased risk of venous thromboembolism (VTE). They postulated that the underlying mechanism is a ZFPM2 mediated decrease in the plasma concentration of the principal inhibitor of plasminogen activator PAI-1, which is encoded by SERPINE1 (Klarin et al 2019) .…”