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

Apr 5, 2017Circulation. Cardiovascular genetics

Genes linked to blood clots in UK Biobank highlight ZFPM2 gene and suggest obesity as a cause

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Abstract

A new genetic variant associated with venous thromboembolism (VTE) was identified, with an odds ratio of 1.11.

A total of 3,290 VTE cases and 116,868 controls were analyzed through billing code-based phenotyping.
The genome-wide association study replicated previous findings and included one new locus at rs4602861 with genome-wide significance.
A genetic risk score based on 10 VTE-associated variants showed an association with coronary artery disease, with an odds ratio of 1.08.
Mendelian randomization analysis indicated that a genetically elevated body mass index is associated with a 57% higher risk of VTE.

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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 ≈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,,,, andloci. We identified 1 new locus-rs4602861-at genome-wide significance (odds ratio, 1.11; 95% confidence interval, 1.07-1.15;=4.9×10) and a new independent variant at thelocus (rs3136516; odds ratio, 1.10; 95% confidence interval, 1.06-1.13;=7.60×10). 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;=1.08×10). 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;=0.003). F5F2ABO F11FGG ZFPM2P F2P P P -10 -9 -9

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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