| Title: | Genetic Analysis of Venous Thromboembolism in UK Biobank Identifies the ZFPM2 Locus and Implicates Obesity as a Causal Risk Factor |
| Journal: | Circulation Genomic and Precision Medicine |
| Published: | 1 Apr 2017 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/28373160/ |
| DOI: | https://doi.org/10.1161/circgenetics.116.001643 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCGENETICS.116.001643 |
Publication 8464
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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.</p>
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).</p>
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.</p>
5 Authors
- Derek Klarin
- Connor A Emdin
- Pradeep Natarajan
- Mark F Conrad
- Sekar Kathiresan
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
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