title: 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.
  
  
  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 theF5,F2,ABO,F11, andFGGloci. We identified 1 new locus-ZFPM2rs4602861-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 theF2locus (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.
authors.affiliation: From the Center for Genomic Medicine (D.K., C.A.E., P.N., S.K.), Department of Surgery (D.K.), and Division of Vascular and Endovascular Surgery (M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (D.K., C.A.E., P.N., S.K.).
authors.forename: Derek
authors.initials: D
authors.lastname: Klarin
authors.affiliation: From the Center for Genomic Medicine (D.K., C.A.E., P.N., S.K.), Department of Surgery (D.K.), and Division of Vascular and Endovascular Surgery (M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (D.K., C.A.E., P.N., S.K.).
authors.forename: Connor A
authors.initials: CA
authors.lastname: Emdin
authors.affiliation: From the Center for Genomic Medicine (D.K., C.A.E., P.N., S.K.), Department of Surgery (D.K.), and Division of Vascular and Endovascular Surgery (M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (D.K., C.A.E., P.N., S.K.).
authors.forename: Pradeep
authors.initials: P
authors.lastname: Natarajan
authors.affiliation: From the Center for Genomic Medicine (D.K., C.A.E., P.N., S.K.), Department of Surgery (D.K.), and Division of Vascular and Endovascular Surgery (M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (D.K., C.A.E., P.N., S.K.).
authors.forename: Mark F
authors.initials: MF
authors.lastname: Conrad
authors.affiliation: From the Center for Genomic Medicine (D.K., C.A.E., P.N., S.K.), Department of Surgery (D.K.), and Division of Vascular and Endovascular Surgery (M.E.C.), Massachusetts General Hospital, Harvard Medical School, Boston; and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (D.K., C.A.E., P.N., S.K.). skathiresan1@mgh.harvard.edu.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
mesh_terms: D000368:Aged; D018070:Biological Specimen Banks; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom; D054556:Venous Thromboembolism / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C117427:ZFPM2 protein, human
keywords: Mendelian randomization analysis; body mass index; epidemiology; genetics; venous thromboembolism