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A genome-wide association study for venous thromboembolism: the extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
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  • Pubmed ID:
    23650146
  • Pubmed Central ID:
    PMC3990406
  • Funding:
    HHSN268201100012C/HL/NHLBI NIH HHS/United States
    HL073410/HL/NHLBI NIH HHS/United States
    U01 DD000235/DD/NCBDD CDC HHS/United States
    R01 HL060739/HL/NHLBI NIH HHS/United States
    N01 HC085086/HC/NHLBI NIH HHS/United States
    HHSN268201100009I/HL/NHLBI NIH HHS/United States
    R01 HL095080/HL/NHLBI NIH HHS/United States
    UL1TR000124/TR/NCATS NIH HHS/United States
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    R01 HL083141/HL/NHLBI NIH HHS/United States
    N01 HC085081/HC/NHLBI NIH HHS/United States
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    R01HL59367/HL/NHLBI NIH HHS/United States
    HHSN268201100010C/HL/NHLBI NIH HHS/United States
    UL1 RR025005/RR/NCRR NIH HHS/United States
    R01 AG015928/AG/NIA NIH HHS/United States
    HHSN268201100008C/HL/NHLBI NIH HHS/United States
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  • Document Type:
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  • Description:
    Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.