A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q
Published Date:Aug 2012
Source:J Thromb Haemost. 2012; 10(8):1521-1531.
Keywords:ABO Blood-Group System
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 9
Deep Vein Thrombosis
European Continental Ancestry Group
Genetic Predisposition To Disease
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Pubmed Central ID:PMC3419811
Funding:AG0346760/AG/NIA NIH HHS/United States
CA92153/CA/NCI NIH HHS/United States
DD000235/DD/NCBDD CDC HHS/United States
HG04735/HG/NHGRI NIH HHS/United States
HL66216/HL/NHLBI NIH HHS/United States
HL83141/HL/NHLBI NIH HHS/United States
R01 CA092153/CA/NCI NIH HHS/United States
R01 HL066216/HL/NHLBI NIH HHS/United States
R01 HL083141/HL/NHLBI NIH HHS/United States
U01 HG004735/HG/NHGRI NIH HHS/United States
To identify venous thromboembolism (VTE) disease-susceptibility genes.
We performed in silico genome wide association (GWAS) analyses using genotype data imputed to ~2.5 million single nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency-matched on age and sex (n=1459; discovery population). SNPs exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were resequenced.
Seven SNPs exceeded genome-wide significance (P < 5 × 10-8); four on chromosome 1q24.2 (F5 rs6025 [Factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7, and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO resequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3’ UTR that were strongly associated with VTE (P < 10-4) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (α=1 × 10-8; 1% VTE prevalence).
Aside from F5 rs6025, ABO rs8176719 and rs2519093, and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.
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