Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10-8 including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10-16) and 1.21 (p = 2.75 × 10-15), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology.
Bibliographical noteFunding Information:
This work is the product of the International Network against Thrombosis (INVENT) collaboration. This work was financially supported by the French National Institute for Health and Medical Research; French Ministry of Health; French Medical Research Foundation; French Agency for Research; National Heart, Lung, and Blood Institute (USA); National Institute for Health Research (USA); National Human Genome Research Institute (USA); National Cancer Institute (USA); the Donald W. Reynolds Foundation; Fondation Leducq; The European Commission; Netherlands Organisation for Scientific Research; Netherlands Heart Foundation; Dutch Cancer Foundation; Canadian Institutes of Health Research; Heart and Stroke Foundation of Canada; British Heart Foundation; and ICAN Institute for Cardiometabolism and Nutrition. The lists of grants supporting this research can be found in the Supplemental Data .
© 2015 The American Society of Human Genetics.