Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism

Abstract

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.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

“…To systematically explore the genetic overlap between stroke and these traits, we surveyed published GWAS for BP, blood lipids, type 2 diabetes (T2D), cIMT, cPL, AF, venous thromboembolism (VTE), CAD, and WMH, assembled through the IGEN-BP 24 , ENGAGE 25 , DIAGRAM 26 , CHARGE 27,28 , AFGen 29 , INVENT 30 , and CARDIoGRAMplusC4D 31 consortia (Supplementary Table 12). When constructing sets of index SNPs of the nonstroke phenotypes (Bonferroni-adjusted P <1.3 ×10 −4 = 0.05/32 loci/12 related vascular traits) and SNPS in high linkage disequilibrium (LD) ( r 2 >0.9 in the 1000G European-ancestry dataset (EUR)) with those index variants, 17 of the 32 stroke lead variants showed overlap with these sets (Fig.…”

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism

“…The allele frequency of the F5 rs4524 variant was 0.732 in our population, which is similar to that in a reference population of European ancestry (0.736). 34 The frequency of this allele was also higher in VTE cases than in the sub-cohort (0.775 versus 0.732, respectively). There were 899 heterozygous individuals (39.1%) and 1,233 O.V.…”

The European Hematology Association Roadmap for European Hematology Research: a consensus document

“…VT: high-throughput genotyping technologies in the framework of genome-wide association studies have led to the identification of at least eight new loci associated with the risk of first VT. 247 However, the currently known genetic factors explain only approximately 5% of VT heritability. 248 An important question is how to discover the missing heritability.…”