Multi-ancestry GWAS for venous thromboembolism identifies novel loci followed by experimental validation in zebrafish

Genome wide association study (GWAS) results for Venous Thromboembolism (VTE) across 9 international cohorts of the Global Biobank Meta-analysis Initiative (GBMI), with representation across six ancestry groups (cases=27,987, controls=1,035,290), were combined using inverse-variance weighted meta-analysis. This multi-ancestry GWAS resulted in 38 genome-wide significant loci, 9 of which are potentially novel. For each autosomal locus we performed gene prioritization using seven independent, yet converging, lines of evidence. Through prioritization we identified genes known for VTE (e.g., F5, F11, VWF), genes known to modify blood coagulation (e.g., STAB2), and genes without known coagulation mechanisms from functional studies (e.g., PLCG2, TC2N). We evaluated the function of six prioritized genes, including F7 as a positive control, using laser mediated endothelial injury to induce thrombosis in zebrafish. We used CRISPR/Cas9 to knock down these potentially causal genes and measured time to occlusion after laser injury. From this assay we have supportive evidence for a role of RASIP1 and TC2N in the modification of human VTE, and suggestive evidence for STAB2 and TSPAN15. This study expands the currently identified genomic architecture of VTE through biobank-based multi-ancestry GWAS, in silico candidate gene predictions, and in vivo functional follow-up of novel candidate genes.