Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease

Venous thromboembolism (VTE) is a significant cause of mortality1, yet its genetic determinants remain incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank testing ~13 million DNA sequence variants for association with VTE (26,066 cases; 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 VTE cases and 167,295 controls. We identified 22 novel loci, bringing the total number of VTE-associated loci to 33 and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for VTE that identifies 5% of the population at equivalent incident VTE risk to carriers of the established F5 Leiden (p.R506Q) and prothrombin G20210A mutations. Our data provide new mechanistic insights into the genetic epidemiology of VTE and suggest a greater overlap among venous and arterial cardiovascular disease than previously suggested.
Editorial summary Genome-wide analysis of venous thromboembolism identifies 22 new risk loci and facilitates construction of a polygenic risk score. Comparison to arterial vascular disease highlights shared pathophysiology and potential therapeutic strategies.