Abstract

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality worldwide. The extent to which genetic factors increase risk for PAD, however, has remained largely unknown as previous efforts at genome-wide analysis have been limited by sample size and power. Using data from the United States Department of Veteran’s Affairs Million Veteran Program (MVP), a large electronic health record linked genetic biobank, we have performed a genome-wide association study leveraging data from 31,307 MVP participants with PAD and 211,753 controls. We identified 19 PAD loci, 18 of which had not been previously reported. Among the risk loci associated only with PAD, we identified F5 p.R506Q (Factor 5 Leiden), highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Causal inference studies using mendelian randomization have identified causal roles for hypertension and extra-small very low-density lipoprotein particles highlighting novel therapeutic opportunities.