Genome-wide Association Study of Peripheral Artery Disease in the Million Veteran Program

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality(1); however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African, and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. 11 of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL, and LPA, suggesting that therapeutic modulation of LDL cholesterol, the LPL pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, 4 of the variants appeared to be specific for PAD, including F5 p.R506Q, 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. Our results highlight mechanistic similarities and differences among coronary, cerebral, and peripheral atherosclerosis and provide therapeutic insights.