An integrated polygenic score stratifies risk of peripheral artery disease and adverse limb events in ancestrally diverse cohorts

Background and Aims: Peripheral artery disease (PAD) is a heritable atherosclerotic condition that is underdiagnosed and undertreated. With growing knowledge of the genetic basis for PAD and related risk factors, this study sought to construct a new polygenic score for PAD (GPS PAD ). Methods: GPS PAD was constructed by integrating multi-ancestry summary statistics for PAD and related traits. GPS PAD was trained in a UK Biobank dataset of 96,239 individuals and validated in a holdout UK Biobank dataset (N=304,294) and All of Us (AoU; N=237,173) and Mass General Brigham Biobank (MGBB, N=37,017). Results: GPS PAD was associated with an OR-per SD increase of 1.64 in the UK Biobank dataset (95% CI 1.60-1.68). Compared to previously published PAD polygenic scores, GPS PAD was more strongly associated with PAD in AoU and MGBB, including enhanced transferability to non-European subgroups. GPS PAD improved discrimination of incident PAD (ΔC-statistic 0.030) that was nearly equivalent to the additive performances of diabetes (ΔC-statistic 0.029) and smoking (ΔC-statistic 0.034). GPS PAD was associated with reduced ankle-brachial index in the MGBB with the top 8% of individuals having a mean ABI <0.90 when assessed. Among individuals with prevalent PAD, GPS PAD consistently identified individuals at high MALE-risk in the UK Biobank (HR 1.48; 95% CI 1.24-1.77), MGBB, (HR 1.34; 95% CI 1.12-1.60), and AoU (HR 1.33; 95% CI 1.12-1.58). Conclusions: An integrated, multi-ancestry polygenic score for PAD predicts disease and adverse limb outcomes in three diverse cohorts. Incorporating polygenic risk into PAD care has the potential to guide screening and tailor management to prevent MALE.