Abstract Body (Do not enter title and authors here): Background: Peripheral artery disease (PAD) is a heritable atherosclerotic condition. With growing knowledge of the genetic basis for PAD and related risk factors, there is opportunity to identify high-risk individuals for prevention and potentially intervention based on polygenic background.

Aims: To develop and validate an integrated genome-wide polygenic score for PAD (GPS_PAD), evaluate association of polygenic risk with major adverse limb events (MALE), and compare predictive performance in diverse ancestral populations to previously published polygenic scores.

Methods: We developed GPS_PAD by integrating genetic association summary statistics for PAD and related traits stratified by ancestry. GPS_PAD was trained in a sample of 96,239 European individuals from the UK Biobank, and validated in multi-ancestry cohorts, including a holdout validation UK Biobank dataset (N=304,294), and external All of Us (AoU; N=237,173) and Mass General Brigham Biobank datasets (N=37,017). GPS_PAD performance was benchmarked against previously published polygenic scores and clinical risk factors.

Results: GPS_PAD was comprised of 603,595 variants with weights informed by association with PAD and ten PAD risk factors across five ancestry groups. GPS_PAD had an OR-per SD of 1.63 in the holdout UK Biobank dataset (95% CI 1.60-1.68). GPS_PAD outperformed previously published scores in non-European subgroups in the UK Biobank and achieved superior cross-population portability in external validation cohorts. GPS_PAD was associated with incident PAD in the UK Biobank (HR 1.66; 95% CI 1.61-1.71) and achieved improvements in discrimination (ΔC-statistic 0.030) that were nearly equivalent to the additive performances of diabetes (ΔC-statistic 0.029) and smoking (ΔC-statistic 0.034) to the baseline model including age, sex, and 10 principal components of ancestry. Among individuals with prevalent PAD, GPS_PAD was associated with incident MALE in the UK Biobank (HR 1.48; 95% CI 1.24-1.77). GPS_PAD consistently identified individuals with PAD at high MALE-risk in the Mass General Brigham Biobank (HR 1.34; 95% CI 1.12-1.60), and AoU (HR 1.33; 95% CI 1.12-1.58).

Conclusions: These findings contribute a polygenic score for PAD that predicts disease and MALE with cross-cohort performance and transferability to diverse ancestries. Integrated polygenic scores may be used to stratify PAD risk and target more aggressive management, lifestyle modification, and surveillance efforts.