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 (GPSPAD). Methods: GPSPAD was constructed by integrating multi-ancestry summary statistics for PAD and related traits. GPSPAD 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: GPSPAD 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, GPSPAD was more strongly associated with PAD in AoU and MGBB, including enhanced transferability to non-European subgroups. GPSPAD 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). GPSPAD 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, GPSPAD 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.

P.N. reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech / Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech / Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, TenSixteen Bio, and Tourmaline Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. All other authors have no relevant disclosures.

This work was supported by the Harvard Medical School LaDue Fellowship in Cardiovascular Medicine (to A.M.F.) and National Institutes of Health (grants R01HL127564 and U01HG011719 to P.N. and K08HL168238 to A.P.P.).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research was conducted using the UK Biobank resource under application number 7089. Secondary analyses of the UK Biobank, MGBB, and AoU was approved by the Massachusetts General Hospital Institutional Review Board.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Individual-level data from the UK Biobank and All of Us are available upon request from researchers to each organization. This study used Controlled Tier data from All of Us which is available to authorized users on the All of Us Researcher Workbench. GPSPAD constructed in this paper will be made available in the Polygenic Score Catalog following publication. Polygenic scores used for comparison of GPSPAD performance are available in the Polygenic Score Catalog through accession ID PGS001843 and PGS002055.