{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T11:14:53Z","timestamp":1775819693425,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Peripheral artery disease (PAD) is a global health burden affecting over 200 million individuals and is frequently complicated by limb-threatening ischemia, leading to major amputations. Despite known clinical risk factors, the genetic basis underlying amputation risk in PAD remains poorly defined. In this study, we performed a multi-pronged genome-wide association study (GWAS) to identify genetic variants associated with lower extremity amputation in patients with PAD, using data from the All of Us Research Program. Two analytical strategies were employed: a targeted GWAS using ClinVar variants on the full cohort and a comprehensive genome-wide association study using Allele Count\/Allele Frequency (ACAF) data on a balanced subset of the cohort. The ClinVar analysis of 118,871 variants in 7558 PAD patients (405 with amputation, 7153 without) identified 3 suggestive associations with a genomic inflation factor of 1.046. The ACAF analysis of 7,784,837 quality-controlled variants in 804 balanced samples (399 cases, 405 controls) yielded 35 suggestive associations (p &lt; 1 \u00d7 10\u22125) with a genomic inflation factor of 1.017. No variants achieved suggestive significance in both analyses. These findings highlight candidate loci for further validation and may inform future development of risk prediction tools and targeted interventions to reduce limb loss in PAD. All associations are exploratory and require independent replication.<\/jats:p>","DOI":"10.3390\/ijms27083405","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:20:16Z","timestamp":1775816416000},"page":"3405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-Wide Association Study of Genetic Variants Associated with Lower Extremity Amputation Risk in Peripheral Artery Disease"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2071-5236","authenticated-orcid":false,"given":"Rajashekar","family":"Korutla","sequence":"first","affiliation":[{"name":"College of Engineering, The Roux Institute, Northeastern University, Portland, ME 04101, USA"},{"name":"Department of Bioengineering, College of Engineering, Northeastern University, Boston, MA 02120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanisha","family":"Garg","sequence":"additional","affiliation":[{"name":"College of Science, The Roux Institute, Northeastern University, Portland, ME 04101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael P.","family":"Wilczek","sequence":"additional","affiliation":[{"name":"College of Science, The Roux Institute, Northeastern University, Portland, ME 04101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9366-0109","authenticated-orcid":false,"given":"Elsie G.","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery, San Diego School of Medicine, University of California, La Jolla, San Diego, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-6986","authenticated-orcid":false,"given":"Saeed","family":"Amal","sequence":"additional","affiliation":[{"name":"College of Engineering, The Roux Institute, Northeastern University, Portland, ME 04101, USA"},{"name":"Department of Bioengineering, College of Engineering, Northeastern University, Boston, MA 02120, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/S0140-6736(13)61249-0","article-title":"Comparison of Global Estimates of Prevalence and Risk Factors for Peripheral Artery Disease in 2000 and 2010: A Systematic Review and Analysis","volume":"382","author":"Fowkes","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1161\/CIRCULATIONAHA.111.033878","article-title":"Genetics of Peripheral Artery Disease","volume":"125","author":"Leeper","year":"2012","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1016\/j.jvs.2006.12.037","article-title":"Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II)","volume":"45","author":"Norgren","year":"2007","journal-title":"J. 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