{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:09:52Z","timestamp":1785431392416,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,22]]},"group-title":"Genetic and Genomic Medicine","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Expanded short tandem repeats contribute to a broad spectrum of neurodegenerative diseases, yet their roles in Parkinson\u2019s disease (PD) and parkinsonism remain incompletely characterized, especially across diverse ancestries. We analyzed short-read whole-genome (WGS) and clinical exome sequencing (CES) data from 38,365 individuals (28,861 WGS; 9,504 CES), encompassing 23,242 patients with PD, 4,729 patients with atypical parkinsonism and 10,394 healthy controls from 11 genetic ancestries. To determine carrier frequencies and characterize repeat structures across diverse ancestries, we genotyped 12 established pathogenic loci where normal, intermediate, and pathogenic alleles can be reliably differentiated using short-read sequencing data. Additionally, we conducted threshold-based associations to determine the minimum threshold associated with increased PD risk in 15,995 individuals (8,591 PD, 7,404 controls) of European ancestry.<\/jats:p>\n                <jats:p>\n                  Pathogenic repeat expansions were detected in 62 patients (56 PD and 6 atypical parkinsonism) and 5 controls across seven loci (\n                  <jats:italic>AR<\/jats:italic>\n                  ,\n                  <jats:italic>ATXN1<\/jats:italic>\n                  ,\n                  <jats:italic>ATXN2<\/jats:italic>\n                  ,\n                  <jats:italic>ATXN3<\/jats:italic>\n                  ,\n                  <jats:italic>CACNA1A<\/jats:italic>\n                  ,\n                  <jats:italic>HTT<\/jats:italic>\n                  and\n                  <jats:italic>THAP11<\/jats:italic>\n                  ), spanning seven ancestries. Among these,\n                  <jats:italic>ATXN2<\/jats:italic>\n                  expansions were the most frequently observed in PD and were present in African, East Asian, European and Middle Eastern ancestries. Additionally, intermediate\n                  <jats:italic>ATXN2<\/jats:italic>\n                  repeat expansions exhibited a strong, length-dependent association with PD risk in the European population, with individuals with \u226532 repeats having a more than four-fold increased risk (odds ratio 4.25, 95% confidence interval 1.80-12.05). Overall, &gt;92% of expanded alleles harbor CAA interruptions within the CAG tract. Pathogenic expansions at other loci, such as\n                  <jats:italic>ATXN3<\/jats:italic>\n                  and\n                  <jats:italic>THAP11<\/jats:italic>\n                  , showed more ancestry-specific distributions. Clinically, individuals with pathogenic\n                  <jats:italic>ATXN2<\/jats:italic>\n                  and\n                  <jats:italic>ATXN3<\/jats:italic>\n                  expansions most often presented with typical PD features but frequently showed earlier disease onset and a strong family history of PD.\n                <\/jats:p>\n                <jats:p>\n                  This large-scale, multi-ancestry study comprehensively maps the genetic landscape of pathogenic and intermediate repeat expansions in PD. Our findings confirm a length- and structure-dependent risk association for\n                  <jats:italic>ATXN2<\/jats:italic>\n                  with PD in the European population and highlight the pleiotropic effects of repeat expansions across the parkinsonian spectrum.\n                <\/jats:p>","DOI":"10.64898\/2026.06.12.26354932","type":"posted-content","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T23:05:18Z","timestamp":1782169518000},"source":"Crossref","is-referenced-by-count":0,"title":["Repeat expansions in Parkinson\u2019s disease and parkinsonism across ancestries: insights from a global genetic cohort"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7162-9821","authenticated-orcid":false,"given":"Lara M.","family":"Lange","sequence":"first","affiliation":[{"name":"Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA"},{"name":"Institute of Neurogenetics, University of Luebeck, Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-0261","authenticated-orcid":false,"given":"Catalina","family":"Cerquera-Cleves","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neurosciences, Hospital Universitario San Ignacio, Bogot\u00e1, Colombia"},{"name":"CHU de Qu\u00e9bec Research Center, Axe Neurosciences, Laval University, Quebec City, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-3839","authenticated-orcid":false,"given":"Ai Huey","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6942-2522","authenticated-orcid":false,"given":"Shen-Yang","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2975-8803","authenticated-orcid":false,"given":"Njideka U.","family":"Okubadejo","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Medicine, College of Medicine, University of Lagos, Lagos State, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8566-7573","authenticated-orcid":false,"given":"Chin-Hsien","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3992-1942","authenticated-orcid":false,"given":"Pin-Shiuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-3612","authenticated-orcid":false,"given":"Jung Hwan","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Neurology, Seoul National University Hospital, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6329-4366","authenticated-orcid":false,"given":"Azlina","family":"Ahmad-Annuar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8630-6754","authenticated-orcid":false,"given":"Laurel A.","family":"Screven","sequence":"additional","affiliation":[{"name":"The Global Parkinson\u2019s Genetics Program (GP2), Chevy Chase, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5817-6290","authenticated-orcid":false,"given":"Viorica","family":"Chelban","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute Parkinson\u2019s Research Centre at UCL, London, WC1N 3BG, UK"},{"name":"University College London, Institute of Neurology, Department of Neuromuscular Diseases, Queen Square, London, WC1N 3BG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-9304","authenticated-orcid":false,"given":"Allison A.","family":"Dilliot","sequence":"additional","affiliation":[{"name":"Parkinson\u2019s 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