{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T08:23:28Z","timestamp":1793694208984,"version":"4.5.1"},"posted":{"date-parts":[[2025,7,11]]},"group-title":"Genetic and Genomic Medicine","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background:<\/jats:title>\n                  <jats:p>The genetic architecture of Parkinson\u2019s disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting insights into the genetic landscape of PD at a global scale.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods:<\/jats:title>\n                  <jats:p>We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson\u2019s Genetics Program (GP2), we analyzed sequencing and genotyping data from 105,588 individuals, including 63,837 affected and 41,751 unaffected, from eleven different ancestries. Approximately 29% of individuals included were from underrepresented populations.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings:<\/jats:title>\n                  <jats:p>\n                    Our findings revealed shared and ancestry-specific patterns in the prevalence and variant spectrum. Overall, \u223c2% of PD individuals carried a causative variant, with substantial variations across ancestries ranging from \u223c0\u00b75% in African to \u223c7% in Middle Eastern and &gt;10% Ashkenazi Jewish ancestries. Including disease-associated\n                    <jats:italic>GBA1<\/jats:italic>\n                    and\n                    <jats:italic>LRRK2<\/jats:italic>\n                    risk variants raised the yield to 13\u00b76%, largely driven by\n                    <jats:italic>GBA1<\/jats:italic>\n                    , except in East Asians, where\n                    <jats:italic>LRRK2<\/jats:italic>\n                    risk variants dominated.\n                    <jats:italic>GBA1<\/jats:italic>\n                    variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While\n                    <jats:italic>GBA1<\/jats:italic>\n                    variants were identified across all ancestries, frequencies ranged from \u223c5% in Middle Eastern and South Asian to \u223c52% in African ancestry. Similarly,\n                    <jats:italic>LRRK2<\/jats:italic>\n                    variants showed ancestry-specific enrichment, with p.G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish populations, and risk variants predominating in East Asians. Notably, clinical trials targeting specific genetic variants are currently primarily based in Europe and North America. Another globally PD-relevant gene was\n                    <jats:italic>PRKN<\/jats:italic>\n                    , with variant carriers identified across almost all ancestries.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation:<\/jats:title>\n                  <jats:p>This large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased ancestral diversity in PD research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable development and application of emerging precision therapies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding:<\/jats:title>\n                  <jats:p>Aligning Science Across Parkinson\u2019s (ASAP) Global Parkinson\u2019s Genetics Program (GP2)<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.08.25330815","type":"posted-content","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T22:40:10Z","timestamp":1752273610000},"source":"Crossref","is-referenced-by-count":11,"title":["The Global Landscape of Genetic Variation in Parkinson\u2019s disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance"],"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\/0000-0002-0225-8772","authenticated-orcid":false,"given":"Zih-Hua","family":"Fang","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE), Tu_bingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-1051","authenticated-orcid":false,"given":"Mary B.","family":"Makarious","sequence":"additional","affiliation":[{"name":"DataTecnica, Washington, DC, USA"},{"name":"Center for Alzheimer\u2019s and Related Dementias (CARD), National Institute on 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Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Ballard","sequence":"additional","affiliation":[{"name":"DataTecnica, Washington, DC, USA"},{"name":"Center for Alzheimer\u2019s and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-3438","authenticated-orcid":false,"given":"Soraya","family":"Bardien","sequence":"additional","affiliation":[{"name":"Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University; South African Medical Research Council\/Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South 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