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Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications

Lange LM 1 , Fang ZH 2 , Makarious MB 3 , Kuznetsov N 3 , Atterling Brolin K 4 , Ballard S 3 Show all authors , Bardien S 5 , Doquenia ML 6 , Heutink P 7 , Houlden H 8 , Iwaki H 3 , Jasaityte S 9 , Jones L 3 , Junker J 10 , Kaiyrzhanov R 11 , Koretsky MJ 3 , Kumar KR 12 , Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD) , Leonard HL 3 , Levine KS 3 , Lim SY 13 , Mencacci NE 14 , Mohamed WMY 15 , Nalls MA 3 , Noyce AJ 16 , Ojha R 17 , Okubadejo NU 18 , Ur Rehman S 19 , Screven L 7 , Shashkin C 20 , Sopromadze S 21 , Stafford EJ 9 , Tan AH 13 , Tan M 22 , Tavadyan Z 23 , Trinh J 24 , Tserensodnom B 25 , Valente EM 26 , Vitale D 3 , Zharkinbekova N 27 , Lohmann K 24 , Bandres-Ciga S 28 , Blauwendraat C 29 , Singleton AB 7 , Morris HR 30 , Klein C 31 , Global Parkinson's Genetics Program (GP2)

Affiliations 

  • 1 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Institute of Neurogenetics, University of Luebeck, Lübeck, Germany. Electronic address: lara@gp2.org
  • 2 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
  • 3 DataTecnica, Washington, DC, USA; Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  • 4 Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden; Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
  • 5 Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; South African Medical Research Council, Stellenbosch University Genomics of Brain Disorders Research Unit, Cape Town, South Africa
  • 6 Department of Neuroscience and Brain Health, Metropolitan Medical Center, Manila, Philippines; Department of Clinical Neurosciences, Mary Mediatrix Medical Center, Lipa, Batangas, Philippines; Department of Anatomy, University of the East Ramon Magsaysay Memorial Medical Center, Quezon City, Philippines
  • 7 The Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA
  • 8 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK
  • 9 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
  • 10 University Hospital Schleswig Holstein, Campus Lübeck, Lübeck, Germany; Center for Movement Disorders and Neuromodulation, University Hospital Düsseldorf, Düsseldorf, Germany
  • 11 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan
  • 12 Neurology Department and Molecular Medicine Laboratory, Concord Repatriation General Hospital and University of Sydney, Concord, NSW, Australia; Translational Neurogenomics Group, Genomics and Inherited Disease Program, The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  • 13 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 14 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  • 15 Department of Basic Medical Sciences, Kulliyyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Malaysia; Clinical Pharmacology Department, Menoufia Medical School, Menoufia University, Shebin El-Kom, Menoufia, Egypt
  • 16 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
  • 17 Department of Neurology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
  • 18 Neurology Unit, Department of Medicine, College of Medicine, University of Lagos, Lagos State, Nigeria
  • 19 Department of Biotechnology, University of Science and Technology Bannu, Bannu, Pakistan
  • 20 International Research Institute of Postgraduate Education, Department of Neurosurgery and Neurology, Almaty, Kazakhstan; Shashkin Clinic, Almaty, Kazakhstan
  • 21 Department of Neurology, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia; East European University, Tbilisi, Georgia
  • 22 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK; Department of Neurology, Oslo University Hospital, Oslo, Norway
  • 23 National Institute of Health, Yerevan, Armenia
  • 24 Institute of Neurogenetics, University of Luebeck, Lübeck, Germany
  • 25 Department of Neurology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
  • 26 Department of Molecular Medicine, University of Pavia, Pavia, Italy; Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
  • 27 Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan
  • 28 Center for Alzheimer's and Related Dementias (CARD), National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  • 29 The Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA; Coalition for Aligning Science, Chevy Chase, MD, USA
  • 30 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK
  • 31 Institute of Neurogenetics, University of Luebeck, Lübeck, Germany. Electronic address: christine.klein@uni-luebeck.de
Lancet Neurol, 2026 Aug;25(8):741-754.
PMID: 42456684 DOI: 10.1016/S1474-4422(26)00198-5

Abstract

BACKGROUND: The genetic architecture of Parkinson's disease varies considerably across ancestries, yet most previous genetic studies have focused on individuals of European ancestry. We aimed to characterise the distribution of established Parkinson's disease causal variants, as well as risk-associated variants with clinical implications (ie, variants in genes involved in pathways targeted by ongoing clinical trials), across ancestrally diverse populations.

METHODS: We conducted a multi-ancestry, observational, cross-sectional genetic study using retrospective data from the Global Parkinson's Genetics Program (GP2) release 11 (released in December, 2025). The study investigated causal and risk variants, including copy number variants, in established Parkinson's disease and parkinsonism-associated genes, following the recommendations of the Movement Disorder Society (MDS) Task Force on the Nomenclature of Genetic Movement Disorders, including GBA1, LRRK2, SNCA, VPS35, RAB32, PINK1, PRKN, PARK7, ATP13A2, DCTN1, DNAJC6, FBXO7, JAM2, RAB39B, SLC20A2, SYNJ1, VPS13C, and WDR45. Individuals with Parkinson's disease were diagnosed based on established clinical criteria, including the Parkinson's UK Brain Bank or MDS diagnostic criteria (or both), and healthy control participants were defined as individuals without evidence of neurodegenerative disease and unrelated to participants with Parkinson's disease. We analysed genome and exome sequencing and array genotyping data of 99 783 individuals, including 58 559 individuals with Parkinson's disease and 41 224 controls, from 11 genetically inferred ancestries (African, African admixed, Ashkenazi Jewish, Latino and Indigenous people of the Americas, central Asian, complex admixture, east Asian, European, Finnish, Middle Eastern, and south Asian), defined using reference population-based ancestry inference methods. We calculated allele frequencies for all investigated variants in individuals with Parkinson's disease and controls, both overall and stratified by ancestry.

FINDINGS: Approximately 29% of individuals (29 001 of 99 783; 15 443 [26·4%] of 58 559 individuals with Parkinson's disease and 13 558 [32·9%] of 41 224 controls) were from under-represented populations (ie, non-European and non-Ashkenazi Jewish). Our findings indicated both shared genetic contributors across ancestries as well as ancestry-specific differences in variant frequencies and the spectrum of variants within Parkinson's disease-associated genes. Overall, 1217 (2·1%) of 58 559 individuals with Parkinson's disease carried a causal variant, with substantial variations across ancestries ranging from ten (0·4%) of 2844 African individuals to 251 (10·7%) of 2343 individuals of Ashkenazi Jewish ancestry. Risk variants in GBA1 and LRRK2 were identified in 6893 (11·8%) of 58 559 individuals with Parkinson's disease and 3578 (8·7%) of 41 224 controls. GBA1 risk variants were most frequent overall and identified across all ancestries, but variant frequency and spectra differed substantially between ancestries, from 195 (4·1%) of 4773 in the east Asian ancestry group to 1505 (52·9%) of 2844 in the African ancestry group. Similarly, LRRK2 causal and risk variants showed ancestry-specific enrichment, with the highest frequencies of causal variants in the Ashkenazi Jewish (250 [10·7%] of 2343) and Middle Eastern (59 [4·4%] of 1347) ancestry groups, whereas risk variants were predominantly identified in the east Asian ancestry group (601 [12·6%] of 4773). Carriers of biallelic causal variants in PRKN, commonly including deletions and duplications, were also identified across all ancestries except Ashkenazi Jewish; the highest frequency was in the Middle Eastern ancestry group (17 [1·3%] of 1347), and frequencies in all other ancestries were less than 1%.

INTERPRETATION: This large-scale, multi-ancestry genetic study offers crucial insights into the population-specific genetic architecture of Parkinson's disease. Whereas clinical trials targeting GBA1 and LRRK2 variant carriers are primarily performed in Europe and the USA, increased ancestral diversity in Parkinson's disease research will be crucial to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure equitable application of and access to emerging genetically informed therapies.

FUNDING: Aligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2).

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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