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The Global Landscape of Genetic Variation in Parkinson's disease: Multi-Ancestry Insights into Established Disease Genes and their Translational Relevance

Lange LM 1 , Fang ZH 2 , Makarious MB 3 , Kuznetsov N 3 , Brolin KA 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 8 , Koretsky MJ 3 , Kumar KR 11 , Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD) , Leonard HL 3 , Levine KS 3 , Lim SY 12 , Mencacci NE 13 , Mohamed WMY 14 , Nalls MA 3 , Noyce AJ 15 , Ojha R 16 , Okubadejo NU 17 , Rehman SU 18 , Screven L 7 , Shashkin C 19 , Sopromadze S 20 , Stafford EJ 9 , Tan AH 12 , Tan M 15 , Tavadyan Z 21 , Trinh J 22 , Tserensodnom B 23 , Valente EM 24 , Vitale D 3 , Zharkinbekova N 11 , Lohmann K 22 , Bandres-Ciga S 25 , Blauwendraat C 7 , Singleton A 7 , Morris HR 9 , Klein C 22 , Global Parkinson’s Genetics Program (GP2)

Affiliations 

  • 1 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA
  • 2 German Center for Neurodegenerative Diseases (DZNE), Tu bingen, Germany
  • 3 DataTecnica, Washington, DC, USA
  • 4 Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
  • 5 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 Africa
  • 6 Department of Neuroscience and Brain Health, Metropolitan Medical Center, Manila, Philippines
  • 7 The Global Parkinson's Genetics Program (GP2)
  • 8 University College London, Institute of Neurology, Department of Neuromuscular Diseases, Queen Square, WC1N 3BG London, UK
  • 9 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
  • 10 University Hospital Schleswig Holstein, Campus Luebeck, Luebeck, Germany
  • 11 Neurology Department and Molecular Medicine Laboratory, Concord Repatriation General Hospital and University of Sydney, Concord, NSW, 2139
  • 12 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 13 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  • 14 Department of Basic Medical Sciences, Kulliyyah of Medicine, International Islamic University Malaysia (IIUM), Kuantan, Pahang, Malaysia
  • 15 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom
  • 16 Department of Neurology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal
  • 17 Neurology Unit, Department of Medicine, College of Medicine, University of Lagos, Lagos State, Nigeria
  • 18 Department of Biotechnology, University of science and Technology Bannu, Pakistan
  • 19 International Research Institute of Postgraduate Education, Department of Neurosurgery and Neurology, Almaty, Kazakhstan
  • 20 Department of Neurology, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
  • 21 National Institute of Health, Yerevan, Armenia
  • 22 Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 23 Department of Neurology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
  • 24 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  • 25 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
medRxiv, 2025 Jul 11.
PMID: 40672482 DOI: 10.1101/2025.07.08.25330815

Abstract

BACKGROUND: The genetic architecture of Parkinson's disease (PD) varies considerably across ancestries, yet most genetic studies have focused on individuals of European descent, limiting our insights into the genetic architecture of PD at a global scale.

METHODS: We conducted a large-scale, multi-ancestry investigation of causal and risk variants in PD-related genes. Using genetic datasets from the Global Parkinson's Genetics Program, we analyzed sequencing and genotyping data from 69,881 individuals, including 41,139 affected and 28,742 unaffected, from eleven different ancestries, including ~30% of individuals from non-European ancestries.

FINDINGS: Our findings revealed shared and ancestry-specific patterns in the prevalence and spectrum of PD-associated variants. Overall, ~2% of affected individuals carried a causative variant, with substantial variations across ancestries ranging from <0·5% in African, African-admixed, and Central Asian to >10% in Middle Eastern and Ashkenazi Jewish ancestries. Including disease-associated GBA1 and LRRK2 risk variants raised the yield to ~12.5%, largely driven by GBA1, except in East Asians, where LRRK2 risk variants dominated. GBA1 variants were most frequent globally, albeit with substantial differences in frequencies and variant spectra. While GBA1 variants were identified across all ancestries, frequencies ranged from 3·4% in Middle Eastern to 51·7% in African ancestry. Similarly, LRRK2 variants showed ancestry-specific enrichment, with G2019S most frequently seen in Middle Eastern and Ashkenazi Jewish, and risk variants predominating in East Asians. However, clinical trials targeting proteins encoded by these genes are primarily based in Europe and North America.

INTERPRETATION: This large-scale, multi-ancestry assessment offers crucial insights into the population-specific genetic architecture of PD. It underscores the critical need for increased diversity in PD genetic research to improve diagnostic accuracy, enhance our understanding of disease mechanisms across populations, and ensure the equitable development and application of emerging precision therapies.

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

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