Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications
12 affiliations
- 1Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Institute of Neurogenetics, University of Luebeck, Lübeck, Germany. Electronic address: [email protected]
- 2German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- 3DataTecnica, 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
- 4Translational 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
- 5Division 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
- 6Department 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
- 7The Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA
- 8Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK
- 9Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK
- 10University Hospital Schleswig Holstein, Campus Lübeck, Lübeck, Germany; Center for Movement Disorders and Neuromodulation, University Hospital Düsseldorf, Düsseldorf, Germany
- 11Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan
- 12Neurology 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
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).
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BibTeX
@article{lange2026parkinsons,
title = {{Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications}},
author = {Lara Mariah Lange and Zih‐Hua Fang and Mary B. Makarious and Nicole Kuznetsov and Kajsa Atterling Brolin and Shannon Ballard and Soraya Bardien and Maria Leila M. Doquenia and Peter Heutink and Henry Houlden and Hirotaka Iwaki and Simona Jasaityte and Lietsel Jones and Johanna Junker and Rauan B. Kaiyrzhanov and Mathew J. Koretsky and K Suresh Kumar and Emilia Mabel Gatto and C E Perandones and Martin Radrizani and Gustavo Da Prat and Natalia Gonzalez Rojas and Espindola Melisa and Martin Cesarini and María Valentina Müller and Carlos Matias López Razquin and Bibiana Pizarro and Lucía Wang and C Marchetti and Cesar Avila and Griselda Judith Alvarado and Luciana Rojas Vazquez and Juan Pablo Diaz-Rearte and Marcelo Andrés Kauffman and Sergio Rodriguez and Dolores Gonzales and Pavel Alejandro Hernandez and Belen Ceballos and Florencia Echeverria and Gabriela da Costa and Marcelo Merello and Federico J Capparelli and Florencia Nicole Wainberg and Tomas Poklepovich and Florencia Mallou and Denise De Belder and Erick Gonzalez and Enrique Wagner and Robin Rodriguez and Alexander Quecana Janco and Bruno Lopes Santos‐Lobato and Gracivane Lopes Eufraseo and Juliana Duarte and Marcella Vieira Barroso Montenegro and Tatiane De Souza and Camille Sena-dos-Santos and Ândrea Ribeiro‐dos‐Santos and Pedro Braga‐Neto and Deborah Moreira Rangel and Marconny Cavalcante},
journal = {The Lancet Neurology},
year = {2026},
month = jul,
doi = {10.1016/s1474-4422(26)00198-5},
url = {https://doi.org/10.1016/s1474-4422(26)00198-5},
note = {CC BY},
}
RIS
TY - JOUR
TI - Parkinson's disease genetics across diverse ancestries: an observational genetic study of causal and risk variants with translational implications
AU - Lara Mariah Lange
AU - Zih‐Hua Fang
AU - Mary B. Makarious
AU - Nicole Kuznetsov
AU - Kajsa Atterling Brolin
AU - Shannon Ballard
AU - Soraya Bardien
AU - Maria Leila M. Doquenia
AU - Peter Heutink
AU - Henry Houlden
AU - Hirotaka Iwaki
AU - Simona Jasaityte
AU - Lietsel Jones
AU - Johanna Junker
AU - Rauan B. Kaiyrzhanov
AU - Mathew J. Koretsky
AU - K Suresh Kumar
AU - Emilia Mabel Gatto
AU - C E Perandones
AU - Martin Radrizani
AU - Gustavo Da Prat
AU - Natalia Gonzalez Rojas
AU - Espindola Melisa
AU - Martin Cesarini
AU - María Valentina Müller
AU - Carlos Matias López Razquin
AU - Bibiana Pizarro
AU - Lucía Wang
AU - C Marchetti
AU - Cesar Avila
AU - Griselda Judith Alvarado
AU - Luciana Rojas Vazquez
AU - Juan Pablo Diaz-Rearte
AU - Marcelo Andrés Kauffman
AU - Sergio Rodriguez
AU - Dolores Gonzales
AU - Pavel Alejandro Hernandez
AU - Belen Ceballos
AU - Florencia Echeverria
AU - Gabriela da Costa
AU - Marcelo Merello
AU - Federico J Capparelli
AU - Florencia Nicole Wainberg
AU - Tomas Poklepovich
AU - Florencia Mallou
AU - Denise De Belder
AU - Erick Gonzalez
AU - Enrique Wagner
AU - Robin Rodriguez
AU - Alexander Quecana Janco
AU - Bruno Lopes Santos‐Lobato
AU - Gracivane Lopes Eufraseo
AU - Juliana Duarte
AU - Marcella Vieira Barroso Montenegro
AU - Tatiane De Souza
AU - Camille Sena-dos-Santos
AU - Ândrea Ribeiro‐dos‐Santos
AU - Pedro Braga‐Neto
AU - Deborah Moreira Rangel
AU - Marconny Cavalcante
PY - 2026
DA - 2026/07/16
JO - The Lancet Neurology
DO - 10.1016/s1474-4422(26)00198-5
UR - https://doi.org/10.1016/s1474-4422(26)00198-5
AB - 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).
SN - 1474-4422
SN - 1474-4465
ER -