Evidence map›Paper›PMID 42456684›Full record

Observational studyThe Lancet. Neurology2026

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

Lara M Lange, Zih-Hua Fang, Mary B Makarious, Nicole Kuznetsov, Kajsa Atterling Brolin, Shannon Ballard, Soraya Bardien, Maria Leila Doquenia, Peter Heutink, Henry Houlden and 37 more

Abstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in The Lancet. Neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
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4 · The record

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5 · Who and what money

Authors and funding

47 authors.

Lara M LangeLaboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Institute of Neurogenetics, University of Luebeck, Lübeck, Germany. Electronic address: lara@gp2.org.
Zih-Hua FangGerman Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Mary B MakariousDataTecnica, 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.
Nicole KuznetsovDataTecnica, 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.
Kajsa Atterling BrolinTranslational 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.
Shannon BallardDataTecnica, 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.
Soraya BardienDivision 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.
Maria Leila DoqueniaDepartment 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.
Peter HeutinkThe Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.
Hirotaka IwakiDataTecnica, 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.
Simona JasaityteDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Lietsel JonesDataTecnica, 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.
Johanna JunkerUniversity Hospital Schleswig Holstein, Campus Lübeck, Lübeck, Germany; Center for Movement Disorders and Neuromodulation, University Hospital Düsseldorf, Düsseldorf, Germany.
Rauan KaiyrzhanovDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK; Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan.
Mathew J KoretskyDataTecnica, 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.
Kishore R KumarNeurology 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.
Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD)
Hampton L LeonardDataTecnica, 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.
Kristin S LevineDataTecnica, 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.
Shen-Yang LimDivision of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Niccoló E MencacciDepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Wael M Y MohamedDepartment 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.
Mike A NallsDataTecnica, 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.
Alastair J NoyceCentre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
Rajeev OjhaDepartment of Neurology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal.
Njideka U OkubadejoNeurology Unit, Department of Medicine, College of Medicine, University of Lagos, Lagos State, Nigeria.
Shoaib Ur RehmanDepartment of Biotechnology, University of Science and Technology Bannu, Bannu, Pakistan.
Laurel ScrevenThe Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA.
Chingiz ShashkinInternational Research Institute of Postgraduate Education, Department of Neurosurgery and Neurology, Almaty, Kazakhstan; Shashkin Clinic, Almaty, Kazakhstan.
Sophia SopromadzeDepartment of Neurology, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia; East European University, Tbilisi, Georgia.
Eleanor J StaffordDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Ai Huey TanDivision of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Manuela TanCentre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK; Department of Neurology, Oslo University Hospital, Oslo, Norway.
Zaruhi TavadyanNational Institute of Health, Yerevan, Armenia.
Joanne TrinhInstitute of Neurogenetics, University of Luebeck, Lübeck, Germany.
Bayasgalan TserensodnomDepartment of Neurology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia.
Enza Maria ValenteDepartment of Molecular Medicine, University of Pavia, Pavia, Italy; Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy.
Dan VitaleDataTecnica, 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.
Nazira ZharkinbekovaDepartment of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan.
Katja LohmannInstitute of Neurogenetics, University of Luebeck, Lübeck, Germany.
Sara Bandres-CigaCenter 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.
Cornelis BlauwendraatThe Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA; Coalition for Aligning Science, Chevy Chase, MD, USA.
Andrew B SingletonThe Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA.
Huw R MorrisDepartment 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.
Christine KleinInstitute of Neurogenetics, University of Luebeck, Lübeck, Germany. Electronic address: christine.klein@uni-luebeck.de.
Global Parkinson's Genetics Program (GP2)

Funding

Understanding the role of BORCS5 in neuronal lysosomal function and neurodegenerationK08NS131581 · NINDS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI Niccolo E Mencacci · 2024 to 2026
$673k
Intramural NIH HHS Z99 AG999999NINDS NIH HHS K08 NS131581Wellcome Trust
6 · The paper itself

Abstract

backgroundThe 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.

methodsWe 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.

findingsApproximately 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%.

interpretationThis 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.

fundingAligning Science Across Parkinson's (ASAP) through the Global Parkinson's Genetics Program (GP2).

Indexed as

Genetic Predisposition to DiseaseParkinson DiseaseAgedBlack PeopleCentral Asian PeopleCross-Sectional StudiesEast Asian PeopleEuropean PeopleFemaleGenetic VariationHispanic or LatinoHumansIndigenous PeoplesJewsMaleMiddle Aged

Identifiers

PMID42456684
PMCPMC13446284

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