Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset

Lim K.S. Periñan M.T. Chew E.G.Y. Lee P.S. Akçimen F. Lim J.L. Koretsky M.J. Funayama M. Yoshino H. Hattori N. Kaiyrzhanov R. Houlden H. Isayan M. Tay Y.W. Toh T.S. Lit L.-C. Khairul Anuar A.N. Ding H.X. Screven L. Ibrahim N.M. Lin C.-H. Kim H.-J. Lee J.-Y. Chung S.J. Foo J.N. Tan E.-K. Lim S.-Y. Tan A.H. Bandres-Ciga S. Ahmad-Annuar A. Atadzhanov M. Nguyen T. Nguyen D. Foroud T. Xie T. Walker R. Alcalay R. Albin R. Shulman L. Dean M. Ruffrage L. Chahine L.M. Marek K. Markopoulou K. Kieburtz K. Nuytemans K. Shulman J. Inca-Martinez M. Jankovic J. Lubbe S. Mencacci N.E. Keller Sarmiento I.J. Chen H. Beach T. Serrano G.E. Dumanis S. Riley E. Williamson J. Shamim E. Hall D. Wegel C. Pantazis C.B. Cruchaga C. Jonas C. Sobering A.K. Sherer T. Chowdhury S. Louie N. Kuhl M. Murphy K. Solle J.C. Comart C. Fiske B. Casey B. Siddiqi B. O’Grady A. Marsili L. Espay A. Stott S. Love S. Lewis P.A. Williams N. Mok K.Y. Grosset D. Bale C. Carroll C. Obese V. Jasaitye S. Weil R. Okunoye O. Wood N. Hardy J. Morris H. Stafford E.J. Schapira A. Schrag A. Martínez-Carrasco A. Genc G. Ertan S. Çakmak Ö.Ö. Başak A.N. Sassi S.B. Amouri R. Wu S. Kung P.-J. Wu Y.-R. Wu H.-C. Wu R.-M. Krack P. Zweier C. El-Sadig S. Pastor P. Beyer K. Hoenicka J. Alvarez I. Cubo E. Kim Y.J. Jeon B. Bardien S. Carr J. Amod F. Umair M. Mubarak B.A. Iakovenko E. Vinuela A. Rosales R. Doquenia M.L. Cornejo-Olivas M. Ur-Rehman S. Tan M. Pihlstrøm L. Aasly J.O. Ojo O. Pitcher T.L. Anderson T.J. Ojha R. Tserensodnom B. Reayes-Perez P. Rodriguez-Violante M. Martinez-Ramirez D. Mohamed W. Azmin S. Abdul Murad N.A. Krüger R. Shambetova C. Kaishibayeva G. Karimova A. Shiraishi T. Schirinzi T. Parnetti L. Avenali M. Valente E.M. Quattrone A. Salari M. Borgohain R. Rajan R. Kukkle P.L. Pal P. Divya K.P. Kishore A. Zhou X. Chan P. Ip N. Cheung N.Y.-F. Chan G.H.-F. Medina A. Stamelou M. Stefanis L. Tarnanas I. Dagklis I. Dardiotis E. Hadjigeorgiou G. Xiromerisiou G. Akpalu A. Groppa S. Fang Z.-H. Gasser T. Sharma M. Lange L.M. Höglinger G. Hopfner F. Mollenhauer B. Illarionova A. Lohmann K. Junker J. Trinh J. Madoev H. Vollstedt E.-J. Klein C. Westenberger A. Corvol J.-C. Brice A. Zewde Y.Z. Kamel W.A. Salama M. Hernandez A. del Rio M.J. Orozco J. Arboleda G. Luo W. Chan P. Guo J. Shang H. Tang B. Bustamante M.L. Miranda M. Olguin P. Galleguillos B.P. Monchi O. Fon T. Fon E.A. Camargos S. Tumas V. Rieder C. Zimprich A. Koks S. Rentería M.E. Ellis M. Kumar K. Hunter J. Shepherd C.E. Tavadyan Z. Khachatryan S. Kauffman M. Gatto E.M. Okubadejo N. Rizig M. Yan Chew E.G.
December 2026 Nature Research

npj Parkinsons Disease
2026 #12 Issue 1

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling. (Figure presented.)

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Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, Seville, Spain
Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
Center for Alzheimer’s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson’s & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
International Collaborative Research Administration, Juntendo University, Tokyo, Japan
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
South Kazakhstan Medical Academy, Department of Neurology, 1/1 Al-Farabi Avenue, Shymkent, 160019, Kazakhstan
Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia
Department of Physiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia
The Global Parkinson’s Genetics Program (GP2), Bethesda, United States
Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Selangor, Malaysia
Department of Neurology, National Taiwan University Hospital Taipei, Taipei, Taiwan
Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea
Department of Neurology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea
Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
Duke-National University of Singapore Medical School, Singapore, Singapore; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom
Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria
Sanatorio de la Trinidad Mitre-INEBA, Buenos Aires, Argentina
Hospital JM Ramos Mejia, Buenos Aires, Argentina
Somnus Neurology Clinic, Yerevan, Armenia
Neuroscience Research Australia, Sydney, NSW, Australia
ANZAC Research Institute, Concord, NSW, Australia
Garvan Institute of Medical Research and Concord Repatriation General Hospital, Darlinghurst, NSW, Australia
Concord Hospital, Concord, NSW, Australia
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
Murdoch University, Perth, WA, Australia
Medical University of Vienna, Vienna, Austria
Universidade Federal do Rio Grande do Sul / Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
University of São Paulo, São Paulo, Brazil
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
McGill University, Montreal, QC, Canada
Universidad de Chile, Santiago, Chile
Fundación Diagnosis, Santiago, Chile
Faculty of Medicine, Universidad de Chile, Santiago, Chile
CETRAM, Santiago, Chile
Central South University, Changsha, China
West China Hospital, Sichuan University, Chengdu, China
Xiangya Hospital, Central South University, Changsha, China
Capital Medical University, Beijing, China
Zhejiang University, Hangzhou, China
Universidad Nacional de Colombia, Bogotá, Colombia
Fundación Valle del Lili, Santiago de Cali, Colombia
University of Antioquia, Medellín, Colombia
University of Costa Rica, San José, Costa Rica
The American University in Cairo, Cairo, Egypt
Beni-Suef University, Beni Suef, Egypt
Addis Ababa University, Addis Ababa, Ethiopia
Paris Brain Institute, Paris, France
Sorbonne Université, Paris, France
University of Lübeck, Lübeck, Germany
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
University Medical Center Göttingen, Göttingen, Germany
University Hospital LMU Munich, Munich, Germany
Hannover Medical School, Hannover, Germany
University Medical Center Schleswig-Holstein, Lübeck, Germany
University of Tübingen, Tübingen, Germany
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
University of Mainz, Mainz, Germany
University of Ghana Medical School, Accra, Ghana
University of Thessaly, Larissa, Greece
Aristotle University of Thessaloniki, Thessaloniki, Greece
Ionian University, Corfu, Greece
Biomedical Research Foundation of the Academy of Athens, Athens, Greece
Diagnostic and Therapeutic Centre HYGEIA Hospital, Marousi, Greece
Hospital San Felipe, Tegucigalpa, Honduras
Queen Elizabeth Hospital, Kowloon, Hong Kong
The Hong Kong University of Science and Technology, Kowloon, Hong Kong
Aster Medcity, Kochi, India
Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India
National Institute of Mental Health & Neurosciences (NIMHANS), Bengaluru, India
Manipal Hospital, Delhi, India
All India Institute of Medical Sciences, Delhi, India
Nizam’s Institute of Medical Sciences, Hyderabad, India
Shahid Beheshti University of Medical Sciences, Tehran, Iran
Magna Græcia University of Catanzaro, Catanzaro, Italy
University of Pavia, Pavia, Italy
University of Perugia, Perugia, Italy
University of Rome Tor Vergata, Rome, Italy
Jikei University School of Medicine, Tokyo, Japan
Institute of Neurology and Neurorehabilitation, Almaty, Kazakhstan
Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
UKM Medical Molecular Biology Institute (UMBI), Kuala Lumpur, Malaysia
Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Neuroscience Unit, Clinical Pharmacology Dept, Menoufia Medical School, Shebeen El-Kom, Egypt
Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico
Universidad Nacional Autónoma de México, Mexico City, Mexico
Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
Tribhuvan University, Kirtipur, Nepal
University of Otago, Christchurch, New Zealand
College of Medicine, University of Lagos, Lagos, Nigeria
Norwegian University of Science and Technology, Trondheim, Norway
Oslo University Hospital, Oslo, Norway
University of Science and Technology Bannu, Khyber Pakhtunkhwa, Pakistan
Instituto Nacional de Ciencias Neurológicas, Lima, Peru
Metropolitan Medical Center, Manila, Philippines
University of Puerto Rico, San Juan, Puerto Rico
Research Center of Neurology, Moscow, Russian Federation
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
University of KwaZulu-Natal, Durban, South Africa
University of Stellenbosch, Stellenbosch, South Africa
Seoul National University Hospital, Seoul, South Korea
Yongin Severance Hospital, Seoul, South Korea
Hospital Universitario de Burgos, Burgos, Spain
University Hospital Mutua Terrassa, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Research Institute Germans Trias i Pujol, Badalona, Spain
University Hospital Germans Trias i Pujol, Badalona, Spain
Faculty of Medicine, University of Khartoum, Khartoum, Sudan
Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
National Taiwan University Hospital, Taipei City, Taiwan
Chang Gung Memorial Hospital, Taoyuan City, Taiwan
National Taiwan University, Taipei City, Taiwan
Chang Gung University, Taoyuan City, Taiwan
National Institute Mongi Ben Hamida of Neurology, Tunis, Tunisia
Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia
Koç University, Istanbul, Turkey
Şişli Etfal Training and Research Hospital, Istanbul, Turkey
University College London, London, United Kingdom
University of Plymouth, Plymouth, United Kingdom
Parkinson’s UK, London, United Kingdom
University of Glasgow, Glasgow, United Kingdom
Queen Mary University of London, London, United Kingdom
Cardiff University, Cardiff, United Kingdom
Royal Veterinary College, University of London, London, United Kingdom
University of Bristol, Bristol, United Kingdom
Cure Parkinson’s Trust, London, United Kingdom
University of Cincinnati, Cincinnati, OH, United States
The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, United States
Augusta University / University of Georgia Medical Partnership, Athens, GA, United States
Mid-Atlantic Permanente Medical Group, Rockville, MD, United States
Washington University in St. Louis, St. Louis, MO, United States
National Institutes of Health, Bethesda, MD, United States
Indiana University, Bloomington, IN, United States
Rush University Medical Center, Chicago, IL, United States
Kaiser Permanente, Oakland, CA, United States
Aligning Science Across Parkinson’s, Washington, DC, United States
Banner Sun Health Research Institute, Sun City, AZ, United States
Michigan State University, East Lansing, MI, United States
Northwestern University, Chicago, IL, United States
Baylor College of Medicine, Houston, TX, United States
Baylor College of Medicine/Texas Children’s Hospital, Houston, TX, United States
University of Miami Miller School of Medicine, Miami, FL, United States
Beth Israel Deaconess Medical Center, Boston, MA, United States
NorthShore University HealthSystem, Evanston, IL, United States
Institute for Neurodegenerative Disorders, New Haven, CT, United States
University of Pittsburgh, Pittsburgh, PA, United States
University of Alabama at Birmingham, Birmingham, AL, United States
University of Maryland School of Medicine, Baltimore, MD, United States
University of Michigan, Ann Arbor, MI, United States
Columbia University Irving Medical Center, New York, NY, United States
James J. Peters VA Medical Center, Bronx, NY, United States
University of Chicago, Chicago, IL, United States
Indiana University School of Medicine, Indianapolis, IN, United States
Hue University, Huế, Viet Nam
University of Zambia, Lusaka, Zambia

Department of Biomedical Science
Department of Medicine
Unidad de Trastornos del Movimiento
Centre for Preventive Neurology
Lee Kong Chian School of Medicine
Center for Alzheimer’s and Related Dementias
Laboratory of Neurogenetics
The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson’s & Related Disorders
Department of Neurology
Research Institute for Diseases of Old Age
International Collaborative Research Administration
Department of Neuromuscular Diseases
South Kazakhstan Medical Academy
Department of Neurology and Neurosurgery
Department of Physiology
The Global Parkinson’s Genetics Program (GP2)
Department of Medicine
Department of Neurology
Department of Neurology
Department of Neurology
Department of Neurology
Duke-National University of Singapore Medical School
Preventive Neurology Unit
Department of Medicine
Sanatorio de la Trinidad Mitre-INEBA
Hospital JM Ramos Mejia
Somnus Neurology Clinic
Neuroscience Research Australia
ANZAC Research Institute
Garvan Institute of Medical Research and Concord Repatriation General Hospital
Concord Hospital
QIMR Berghofer Medical Research Institute
Murdoch University
Medical University of Vienna
Universidade Federal do Rio Grande do Sul / Hospital de Clínicas de Porto Alegre
University of São Paulo
Universidade Federal de Minas Gerais
McGill University
Universidad de Chile
Fundación Diagnosis
Faculty of Medicine
CETRAM
Central South University
West China Hospital
Xiangya Hospital
Capital Medical University
Zhejiang University
Universidad Nacional de Colombia
Fundación Valle del Lili
University of Antioquia
University of Costa Rica
The American University in Cairo
Beni-Suef University
Addis Ababa University
Paris Brain Institute
Sorbonne Université
University of Lübeck
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
University Medical Center Göttingen
University Hospital LMU Munich
Hannover Medical School
University Medical Center Schleswig-Holstein
University of Tübingen
German Center for Neurodegenerative Diseases (DZNE)
University of Mainz
University of Ghana Medical School
University of Thessaly
Aristotle University of Thessaloniki
Ionian University
Biomedical Research Foundation of the Academy of Athens
Diagnostic and Therapeutic Centre HYGEIA Hospital
Hospital San Felipe
Queen Elizabeth Hospital
The Hong Kong University of Science and Technology
Aster Medcity
Sree Chitra Tirunal Institute for Medical Sciences and Technology
National Institute of Mental Health & Neurosciences (NIMHANS)
Manipal Hospital
All India Institute of Medical Sciences
Nizam’s Institute of Medical Sciences
Shahid Beheshti University of Medical Sciences
Magna Græcia University of Catanzaro
University of Pavia
University of Perugia
University of Rome Tor Vergata
Jikei University School of Medicine
Institute of Neurology and Neurorehabilitation
Kyrgyz State Medical Academy
Luxembourg Centre for Systems Biomedicine
UKM Medical Molecular Biology Institute (UMBI)
Universiti Kebangsaan Malaysia Medical Centre
Neuroscience Unit
Instituto Nacional de Neurología y Neurocirugía
Universidad Nacional Autónoma de México
Mongolian National University of Medical Sciences
Tribhuvan University
University of Otago
College of Medicine
Norwegian University of Science and Technology
Oslo University Hospital
University of Science and Technology Bannu
Instituto Nacional de Ciencias Neurológicas
Metropolitan Medical Center
University of Puerto Rico
Research Center of Neurology
King Faisal Specialist Hospital and Research Center
King Abdullah International Medical Research Center
University of KwaZulu-Natal
University of Stellenbosch
Seoul National University Hospital
Yongin Severance Hospital
Hospital Universitario de Burgos
University Hospital Mutua Terrassa
Institut de Recerca Sant Joan de Déu
Research Institute Germans Trias i Pujol
University Hospital Germans Trias i Pujol
Faculty of Medicine
Inselspital
National Taiwan University Hospital
Chang Gung Memorial Hospital
National Taiwan University
Chang Gung University
National Institute Mongi Ben Hamida of Neurology
Mongi Ben Hmida National Institute of Neurology
Koç University
Şişli Etfal Training and Research Hospital
University College London
University of Plymouth
Parkinson’s UK
University of Glasgow
Queen Mary University of London
Cardiff University
Royal Veterinary College
University of Bristol
Cure Parkinson’s Trust
University of Cincinnati
The Michael J. Fox Foundation for Parkinson’s Research
Augusta University / University of Georgia Medical Partnership
Mid-Atlantic Permanente Medical Group
Washington University in St. Louis
National Institutes of Health
Indiana University
Rush University Medical Center
Kaiser Permanente
Aligning Science Across Parkinson’s
Banner Sun Health Research Institute
Michigan State University
Northwestern University
Baylor College of Medicine
Baylor College of Medicine/Texas Children’s Hospital
University of Miami Miller School of Medicine
Beth Israel Deaconess Medical Center
NorthShore University HealthSystem
Institute for Neurodegenerative Disorders
University of Pittsburgh
University of Alabama at Birmingham
University of Maryland School of Medicine
University of Michigan
Columbia University Irving Medical Center
James J. Peters VA Medical Center
University of Chicago
Indiana University School of Medicine
Hue University
University of Zambia

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