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

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.

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Journal
npj Parkinson s Disease
Published
2026-02-02
DOI
https://doi.org/10.1038/s41531-026-01265-3
Primary Topic
Parkinson's Disease Mechanisms and Treatments
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article
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0.00

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article

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

Mario Cornejo‐Olivas, Jorge Orozco, Tim Anderson, J Solle et al.
npj Parkinson s Disease
Parkinson's Disease Mechanisms and Treatments
article

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

Mario Cornejo‐Olivas, Jorge Orozco, Tim Anderson, J Solle, Fulya Akçimen, Georgia Xiromerisiou, Sarah Camargos, Alex Medina, Ignacio Morales Álvarez, Phillip Chan, Katerina Markopoulou, Paul Suhwan Lee, Roy N. Alcalay, Marcelo Kauffman, S. Kõks, Tzi Shin Toh, P. Krack, Manabu Funayama, Lara Mariah Lange, Sonya B. Dumanis, Mariam Isayan, Ferzana Amod, Claire J. Bale, Anis Nadhirah Khairul Anuar, Yih‐Ru Wu, Eleanor J. Stafford, Oluwadamilola O. Ojo, Albert Kwaku Akpalu, Nelson Yuk-Fai Cheung, Kung PJ, Sarah El-Sadig, Simona Jasaitye, Nancy Y. Ip, Han-joon Kim, Kishore Kumar, Zih-Hua Fang, Pau Pastor, Mehri Salari, Brice Alexis, Kaileigh Murphy, Rejko Krüger, Y. J. J. Wu, Jia Nee Foo, Charisse Comart, Luca Marsili, Marcelo Miranda, Hiroyo Yoshino, W Wood Nicholas, Kai Shi Lim, Raymond L. Rosales, Henry Houlden, Lucilla Parnetti, Lei-Cheng Lit, Ejaz A. Shamim, Emilia Gatto, Ana Westenberger, Ai Huey Tan, Tao Xie, Melina Ellis, Joanne Trinh, Esther Cubo, Ioannis Tarnanas, Rajeev Ojha, Katrin Beyer, Brian Fiske, Mie Rizig, Claire Wegel, Todd Sherer, Vitor Tumas, Yi Wen Tay, Shen-Yang Lim, Johanna Junker, Laurel Screven, Angel Vinuela, Thomas Beach, Marlene Jimenez del Rio, Serena Wu, Leonidas Stefanis, Jonathan Carr, Camille Carroll, Njideka Okubadejo, Mayela Rodriguez-Violante, Toan Nguyen, Samia Ben Sassi, Mathew J. Koretsky, Maggie Kuhl, Beisha Tang, Olaitan Okunoye, Enza Maria Valente, Anastasia Illarionova, Ruey-Meei Wu, Carlos Rieder, K. P. Divya, Vida Obese, Jee-Young Lee, Duan Nguyen, Nigel Williams, Gencer Genc, Ted Fon, Micol Avenali, Maria Stamelou, Joshua Shulman, Nobutaka Hattori, Maria Leila Doquenia, Rupam Borgohain, Prashanth Lingappa Kukkle, Donald Grosset, Toni L. Pitcher, Karen Nuytemans, Alejandro Martínez-Carrasco, Zaruhi Tavadyan, Rim Amouri, Anthony Schapira, the Global Parkinson’s Genetics Program (GP2), Paula Reayes-Perez, Yared Z. Zewde, Roopa Rajan, Soraya Bardien, Samson Khachatryan, Deborah Hall, Andrea Quattrone, Benjamin Pizarro Galleguillos, Geidy E. Serrano, Carlos Cruchaga, Roger Albin, Katja Lohmann, Wael Mohamed, Manu Sharma, Huifang Shang, Cabell Jonas, Patricio Olguin, Thomas Gasser, Steven Lubbe, Huw Morris, Janet Hoenicka, Özgür Öztop Çakmak, Ekemini Riley, Andrew K. Sobering, Rauan Kaiyrzhanov, Eva-Juliane Vollstedt, Azlina Ahmad-Annuar, Elena Iakovenko, Cholpon Shambetova, Miguel Inca-Martinez, Beomseok Jeon, Norlinah Mohamed Ibrahim, Tomotaka Shiraishi, Anette Schrag, Lana M. Chahine, Lisa Shulman, Christine Klein, Jean-Christophe Corvol, Joseph Jankovic, Alexander Zimprich, Harutyun Madoev, Chin-Hsien Lin, Bashayer Al Mubarak, Sun Ju Chung, Pramod Pal, Ignacio Juan Keller Sarmiento, Nor Azian Abdul Murad, Ruth Walker, Günter U Höglinger, Ioannis Dagklis, Tommaso Schirinzi, Lauren Ruffrage, Shoaib Ur-Rehman, Sibel Ertan, Sohini Chowdhury, Sergio Groppa, Patrick A. Lewis, Miguel E. Rentería, Bayasgalan Tserensodnom, John Hardy, Asha Kishore, Tatiana Foroud, Honglei Chen, Yun Joong Kim, Rimona Weil, Marissa Dean, Lasse Pihlstrøm, Mohamed Salama, Christiane Zweier, Altynay Karimova, Wei Luo, Julie Hunter, Manuela Tan, A. Nazl Başak, Hans Xing Ding, Shahrul Azmin, Jifeng Guo, Roy Alcalay, Jia Lun Lim, Sara Bandres-Ciga, Edward A. Fon, Germaine Hiu-Fai Chan, Eng-King Tan, Seth Love, Gonzalo Arboleda, Claire E. Shepherd, Caroline B. Pantazis, Naomi Louie, Brit Mollenhauer, Georgios Hadjigeorgiou, Kin Y. Mok, Daniel Martinez-Ramirez, Alvaro Hernandez, Alyssa O’Grady, Franziska Hopfner, Oury Monchi, Kenneth Marek, Piu Chan, Jan O. Aasly
article en

Abstract

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.

npj Parkinson s DiseaseVol. 12(1)
Universidade Federal de Minas Gerais (BR), Northwestern University (US), Beni-Suef University (EG), Jikei University School of Medicine (JP), University of Rome Tor Vergata (IT), Ulsan College (KR), University of Bern (CH), University of London (GB), Kyrgyz State Medical Academy (KG), University of Maryland, Baltimore (US), Oslo University Hospital (NO), Rush University Medical Center (US), National Institutes of Health (US), Universidade Federal do Rio Grande do Sul (BR), Alion Science and Technology (United States) (US), Beth Israel Deaconess Medical Center (US), Royal Veterinary College (GB), NorthShore University HealthSystem (US), Kaiser Permanente (US), Koç University (TR), Garvan Institute of Medical Research (AU), University of Ghana (GH), Seoul National University (KR), Central South University (CN), Nizam's Institute of Medical Sciences (IN), University of Miami (US), University of Thessaly (GR), University of Khartoum (SD), Tribhuvan University (NP), University of Georgia (US), Queen Mary University of London (GB), National Taiwan University (TW), University of Pittsburgh (US), Nanyang Technological University (SG), Chang Gung University (TW), Murdoch University (AU), Universidade de São Paulo (BR), Baylor College of Medicine (US), Capital Medical University (CN), University of Luxembourg (LU), Ionian University (GR), Johannes Gutenberg University Mainz (DE), University of Lagos (NG), University of Puerto Rico System (PR), Hong Kong University of Science and Technology (HK), Washington University in St. Louis (US), Norwegian University of Science and Technology (NO), Fundación Chile (CL), Aristotle University of Thessaloniki (GR), QIMR Berghofer Medical Research Institute (AU), Singapore General Hospital (SG), Sichuan University (CN), University of Pavia (IT), Stellenbosch University (ZA), University of Perugia (IT), University of Michigan (US), Columbia University Irving Medical Center (US), Severance Hospital (KR), Concord Repatriation General Hospital (AU), Sree Chitra Thirunal Institute for Medical Sciences and Technology (IN), King Faisal Specialist Hospital & Research Centre (SA), University Hospital of Bern (CH), Seoul Metropolitan Government (KR), German Center for Neurodegenerative Diseases (DE), University Kebangsaan Malaysia Medical Centre (MY), Asan Medical Center (KR), Michael J. Fox Foundation (US), Seoul National University Hospital (KR), LMU Klinikum (DE), Universidad de Costa Rica (CR), University of Alabama at Birmingham (US), University of Zambia (ZM), University of Malaya (MY), Juntendo University (JP), Medizinische Hochschule Hannover (DE), Universidad de Antioquia (CO), University of Bristol (GB), Universidad Nacional de Colombia (CO), Magna Graecia University (IT), University of Illinois Chicago (US), Sorbonne Université (FR), University of Chicago (US), University of Ulsan (KR), Augusta University Health (US), West China Hospital of Sichuan University (CN), Mongolian National University of Medical Sciences (MN), Biomedical Research Foundation of the Academy of Athens (GR), Taoyuan Chang Gung Memorial Hospital (TW), Hue University (VN), King Abdullah International Medical Research Center (SA), University Hospital Mútua de Terrassa (ES), Hospital de Clínicas de Porto Alegre (BR), Fundación Valle del Lili (CO), SNUH SMG-SNU Boramae Medical Center (KR), Parkinson's UK (GB), Hospital Ramos Mejía (AR), National Institute of Neurological Disorders and Stroke (US), Institute for Neurodegenerative Disorders (US), University Hospital Schleswig-Holstein (DE), Hospital Universitario de Burgos (ES), James J. Peters VA Medical Center (US), Universitätsmedizin Göttingen (DE), South Kazakhstan Medical Academy (KZ), Indiana University Bloomington (US), Universidad Metropolitana de Honduras (HN), Hygeia Hospital (GR), National Institute of Health (AM), Mútua Terrassa (ES), National Neuroscience Institute (SG), Colorado Permanente Medical Group (US), National Taiwan University Hospital (TW), National Institute on Aging (US), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Hospital de Niños de la Santísima Trinidad (AR), Banner Sun Health Research Institute (US), National University Hospital (SG), Instituto Nacional de Neurología y Neurocirugía (MX), Texas Children's Hospital (US), Aster Medcity (IN), National Hospital for Neurology and Neurosurgery (GB), Anzac Research Institute (AU), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), University of Science and Technology Bannu (PK), Şişli Etfal Eğitim ve Araştırma Hastanesi (TR), National Institute of Neurology Mongi-Ben Hamida (TN), Research Center of Neurology (RU), Xiangya Hospital Central South University (CN), Cure Parkinson's Trust (GB), Manipal Hospital (IN), Parkinson's Foundation (US), Queen Elizabeth Hospital (CN), Instituto Nacional de Ciencias Neurológicas, Institut de Recerca Sant Joan de Déu, Indiana University School of Medicine, University College London (GB), Addis Ababa University (ET), McGill University (CA), Indiana University – Purdue University Indianapolis (US), Shahid Beheshti University of Medical Sciences (IR), University of Cincinnati (US), Menoufia University (EG), All India Institute of Medical Sciences (IN), University of Chile (CL), National Institute of Mental Health and Neurosciences (IN), Zhejiang University (CN), Medical University of Vienna (AT), University of Glasgow (GB), Cardiff University (GB), University of Otago (NZ), American University in Cairo (EG), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), Neuroscience Research Australia (AU), Michigan State University (US), National University of Malaysia (MY), Centro de Estudios Científicos (CL), Universidad Nacional Autónoma de México (MX), University of Plymouth (GB), University of Lübeck (DE), University of KwaZulu-Natal (ZA), National Taipei University (TW)
U.S. Department of Health and Human Services, Michael J. Fox Foundation for Parkinson's Research, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Sanofi, Celgene, Japan Agency for Medical Research and Development, Verily Life Sciences, Universiti Malaya, Ministry of Education, India, Bộ Giáo dục và Ðào tạo, Promotion and Mutual Aid Corporation for Private Schools of Japan, National Institutes of Health, Medical Research Council, National Medical Research Council, Japan Society for the Promotion of Science, Japan Science and Technology Agency, National Institute on Aging, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, Moonshot Research and Development Program
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