Association of LRRK2 p.A419V with Parkinson's Disease in East Asians and analysis of age at onset.
| Title: | Association of LRRK2 p.A419V with Parkinson's Disease in East Asians and analysis of age at onset. |
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| Authors: | Lim KS; Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Periñan MT; 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.; Chew EGY; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.; Lee PS; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.; Akçimen F; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Lim JL; The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.; Koretsky MJ; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.; Funayama M; 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.; Yoshino H; Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.; Hattori N; Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.; Kaiyrzhanov R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.; South Kazakhstan Medical Academy, Department of Neurology, 1/1 Al-Farabi Avenue, 160019, Shymkent, Kazakhstan.; Houlden H; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.; Isayan M; Department of Neurology and Neurosurgery, National Institute of Health, Yerevan, Armenia.; Tay YW; Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Toh TS; Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.; Lit LC; Department of Physiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Khairul Anuar AN; Department of Physiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Ding HX; Department of Physiology, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; Screven L; The Global Parkinson's Genetics Program (GP2), Bethesda, USA.; Ibrahim NM; Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Selangor, Malaysia.; Lin CH; Department of Neurology, National Taiwan University Hospital Taipei, Taipei, Taiwan.; Kim HJ; Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea.; Lee JY; Department of Neurology, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.; Chung SJ; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.; Foo JN; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.; Tan EK; Duke-National University of Singapore Medical School, Singapore, Singapore; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore.; Lim SY; Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia.; The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.; Tan AH; Department of Medicine, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia. aihuey.tan@um.edu.my.; The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia. aihuey.tan@um.edu.my.; Bandres-Ciga S; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. sara.bandresciga@nih.gov.; Ahmad-Annuar A; Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603, Kuala Lumpur, Malaysia. azlina_aa@um.edu.my. |
| Corporate Authors: | Global Parkinson’s Genetics Program (GP2) |
| Source: | NPJ Parkinson's disease [NPJ Parkinsons Dis] 2026 Feb 02; Vol. 12 (1), pp. 51. Date of Electronic Publication: 2026 Feb 02. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 101675390 Publication Model: Electronic Cited Medium: Print ISSN: 2373-8057 (Print) Linking ISSN: 23738057 NLM ISO Abbreviation: NPJ Parkinsons Dis Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: [New York, NY] : Nature Publishing Group : Parkinson's Disease Foundation, [2015]- |
| 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.; (© 2026. The Author(s).) |
| Competing Interests: | Competing interests: A.H.T. received speaker honoraria from Eisai and Orion Pharma, and research grants from the Michael J Fox Foundation. M.J.K.’s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. |
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| Grant Information: | GP2 PhD Fellowship Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative; Grant Number: 24H00068; Grant Number: JPMJMS2024-5; Grant Numbers: 25bm1423015h0003, 24ek0109677h0002, JP23dm0207070, and JP23dm0307101; The Japan Society for the Promotion of Science (JSPS) KAKENHI; The Japan Science and Technology Agency (JST) Moonshot R&D Program; The Japan Agency for Medical Research and Development (AMED); Subsidies for Current Expenditures to Private Institutions of Higher Education from the Promotion and Mutual Aid Corporation for Private Schools of Japan, a subaward from Juntendo University; MR/S01165X/1, MR/S005021/1, G0601943 Medical Research Council, United Kingdom; Grant number: 114-2311-B-002-008 National Science and Technology Council; Grant no. : RS-2024-00403047 Boston-Korea Innovative Research Project through the Korea Health Industry Development Institute(KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea; MOH-000207 Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant; MR/S01165X/1, MR/S005021/1, G0601943 United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Investigator: EG Yan Chew; AN Khairul Anuar; M Rizig; N Okubadejo; EM Gatto; M Kauffman; S Khachatryan; Z Tavadyan; CE Shepherd; J Hunter; K Kumar; M Ellis; ME Rentería; S Koks; A Zimprich; C Rieder; V Tumas; S Camargos; EA Fon; T Fon; O Monchi; BP Galleguillos; P Olguin; M Miranda; ML Bustamante; B Tang; H Shang; J Guo; P Chan; W Luo; G Arboleda; J Orozco; MJ Del Rio; A Hernandez; M Salama; WA Kamel; YZ Zewde; A Brice; JC Corvol; A Westenberger; C Klein; EJ Vollstedt; H Madoev; J Trinh; J Junker; K Lohmann; A Illarionova; B Mollenhauer; F Hopfner; G Höglinger; LM Lange; M Sharma; T Gasser; ZH Fang; S Groppa; A Akpalu; G Xiromerisiou; G Hadjigeorgiou; E Dardiotis; I Dagklis; I Tarnanas; L Stefanis; M Stamelou; A Medina; GH Chan; NY Cheung; N Ip; P Chan; X Zhou; A Kishore; KP Divya; P Pal; PL Kukkle; R Rajan; R Borgohain; M Salari; A Quattrone; EM Valente; M Avenali; L Parnetti; T Schirinzi; T Shiraishi; A Karimova; G Kaishibayeva; C Shambetova; R Krüger; NA Abdul Murad; S Azmin; W Mohamed; D Martinez-Ramirez; M Rodriguez-Violante; P Reayes-Perez; B Tserensodnom; R Ojha; TJ Anderson; TL Pitcher; O Ojo; JO Aasly; L Pihlstrøm; M Tan; S Ur-Rehman; M Cornejo-Olivas; ML Doquenia; R Rosales; A Vinuela; E Iakovenko; BA Mubarak; M Umair; F Amod; J Carr; S Bardien; B Jeon; YJ Kim; E Cubo; I Alvarez; J Hoenicka; K Beyer; P Pastor; S El-Sadig; C Zweier; P Krack; RM Wu; HC Wu; YR Wu; PJ Kung; S Wu; R Amouri; SB Sassi; AN Başak; ÖÖ Çakmak; S Ertan; G Genc; A Martínez-Carrasco; A Schrag; A Schapira; EJ Stafford; H Morris; J Hardy; N Wood; O Okunoye; R Weil; S Jasaitye; V Obese; C Carroll; C Bale; D Grosset; KY Mok; N Williams; PA Lewis; S Love; S Stott; A Espay; L Marsili; A O'Grady; B Siddiqi; B Casey; B Fiske; C Comart; JC Solle; K Murphy; M Kuhl; N Louie; S Chowdhury; T Sherer; AK Sobering; C Jonas; C Cruchaga; CB Pantazis; C Wegel; D Hall; E Shamim; J Williamson; E Riley; S Dumanis; GE Serrano; T Beach; H Chen; IJ Keller Sarmiento; NE Mencacci; S Lubbe; J Jankovic; M Inca-Martinez; J Shulman; K Nuytemans; K Kieburtz; K Markopoulou; K Marek; LM Chahine; L Ruffrage; M Dean; L Shulman; R Albin; R Alcalay; R Walker; T Xie; T Foroud; D Nguyen; T Nguyen; M Atadzhanov |
| Entry Date(s): | Date Created: 20260202 Date Completed: 20260217 Latest Revision: 20260220 |
| Update Code: | 20260220 |
| PubMed Central ID: | PMC12913921 |
| DOI: | 10.1038/s41531-026-01265-3 |
| PMID: | 41629305 |
| Database: | MEDLINE |
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