The LRRK2 p.A419V variant associates with risk of Parkinson's disease in the East Asian population and an evaluation on age of onset.
| Title: | The LRRK2 p.A419V variant associates with risk of Parkinson's disease in the East Asian population and an evaluation on age of 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).; Mohamed Ibrahim N; 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.; The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.; 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.; Ahmad-Annuar A; Department of Biomedical Science, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia. |
| Corporate Authors: | Global Parkinson’s Genetics Program (GP2) |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2025 Sep 02. Date of Electronic Publication: 2025 Sep 02. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Common and rare variants in LRRK2 influence Parkinson's disease (PD) risk across diverse populations. We investigated the p.A419V variant across multiple ancestry cohorts comprising over 200,000 individuals. In cases of East Asian ancestry, the variant was significantly associated with increased risk (OR = 2.9; 95% CI: 1.66-5.10; p = 0.0002), It lies on rare EAS haplotypes, and was not in linkage disequilibrium with other LRRK2 coding variants. Although not significant, meta-analysis of age of onset in EAS cases show a suggestive trend (β = -0.89 years; SE = 1.01; p = 0.380). LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB10, RAB29 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 pathway. |
| Competing Interests: | Declaration of conflicting interest The authors declared no potential conflicts of interest for the research, authorship, and/or publication of this article. |
| References: | Parkinsonism Relat Disord. 2022 May;98:103-113. (PMID: 35654702); Eur J Hum Genet. 2006 Mar;14(3):322-31. (PMID: 16333314); Nature. 2019 Dec;576(7785):106-111. (PMID: 31802016); J Hum Genet. 2021 Oct;66(10):957-964. (PMID: 33742109); EMBO J. 2018 Jan 4;37(1):1-18. (PMID: 29212815); PLoS One. 2023 Oct 31;18(10):e0293516. (PMID: 37906549); BMC Res Notes. 2021 Feb 04;14(1):45. (PMID: 33541395); Parkinsonism Relat Disord. 2021 Feb;83:110-112. (PMID: 33561776); Parkinsons Dis. 2017;2017:8093124. (PMID: 29209554); NPJ Parkinsons Dis. 2023 Jun 27;9(1):100. (PMID: 37369645); NPJ Parkinsons Dis. 2025 Feb 17;11(1):30. (PMID: 39962078); Cell Genom. 2024 Nov 13;4(11):100692. (PMID: 39486408); Small GTPases. 2021 Mar;12(2):133-146. (PMID: 31552791); Sci Adv. 2023 Aug 9;9(32):eadg6319. (PMID: 37556544); Nucleic Acids Res. 2024 Jan 5;52(D1):D622-D632. (PMID: 37930845); Lancet Neurol. 2024 Dec;23(12):1267-1280. (PMID: 39447588); Mov Disord. 2025 Jan;40(1):77-86. (PMID: 39503264); Parkinsons Dis. 2020 Feb 19;2020:2763838. (PMID: 32148752); Nucleic Acids Res. 2023 Jan 6;51(D1):D523-D531. (PMID: 36408920); Evid Based Ment Health. 2019 Nov;22(4):153-160. (PMID: 31563865); Cent Asian J Glob Health. 2014 Dec 12;3(Suppl):146. (PMID: 29805883); Biochem J. 2022 Sep 16;479(17):1759-1783. (PMID: 35950872); Hum Mutat. 2010 May;31(5):561-8. (PMID: 20186690); Mov Disord. 2019 Jun;34(6):866-875. (PMID: 30957308); Nat Aging. 2025 Feb;5(2):205-218. (PMID: 39572736); Mov Disord. 2013 Oct;28(12):1740-4. (PMID: 23913756); Cell. 2021 Jun 24;184(13):3519-3527.e10. (PMID: 34107286); Curr Opin Cell Biol. 2020 Apr;63:102-113. (PMID: 32036294); J Parkinsons Dis. 2022;12(1):153-171. (PMID: 34776419); Lancet Neurol. 2019 Dec;18(12):1091-1102. (PMID: 31701892); Neurology. 2022 Aug 16;99(7):e698-e710. (PMID: 35970579); Ann Clin Transl Neurol. 2025 Jan;12(1):34-42. (PMID: 39529459); Mov Disord. 2022 Aug;37(8):1593-1604. (PMID: 35867623); Annu Rev Biochem. 2024 Aug;93(1):261-287. (PMID: 38621236); JAMA Neurol. 2018 Jan 1;75(1):127-128. (PMID: 29131875); Science. 2023 Dec 22;382(6677):1404-1411. (PMID: 38127736); Front Aging Neurosci. 2019 Jan 30;11:13. (PMID: 30760999); Hum Mol Genet. 2017 Jan 1;26(1):226-232. (PMID: 28011712); FEBS J. 2022 Nov;289(22):6871-6890. (PMID: 34196120); Nat Genet. 2009 Dec;41(12):1303-7. (PMID: 19915576); Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835); Lancet Neurol. 2023 Nov;22(11):1015-1025. (PMID: 37633302); Mov Disord. 2021 Sep;36(9):2077-2084. (PMID: 33884653); Ann Acad Med Singap. 2013 May;42(5):237-40. (PMID: 23771111); Cell. 2019 Oct 17;179(3):736-749.e15. (PMID: 31626772); Brain Behav. 2023 Apr;13(4):e2950. (PMID: 36879366); Genome Res. 2009 Sep;19(9):1655-64. (PMID: 19648217); Brain. 2015 Dec;138(Pt 12):3673-84. (PMID: 26490334); Parkinsonism Relat Disord. 2012 Jul;18(6):722-30. (PMID: 22575234); Hum Mol Genet. 2018 Jan 15;27(2):385-395. (PMID: 29177506); NPJ Parkinsons Dis. 2023 Oct 7;9(1):141. (PMID: 37805635); JAMA Neurol. 2020 Jun 1;77(6):746-754. (PMID: 32310270); Lancet Neurol. 2011 Oct;10(10):898-908. (PMID: 21885347); Mov Disord. 2024 Nov;39(11):2039-2048. (PMID: 39283294); Nat Genet. 2024 Jan;56(1):27-36. (PMID: 38155330); Sci Rep. 2024 Jun 25;14(1):14670. (PMID: 38918550) |
| Grant Information: | OT2 OD026556 United States OD NIH HHS; K24 AG000949 United States AG NIA NIH HHS; OT2 OD025315 United States OD NIH HHS; OT2 OD026551 United States OD NIH HHS; U24 OD023121 United States OD NIH HHS; OT2 OD026552 United States OD NIH HHS; OT2 OD026549 United States OD NIH HHS; OT2 OD025337 United States OD NIH HHS; OT2 OD025277 United States OD NIH HHS; OT2 OD026555 United States OD NIH HHS; OT2 OD026550 United States OD NIH HHS; OT2 OD026553 United States OD NIH HHS; OT2 OD023205 United States OD NIH HHS; OT2 OD025276 United States OD NIH HHS; OT2 OD026557 United States OD NIH HHS; OT2 OD026554 United States OD NIH HHS; U24 OD023163 United States OD NIH HHS; OT2 OD023206 United States OD NIH HHS; U24 OD023176 United States OD NIH HHS; Z01 AG000949 United States ImNIH Intramural NIH HHS; OT2 OD026548 United States OD NIH HHS; ZIA AG000949 United States ImNIH Intramural NIH HHS; U2C OD023196 United States OD NIH HHS |
| Contributed Indexing: | Keywords: A419V; Asian; LRRK2; Parkinson’s disease; age at onset; genetics; risk |
| Entry Date(s): | Date Created: 20250915 Date Completed: 20250917 Latest Revision: 20250918 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12424926 |
| DOI: | 10.1101/2025.08.28.25333987 |
| PMID: | 40950508 |
| Database: | MEDLINE |
Journal Article; Preprint