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.

Data availability
Data used in the preparation of this article were obtained from the Global Parkinson’s Genetics Program (GP2; https://gp2.org). Specifically, we used Tier 2 data from GP2 release 9 (https://doi.org/10.5281/zenodo.14510099). GP2 data are available on AMP-PD (https://amp-pd.org).
Code availability
All code generated for this article, and the identifiers for all software programs and packages used, are available on GitHub (https://github.com/GP2code/Multiancestry_LRRK2_p.A419V)and were given a persistent identifier via Zenodo (https://doi.org/10.5281/zenodo.17701937). Genotyping imputation, quality control, ancestry prediction, and processing was performed using GenoTools v1.0, publicly available on GitHub (https://github.com/GP2code/GenoTools).
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Acknowledgements
We gratefully acknowledge all the participants for their contributions, without whom this research would not have been possible. Data and code used to prepare this article were obtained from the Global Parkinson’s Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research (https://gp2.org). For a complete list of GP2 members, see https://gp2.org. Data used to prepare this article were obtained from the Accelerating Medicines Partnership® (AMP®) Parkinson’s Disease (AMP® PD) Knowledge Platform. For up-to-date information on the study, visit https://www.amp-pd.org. ACCELERATING MEDICINES PARTNERSHIP and AMP are registered service marks of the US Department of Health and Human Services. We thank the research participants for consenting to this study. Additionally, data used in this article were obtained from the UK Biobank, the All of Us Research Program, an East Asian whole-exome dataset, and a Japanese whole-exome dataset. This research has been conducted using the UK Biobank Resource under Application Number 33601. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants. We have received an exception to the Data and Statistics Dissemination Policy from the All of Us Resource Access Board. The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. The authors declared no potential conflicts of interest for the research, authorship, and/or publication of this article. We thank Paige Jarreau for assistance with the graphical abstract. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS) and the National Human Genome Research Institute (NHGRI). This project was also supported by the Global Parkinson’s Genetics Program (GP2; https://gp2.org). GP2 is funded by the Aligning Science Across Parkinson’s (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson’s Research (MJFF). For a complete list of GP2 members see https://doi.org/10.5281/zenodo.7904831. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Additional funding was provided by The Michael J. Fox Foundation for Parkinson’s Research through grant MJFF-009421/17483. The AMP® PD program is a public-private partnership managed by the Foundation for the National Institutes of Health and funded by the National Institute of Neurological Disorders and Stroke (NINDS) in partnership with the Aligning Science Across Parkinson’s (ASAP) initiative; Celgene Corporation, a subsidiary of Bristol-Myers Squibb Company; GlaxoSmithKline plc (GSK); The Michael J. Fox Foundation for Parkinson’s Research; Pfizer Inc.; Sanofi US Services Inc.; and Verily Life Sciences. The Malaysian cohort was supported by funding from the Ministry of Higher Education Malaysia Fundamental Research Grant Scheme (FRGS/1/2020/SKK0/UM/01/2) and the University of Malaya Parkinson’s Disease and Movement Disorders Research Program (PV035-2017). The Singapore East Asian work was supported by the Singapore Ministry of Health’s National Medical Research Council Open Fund Large Collaborative Grant (MOH-000207; to E.-K.T), Open Fund Individual Research Grant (MOH-000559; to J.N.F.), as well as the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE-T2EP30220-0005; to J.N.F.) and Tier 3 (MOE-MOET32020-0004; to J.N.F.). The Japan East Asian work was supported by The Japan Society for the Promotion of Science (JSPS) KAKENHI (24K02372 and 23K06958; to F.M. and 24H00068 to H.N.), The Japan Agency for Medical Research and Development (AMED) (25bm1423015h0003; to both F.M. and H.N. while 24ek0109677h0002, JP23dm0207070, and JP23dm0307101 to H.N.), The Japan Science and Technology Agency (JST) Moonshot R&D Program (JPMJMS2024-5 to H.N.) and Promotion and Mutual Aid Corporation for Private Schools of Japan, a subaward from Juntendo University awarded to both F.M. and H.N. The CAT-PD Consortium is supported by the Global Parkinson’s Genetics Program (GP2; grant ID MJFF-022153).
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A.A.A., A.H.T., and L.K.S. conceptualized the manuscript. N.H., H.H., M.I., T.Y.W., T.S.T., L.L.C., A.N.K.A., H.X.D., N.M.I., L.C.H., K.H.J., L.J.Y., C.S.Y., F.J.N., T.E.K., L.S.Y., A.H.T. were involved in patient recruitment and contributed data. L.S. provided logistical support of management between cohorts. A.A.A., L.K.S., S.B.C., M.T.P., E.G.Y.C., R.K., P.S.L., F.A., L.J.L., M.J.K., M.F., H.Y., conducted the formal analysis. A.A.A., L.K.S., S.B.C., and M.T.P. wrote the first draft of the manuscript. All authors reviewed, edited, and approved the final version of the manuscript for submission.
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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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Lim, K.S., Periñan, M.T., Chew, E.G.Y. et al. Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01265-3
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DOI: https://doi.org/10.1038/s41531-026-01265-3