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

Lim, Kai Shi, Periñan, Maria Teresa, Guo Yan Chew, Elaine, Suhwan Lee, Paul, Williams, Nigel ORCID: https://orcid.org/0000-0003-1177-6931 and the Global Parkinson’s Genetics Program (GP2) 2026. Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset. npj Parkinson's Disease 12 , 51. 10.1038/s41531-026-01265-3

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB)

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	For the full list of authors please see article webpage https://doi.org/10.1038/s41531-026-01265-3
Publisher:	Nature Research
Date of First Compliant Deposit:	23 March 2026
Date of Acceptance:	8 January 2026
Last Modified:	23 Mar 2026 14:27
URI:	https://orca.cardiff.ac.uk/id/eprint/185961

Actions (repository staff only)

Edit Item