Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset
- the Global Parkinson's Genetics Program (GP2),
- Kai Shi Lim(Author),
- Maria Teresa Periñan(Author),
- Elaine Guo Yan Chew(Author),
- Paul Suhwan Lee(Author),
- Fulya Akçimen(Author)
- University of Malaya,
- Hospital Virgen del Rocio,
- Queen Mary University of London,
- Lee Kong Chian School of Medicine,
- National Institute on Aging (NIA),
- Juntendo University Graduate School of Medicine
Open access
Publication Information
Output type
Original language
EnglishArticle number
51Journal (Volume, Issue Number)
npj Parkinson's Disease (Volume 12, Issue 1)Publication milestones
- Published - 12/2026
Publication status
Publication IDs
- Scopus: 105032537253
- Scopus: 105031314852
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. (Figure presented.)