NPJ Parkinson's disease · 2026
Association of LRRK2 p.A419V with Parkinson's Disease in East Asians and analysis of age at onset.
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Lim Kai Shi, Periñan Maria Teresa, Chew Elaine Guo Yan, Lee Paul Suhwan, Akçimen Fulya, Lim Jia Lun, Koretsky Mathew J, Funayama Manabu, Yoshino Hiroyo, Hattori Nobutaka, Kaiyrzhanov Rauan, Houlden Henry, Isayan Mariam, Tay Yi Wen, Toh Tzi Shin, Lit Lei-Cheng, Khairul Anuar Anis Nadhirah, Ding Hans Xing, Screven Laurel, Ibrahim Norlinah Mohamed, Lin Chin-Hsien, Kim Han-Joon, Lee Jee-Young, Chung Sun Ju, Foo Jia Nee, Tan Eng-King, Lim Shen-Yang, Tan Ai Huey, Bandres-Ciga Sara, Ahmad-Annuar Azlina, Global Parkinson’s Genetics Program (GP2)
Аннотация
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.