The LRRK2 p.A419V variant associates with risk of Parkinson disease in the East Asian population and an evaluation on age of onset

Kai Shi Lim; María Teresa Periñán; Elaine Guo Yan Chew; Paul Suhwan Lee; Fulya Akçimen; Jia Lun Lim; Mathew J. Koretsky; Manabu Funayama; Hiroyo Yoshino; Nobutaka Hattori; Rauan  B. Kaiyrzhanov; Henry Houlden; Mariam Isayan; Yi Wen Tay; Tzi Shin Toh; Lei Cheng Lit; Anis Nadhirah Khairul Anuar; Hans Xing Ding; Laurel A. Screven; Norlinah Mohamed Ibrahim; Chin‐Hsien Lin; Han‐Joon Kim; Jee‐Young Lee; Sun Ju Chung; Jia Nee Foo; Eng-King Tan; Shen‐Yang Lim; Ai Huey Tan; Sara Bandrés‐Ciga; Azlina Ahmad‐Annuar

doi:10.1101/2025.08.28.25333987

Genetic & Genomic MedicinemedRxivAug 28, 2025

Preprint

The LRRK2 p.A419V variant associates with risk of Parkinson disease in the East Asian population and an evaluation on age of onset

Kai Shi Lim iD, María Teresa Periñán iD, Elaine Guo Yan Chew iD, Paul Suhwan Lee iD, Fulya Akçimen iD, Jia Lun Lim iD, Mathew J. Koretsky iD, Manabu Funayama iD, Hiroyo Yoshino iD, Nobutaka Hattori iD, Rauan B. Kaiyrzhanov iD, Henry Houlden iD, Mariam Isayan iD, Yi Wen Tay iD, Tzi Shin Toh iD, Lei Cheng Lit iD, Anis Nadhirah Khairul Anuar iD, Hans Xing Ding iD, Laurel A. Screven iD, Norlinah Mohamed Ibrahim iD, Chin‐Hsien Lin iD, Han‐Joon Kim iD, Jee‐Young Lee iD, Sun Ju Chung iD, Jia Nee Foo iD, , the Global Parkinson’s Genetics Program (GP2)

Abstract

Common and rare variants in LRRK2 influence Parkinsons 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 ({beta} = -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.

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