TY - JOUR
T1 - Association of LRRK2 p.A419V with Parkinson’s Disease in East Asians and analysis of age at onset
AU - the Global Parkinson's Genetics Program (GP2)
AU - Lim, Kai Shi
AU - Periñan, Maria Teresa
AU - Chew, Elaine Guo Yan
AU - Lee, Paul Suhwan
AU - Akçimen, Fulya
AU - Lim, Jia Lun
AU - Koretsky, Mathew J.
AU - Funayama, Manabu
AU - Yoshino, Hiroyo
AU - Hattori, Nobutaka
AU - Kaiyrzhanov, Rauan
AU - Houlden, Henry
AU - Isayan, Mariam
AU - Tay, Yi Wen
AU - Toh, Tzi Shin
AU - Lit, Lei Cheng
AU - Khairul Anuar, Anis Nadhirah
AU - Ding, Hans Xing
AU - Screven, Laurel
AU - Ibrahim, Norlinah Mohamed
AU - Lin, Chin Hsien
AU - Kim, Han Joon
AU - Lee, Jee Young
AU - Chung, Sun Ju
AU - Foo, Jia Nee
AU - Tan, Eng King
AU - Lim, Shen Yang
AU - Tan, Ai Huey
AU - Bandres-Ciga, Sara
AU - Ahmad-Annuar, Azlina
AU - Atadzhanov, Masharip
AU - Nguyen, Toan
AU - Nguyen, Duan
AU - Foroud, Tatiana
AU - Xie, Tao
AU - Walker, Ruth
AU - Alcalay, Roy
AU - Albin, Roger
AU - Shulman, Lisa
AU - Dean, Marissa
AU - Ruffrage, Lauren
AU - Chahine, Lana M.
AU - Marek, Kenneth
AU - Markopoulou, Katerina
AU - Kieburtz, Karl
AU - Nuytemans, Karen
AU - Shulman, Joshua
AU - Inca-Martinez, Miguel
AU - Jankovic, Joseph
AU - Lubbe, Steven
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - 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.)
AB - 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.)
UR - https://www.scopus.com/pages/publications/105032537253
U2 - 10.1038/s41531-026-01265-3
DO - 10.1038/s41531-026-01265-3
M3 - Article
AN - SCOPUS:105032537253
SN - 2373-8057
VL - 12
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
IS - 1
M1 - 51
ER -