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

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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, the Global Parkinson’s Genetic Program (GP2), Elaine Guo Yan Chew, Mie Rizig, Njideka Ulunma Okubadejo, Emilia M. Gatto, Marcelo Andrés Kauffman, Samson G. Khachatryan, Zaruhi D. Tavadyan, Claire E. Shepherd, Julie Hunter, Kishore R. Kumar, Melina Ellis, Miguel E. Rentería, Sulev Kõks, Alexander A. Zimprich, Carlos Rieder, Vítor Tumas, Sarah Camargos, Edward A. Fon, Ted Fon, Oury Monchi, Benjamin Pizarro Galleguillos, Patricio Olguı́n, Marcelo Miranda, María Leonor Bustamante, Beisha Tang, Huifang Shang, Jifeng Guo, Piu Chan, Wei Luo, Gonzálo Arboleda, Jorge Orozco, Marlene Jiménez-Del-Río, Alvaro Hernandez, Mohamed Salama, Walaa A. Kamel, Yared Zenebe Zewde, Alexis Brice, Jean‐Christophe Corvol, Ana Westenberger, Christine Klein, Eva‐Juliane Vollstedt, Harutyun Madoev, Joanne Trinh, Johanna Junker, Katja Lohmann, Anastasia Illarionova, Brit Mollenhauer, Franziska Hopfner, Günter U. Höglinger, Lara Mariah Lange, Manu Sharma, Thomas Gasser, Zih‐Hua Fang, Sergiu Groppa, Albert Kwaku Akpalu, Georgia Xiromerisiou, Georgios Hadjigeorgiou, Efthymios Dardiotis, Ioannis E. Dagklis, Ioannis Tarnanas, Leonidas Stefanis, María Stamelou, Alex Medina, Germaine Hiu-Fai Chan, Nelson Yuk-Fai Cheung, Nancy Y. Ip, Phillip Chan, Xiaopu Zhou

2026

Полный текст Открытый доступ: Gold Метаданные (CSL-JSON)
DOI 10.1038/s41531-026-01265-3
Достоверность данных 70 средняя
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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.