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. 2025 Nov 18;11(1):320.
doi: 10.1038/s41531-025-01166-x.

LRRK2 p.G2385R and p.R1628P variants in a multi-ethnic Asian Parkinson's Cohort: epidemiology and clinical insights

Jun Wen Goh  1 , Jia Lun Lim  2 , Tzi Shin Toh  1 , Rui Yan Ong  1 , Qing Hui Yong  1 , Cindy Choey Yee Lew  1 , Jia Wei Hor  1 , Yi Wen Tay  2 , Jannah Zulkefli  1   3 , Anis Nadhirah Khairul Anuar  4 , Hans Xing Ding  4 , Jie Ping Schee  1 , Yuan Ye Beh  1 , Khairul Azmi Ibrahim  5 , Ahmad Shahir Mawardi  6 , Thien Thien Lim  7 , Irene Looi  8 , Yuen Kang Chia  9 , Joshua Chin Ern Ooi  9 , Wan Chung Law  10 , Siaw Cheng Wong  10 , Yue Hui Lau  11 , Pei Chiek Teh  12 , Tien Lee Ong  13 , Wee Kooi Cheah  14 , Esther Sammler  15   16 , Shalini Padmanabhan  17 , Lei Cheng Lit  4 , Eng King Tan  18 , Azlina Ahmad-Annuar  19 , Shen-Yang Lim  20 , Ai Huey Tan  21
Affiliations

LRRK2 p.G2385R and p.R1628P variants in a multi-ethnic Asian Parkinson's Cohort: epidemiology and clinical insights

Jun Wen Goh et al. NPJ Parkinsons Dis. .

Abstract

The frequency and clinical impact of LRRK2 p.G2385R and p.R1628P risk variants in Parkinson's disease (PD) remain uncertain, particularly across different Asian populations. We genotyped 3058 multi-ethnic Malaysian PD patients, performed detailed phenotyping in 185, and analyzed disease progression in 635 using longitudinal Clinical Impression of Severity Index for PD scores. p.G2385R was largely confined to Chinese (8.2%), while p.R1628P occurred in mixed ancestry (11.0%), Chinese (8.3%), Malays (7.7%), and is reported for the first time in indigenous groups (3.9%). Double-variant carriers had younger onset and more frequently had positive family history. Compared with non-carriers, p.R1628P carriers had lower rates of dementia and orthostatic hypotension, and slower progression of global PD severity. Our findings highlight ethnic differences in the distribution of LRRK2 Asian variants, and suggest that these variants influence onset age, familial occurrence, non-motor features, and disease course, with implications for personalized approaches to PD in Asian populations.

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Conflict of interest statement

Competing interests: E.S. is employed by the University of Dundee, UK and has received research funding from the MJFF, the Chief Scientist Office in Scotland, and UK Research and Innovation Medical Research Council. S.Y.L. is an employee at the University of Malaya. S.Y.L. has received stipends from the International Parkinson and Movement Disorder Society (MDS) as Chair of the Asian-Oceanian Section, and Science Advances as Associate Editor (Neuroscience). He currently serves as an Associate Editor of npj Parkinson’s Disease but was not involved in the editorial review of or the decision to publish this article. He reports consultancies from the Michael J Fox Foundation (MJFF), the Aligning Science Across Parkinson’s-Global Parkinson’s Genetics Program (ASAP-GP2), and Neurotorium Editorial Board; honoraria for lecturing from the MDS, Lundbeck, Eisai, and Medtronic; and research grants from the Malaysian Ministry of Education Fundamental Research Grant Scheme and the MJFF. A.H.T. is an employee at the University of Malaya. A.H.T. has received grants from and served as a consultant for the MJFF and the ASAP-GP2. A.H.T. has received honoraria for lecturing from the MDS and Boehringer Ingelheim.

Figures

Fig. 1
Fig. 1
Frequency of LRRK2 p.G2385R and p.R1628P among PD patients acrossdiverse ancestral groups in Malaysia (n = 3058 index cases).
Fig. 2
Fig. 2. Frequency of motor symptoms and motor response complications in PD patients with and without LRRK2 p.G2385R and p.R1628P (n = 185).
The frequency of motor features were not significantly different across the four genotypic groups. Upper motor neuron (UMN) signs were clonus, hyperreflexia, and/or extensor plantar response.
Fig. 3
Fig. 3. Frequency of non-motor symptoms in PD patients with and without LRRK2 p.G2385R and p.R1628P (n = 185).
Significant differences between groups are denoted by an asterisk (*).
See this image and copyright information in PMC

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