The genetic spectrum of LRRK2 variants in Parkinson’s disease: findings from a large Chinese cohort

The pathogenicity of variants of uncertain significance in the LRRK2 gene remains underexplored. Investigating the LRRK2 variant spectrum in a large Chinese population cohort can provide deeper insights into its pathogenic mechanisms. This study examined the LRRK2 gene variants in 20,519 Chinese individuals, including 7,562 Parkinson's disease (PD) patients, 3,077 Essential tremor (ET) patients, and 9880 healthy controls. We conducted a genetic analysis of low-frequency and common non-synonymous variants in the LRRK2 gene across the cohorts. A total of 287 low-frequency non-synonymous LRRK2 variants were identified in the PD and control cohorts. Among these, six reported pathogenic variants (p.R1325Q, p.R1441C, p.R1441H, p.V1447M, p.G2019S, p.I2020T) and three reported likely pathogenic variants (p.R1067Q, p.N1437D, p.R1728H) were enriched in PD cases, with a frequency of 0.71%. In contrast, only one pathogenic variant (p.R1325Q) and one likely pathogenic variant (p.R1067Q) were observed in healthy controls (0.11%), and the ET cohort exhibited similar variant distribution to controls (0.19%). Burden analysis and association analysis revealed novel likely pathogenic variants, including p.A312V, p.M968K, and p.R1320S as candidates. These novel variants were significantly more frequent in PD patients (0.79%) compared to healthy controls (0.20%) or ET patients (0.42%). Additionally, seven common missense variants of LRRK2 were identified, and significant associations with PD for p.A419V, p.R1628P, and p.G2385R were confirmed, but no common variants were linked to ET. This study provides the first comprehensive characterization of the LRRK2 variant spectrum in a large Chinese population, underscoring the pivotal role of LRRK2 in PD pathogenesis but not in ET. These findings advance the understanding of LRRK2 in neurodegenerative disorders and lay a foundation for personalized therapeutic strategies based on genetic profiling.

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Publication Details

Journal
npj Parkinson s Disease
Published
2026-03-28
DOI
https://doi.org/10.1038/s41531-026-01315-w
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
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article

The genetic spectrum of LRRK2 variants in Parkinson’s disease: findings from a large Chinese cohort

Kezhong Zhang, Mufang Huang, H. Pan, QinYong Ye et al.
npj Parkinson s Disease
Parkinson's Disease Mechanisms and Treatments
article

The genetic spectrum of LRRK2 variants in Parkinson’s disease: findings from a large Chinese cohort

Kezhong Zhang, Mufang Huang, H. Pan, QinYong Ye, Jun Wen, Zheng Xue, Shanqing Yi, Runcheng He, Shujian Li, C. Mao, Lingyan Yao, Hainan Zhang, Jinyong Tian, Kai Yuan, Zijuan Peng, Yuwen Zhao, Lijun Guo, Hongmei Cao, Nian Xiong, Xinxiang Yan, Oumei Cheng, Lifang Lei, Xuejing Wang, Jinghong Ma, Yuzheng Wang, China Essential Tremor Alliance (CETA), Zhanfang Sun, Meng Nie, Ying Zhou, Li Cao, Jun Liu, Panpan Hu, Wei Di, Lijun Hou, Tao Chen, Xiaomin Liu, Beisha Tang, Rong Zeng, Juan Wan, Hui Guo, Qian Yang, Ling Li, Qiying Sun, Yuling Tian, Juan Chen, Qian Xu, Yuhu Zhang, Dong Chang, Heng Wu, Chunfeng Liu, Xuewei Zhang, Xiaoshuang Xiang, Zhenhua Liu, Lingjing Jin, Guiyun Cui, Qing Wang, Jianjun Ma, Jinchen Li, Jiayu Tang, Hong Jiang, Houfeng Zheng, Yong You, Chao Chen, Li Ling, Wei Huang, Yan Xu, Tao Feng, Tao Wang, Yanming Xu, Hong Liu, Min Ye, Haiyan Li, Guohua Zhao, Puqing Wang, Lu Shen, Jun Chen, Weiguo Liu, Zhentao Zhang, Peishan Li, Jing Xiong, Chunyu Wang, Junling Wang, Mingqiang Li, Yiwen Wu, Jifeng Guo, Ling Chen, Xiang Huang, Zhuohua Zhang, Shusheng Liao, Kun Xia, Piu Chan
article en

Abstract

The pathogenicity of variants of uncertain significance in the LRRK2 gene remains underexplored. Investigating the LRRK2 variant spectrum in a large Chinese population cohort can provide deeper insights into its pathogenic mechanisms. This study examined the LRRK2 gene variants in 20,519 Chinese individuals, including 7,562 Parkinson's disease (PD) patients, 3,077 Essential tremor (ET) patients, and 9880 healthy controls. We conducted a genetic analysis of low-frequency and common non-synonymous variants in the LRRK2 gene across the cohorts. A total of 287 low-frequency non-synonymous LRRK2 variants were identified in the PD and control cohorts. Among these, six reported pathogenic variants (p.R1325Q, p.R1441C, p.R1441H, p.V1447M, p.G2019S, p.I2020T) and three reported likely pathogenic variants (p.R1067Q, p.N1437D, p.R1728H) were enriched in PD cases, with a frequency of 0.71%. In contrast, only one pathogenic variant (p.R1325Q) and one likely pathogenic variant (p.R1067Q) were observed in healthy controls (0.11%), and the ET cohort exhibited similar variant distribution to controls (0.19%). Burden analysis and association analysis revealed novel likely pathogenic variants, including p.A312V, p.M968K, and p.R1320S as candidates. These novel variants were significantly more frequent in PD patients (0.79%) compared to healthy controls (0.20%) or ET patients (0.42%). Additionally, seven common missense variants of LRRK2 were identified, and significant associations with PD for p.A419V, p.R1628P, and p.G2385R were confirmed, but no common variants were linked to ET. This study provides the first comprehensive characterization of the LRRK2 variant spectrum in a large Chinese population, underscoring the pivotal role of LRRK2 in PD pathogenesis but not in ET. These findings advance the understanding of LRRK2 in neurodegenerative disorders and lay a foundation for personalized therapeutic strategies based on genetic profiling.

npj Parkinson s Disease
Union Hospital (HK), Central South University (CN), Nanchang University (CN), Sun Yat-sen University (CN), Shanxi Medical University (CN), Xuzhou Medical College (CN), Capital Medical University (CN), Anhui Medical University (CN), Changzhi Medical College (CN), Sichuan University (CN), Ruijin Hospital (CN), Wuhan University (CN), Soochow University (CN), West China Hospital of Sichuan University (CN), Second Affiliated Hospital of Nanchang University (CN), Nanjing Brain Hospital (CN), Jinhua Academy of Agricultural Sciences (CN), Zhujiang Hospital (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Second Affiliated Hospital of Soochow University (CN), National Clinical Research (US), Hainan General Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), First Affiliated Hospital of Anhui Medical University (CN), Renmin Hospital of Wuhan University (CN), First Affiliated Hospital of University of South China (CN), Jiangsu Province Hospital (CN), Second Xiangya Hospital of Central South University (CN), Guangdong Provincial People's Hospital (CN), Third Xiangya Hospital (CN), Xiangya Hospital Central South University (CN), Tongji Hospital (CN), Shanxi Provincial People’s Hospital (CN), Xiang Yang No.1 People's Hospital (CN), Huazhong University of Science and Technology (CN), Southern Medical University (CN), Hainan Medical University (CN), Nanjing Medical University (CN), Chongqing Medical University (CN), University of South China (CN)
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Parkinson's Disease Mechanisms and Treatments
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