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<p>The pathogenicity of variants of uncertain significance in the <i>LRRK2</i> gene remains underexplored. Investigating the <i>LRRK2</i> variant spectrum in a large Chinese population cohort can provide deeper insights into its pathogenic mechanisms. This study examined the <i>LRRK2</i> 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 <i>LRRK2</i> gene across the cohorts. A total of 287 low-frequency non-synonymous <i>LRRK2</i> 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 <i>LRRK2</i> 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 <i>LRRK2</i> variant spectrum in a large Chinese population, underscoring the pivotal role of <i>LRRK2</i> in PD pathogenesis but not in ET. These findings advance the understanding of <i>LRRK2</i> in neurodegenerative disorders and lay a foundation for personalized therapeutic strategies based on genetic profiling.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年3月28日

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

摘要

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.