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.
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Data availability
The datasets generated and analyzed during the current study are not publicly available due to China's regulations on the management of genetic resources but are available from the corresponding author on reasonable request.
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Acknowledgements
We thank the patients for their participation in this study. We thank the Bioinformatics Center, Xiangya Hospital, Central South University and the Bioinformatics Center, Furong Laboratory for assisting in data analysis. We gratefully acknowledge financial support from the Science and Technology Major Project of Hunan Provincial Science and Technology Department (grant no. 2021SK1010), the Clinical Medical Research “4310” Program of the University of South China (20214310NHYCG08), the National Key Research and Development Program of China (2021YFC2501204), the National Natural Science Foundation of China (82501518), the Postdoctoral Fellowship Program of CPSF (GZC20251437) and the China Postdoctoral Science Foundation - Hunan Joint Support Program (2025T025HN).
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B.T. had full access to all data in the study and assumes responsibility for data integrity and the accuracy of the data analysis. Study concept and design were contributed by B.T., Z.L., J.W., H.P., and D.C. Data acquisition, analysis, and interpretation were performed by J.W., H.P., D.C., Y.Z., Q.X., L.Y., Q.S., X.Z., R.H., C.W., H.Z., L.L., Y.W., M.L., H.W., J.M., Y.W., Y.X., N.X., T.W., X.W., L.C., Y-M.X., H.C., K.Z., W.L., Y.Z., C.M., Q.W., Z.X., Z.Z., O.C., W.H., G.Z., G.C., T.C., P.W., W.D., H.L., H.Z., C.C., H.G., K.X., Z.Z., K.Y., J.L., J-L.W., J.G., L.S., H.J., C.L., J.L., P.C., Z.L., and B.T. The original manuscript was drafted by J.W. and B.T. All authors participated in reviewing and editing the manuscript and approved the final version for submission.
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Wan, J., Pan, H., Chang, D. et al. The genetic spectrum of LRRK2 variants in Parkinson’s disease: findings from a large Chinese cohort. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01315-w
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DOI: https://doi.org/10.1038/s41531-026-01315-w
