Genetic analysis of dystonia-related genes in Parkinson's disease

Yige Wang; Yuwen Zhao; Hongxu Pan; Qian Zeng; Xiaoxia Zhou; Yaqin Xiang; Zhou Zhou; Qian Xu; Qiying Sun; Jieqiong Tan; Xinxiang Yan; Jinchen Li; Jifeng Guo; Beisha Tang; Qiao Yu; Zhenhua Liu

doi:10.3389/fnagi.2023.1207114

Genetic analysis of dystonia-related genes in Parkinson's disease

Front Aging Neurosci. 2023 May 26:15:1207114. doi: 10.3389/fnagi.2023.1207114. eCollection 2023.

Authors

Yige Wang^{1

2}, Yuwen Zhao¹, Hongxu Pan¹, Qian Zeng¹, Xiaoxia Zhou¹, Yaqin Xiang¹, Zhou Zhou³, Qian Xu¹, Qiying Sun³, Jieqiong Tan⁴, Xinxiang Yan¹, Jinchen Li^{2

3

4}, Jifeng Guo^{1

2

4

5}, Beisha Tang^{1

2

4

5}, Qiao Yu^#³, Zhenhua Liu^#^{1

2

4

5}

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
⁵ Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, China.

^# Contributed equally.

Abstract

Objective: Parkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort.

Methods: We comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD.

Results: We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.

Conclusion: Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

Keywords: Parkinson's disease; dystonia-related genes; rare variants; whole-exome sequencing; whole-genome sequencing.

Grants and funding

This study was supported by the Natural Science Foundation of Hunan Province (Grant No. 2022JJ40843), the National Natural Science Foundation of China (Grant No. 82001359), the Scientific Research Project of Hunan Provincial Health Commission (Grant No. 202203074637), the Hunan Innovative Province Construction Project (Grant Nos. 2019SK2335 and 2021SK1010), and the National Key Research and Development Program of China (Grant Nos. 2021YFC2501204 and 2016YFC306000).