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

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1207114

DOI=10.3389/fnagi.2023.1207114

ISSN=1663-4365

ABSTRACT=<sec><title>Objective</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including <italic>COL6A3</italic> and <italic>TH</italic>. 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 <italic>ANO3</italic>, p.R678H in <italic>ADCY5</italic>, and p.R458Q in <italic>SLC2A1</italic>). A gene-based burden analysis revealed the increased burden of variant subgroups of <italic>TH, SQSTM1, THAP1</italic>, and <italic>ADCY5</italic> in sporadic early-onset PD, whereas <italic>COL6A3</italic> was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.</p></sec><sec><title>Conclusion</title><p>Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of <italic>COL6A3</italic> and <italic>TH</italic> genes in PD is highlighted.</p></sec>