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
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Front Aging Neurosci. 2023 May 26;15:1207114. doi: 10.3389/fnagi.2023.1207114. eCollection 2023.
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.
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.
We found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including and . 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 , p.R678H in , and p.R458Q in ). A gene-based burden analysis revealed the increased burden of variant subgroups of , and in sporadic early-onset PD, whereas was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.
Our findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of and genes in PD is highlighted.
帕金森病（PD）和肌张力障碍是两种密切相关的运动障碍，临床表型存在重叠。多个与肌张力障碍相关的基因变异已被证明与PD有关；然而，肌张力障碍相关基因参与PD的遗传证据尚未得到充分研究。在此，我们在中国的一个大型队列中全面研究了肌张力障碍相关基因的罕见变异与PD之间的关联。
我们通过挖掘3959例PD患者和2931例健康对照的全外显子测序（WES）和全基因组测序（WGS）数据，全面分析了47个已知的肌张力障碍相关基因的罕见变异。我们最初根据不同的遗传模型在PD患者中鉴定出肌张力障碍相关基因的潜在致病变异。下一步进行序列核关联测试，以检测罕见变异负担与PD风险之间的关联。
我们发现5例PD患者在隐性肌张力障碍相关基因中携带潜在致病双等位基因变异，包括 和 。此外，基于计算致病性预测，我们在显性肌张力障碍相关基因中鉴定出180个有害变异，其中4个被认为是潜在致病变异（ 中的p.W591X和p.G820S、 中的p.R678H以及 中的p.R458Q）。基于基因的负担分析显示，在散发性早发性PD中， 、 和 的变异亚组负担增加，而 与散发性晚发性PD相关。然而，在Bonferroni校正后，它们均未达到统计学意义。
我们的研究结果表明，几个肌张力障碍相关基因的罕见变异与PD存在提示性关联，综合来看，突出了 和 基因在PD中的作用。
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