Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No.37, Guoxue Lane, Chengdu, 610041, Sichuan, China.
Department of Rheumatology and Immunology, Rare Diseases Center, West China Hospital, Sichuan University, No.37, Guoxue Lane, Chengdu, 610041, Sichuan, China.
Mol Neurobiol. 2021 Jul;58(7):3435-3442. doi: 10.1007/s12035-021-02354-5. Epub 2021 Mar 15.
Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.
功能和遗传研究已经确定了几种锌指（ZNF）蛋白与帕金森病（PD）之间的关联。然而，其中大多数仍有待进一步验证，尤其是在亚洲人群中。在这里，我们系统地选择了与 PD 相关的 ZNF 基因，并在中国的一个大型 PD 队列中分析了这些 ZNF 与 PD 之间的遗传关联。我们使用全外显子测序在 743 名无亲缘关系的早发性 PD（EOPD，发病年龄<50 岁）患者中鉴定了罕见变异（次要等位基因频率<0.01），并在等位基因和基因水平上评估了罕见变异与 EOPD 之间的关联。在 ZNF746、ZNF646、ZNF184、ZNF165、ZND219 和 GLIS1 中总共鉴定出 91 种罕见变异。ZNF219 中的一个变异 p.R373H 和 ZNF746 中的两个变异 p.G161D 和 p.R158H 与 EOPD 显著相关，基于基因的负担分析显示 EOPD 中 ZNF746 的罕见变异富集。我们的发现首次从遗传角度建立了 ZNF746 与 PD 之间的联系，补充了当前对 EOPD 中 ZNF 遗传作用的理解，并拓宽了 PD 的突变谱。
