Li Bin, Zhao Guihu, Zhou Qiao, Xie Yali, Wang Zheng, Fang Zhenghuan, Lu Bin, Qin Lixia, Zhao Yuwen, Zhang Rui, Jiang Li, Pan Hongxu, He Yan, Wang Xiaomeng, Luo Tengfei, Zhang Yi, Wang Yijing, Chen Qian, Liu Zhenhua, Guo Jifeng, Tang Beisha, Li Jinchen
National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Front Neurosci. 2021 Apr 26;15:679568. doi: 10.3389/fnins.2021.679568. eCollection 2021.
Parkinson's disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30-50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with ( = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.
帕金森病（PD）是一种具有强大遗传成分的复杂神经退行性疾病。越来越多的变异体和基因被报道与PD相关；然而，目前尚无整合不同类型遗传数据并支持对PD相关基因（PAGs）进行分析的数据库。通过对多项公共研究进行系统综述和整理，我们整合了多层遗传数据（从PD患者中鉴定出的罕见变异体和拷贝数变异体、从全基因组关联研究中鉴定出的相关变异体、差异表达基因和差异DNA甲基化基因）以及PD的发病年龄。我们整合了来自3000多项研究的具有不同证据水平的五层遗传数据（8302个条目），并对124个具有强证据或提示性证据的PAGs进行了优先级排序。这些PAGs被确定为彼此之间存在显著相互作用，并形成了一个相互连接的功能网络，该网络富含与PD相关的多种功能途径，表明这些基因可能参与了PD的发病机制。此外，我们鉴定出10个基因与青少年发病（年龄≤30岁）相关，11个基因与早发（年龄30 - 50岁）相关，而另外10个基因与晚发（年龄>50岁）相关。值得注意的是，五个基因中功能丧失变异体患者的发病年龄显著低于有害错义变异体患者，而（ = 0.01）患者则相反。最后，我们开发了一个名为Gene4PD（http://genemed.tech/gene4pd）的在线数据库，该数据库整合了已发表的PD遗传数据、PAGs和63个流行的基因组数据源，以及一个用于对PD风险变异体进行优先级排序的在线管道。总之，Gene4PD为研究人员和临床医生提供了关于PD的全面遗传知识和分析平台，也将增进对PD发病机制的理解。
