GCH1 variants contribute to the risk and earlier age-at-onset of Parkinson’s disease: a two-cohort case-control study

作者：Hong-xu Pan, Yuwen Zhao, Junpu Mei, Zhenghuan Fang, Yige Wang, Xun Zhou, Yangjie Zhou, Rui Zhang, Kailin Zhang, Jiang Li, Qian Zeng, Yan He, Zheng Wang, Zhenhua Liu, Qian Xu, Qiying Sun, Yang Yang, Yacen Hu, Yase Chen, Juan Du, Lifang Lei, Hainan Zhang, Chunyu Wang, Xinxiang Yan, Lu Shen, Hong Jiang, Jieqiong Tan, Jinchen Li, Beisha Tang, Jifeng Guo · 发表于：Translational Neurodegeneration · 年份：2020 · DOI：10.1186/s40035-020-00212-3 · 被引用次数：52 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Genomics and Rare Diseases、Lysosomal Storage Disorders Research

BACKGROUND: Common and rare variants of guanosine triphosphate cyclohydrolase 1 (GCH1) gene may play important roles in Parkinson's disease (PD). However, there is a lack of comprehensive analysis of GCH1 genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics of GCH1, including rare and common variants in coding and non-coding regions, in a large population of PD patients in Chinese mainland, as well as the phenotypic characteristics of GCH1 variant carriers. METHODS: In the first cohort of this case-control study, we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls; then in the second cohort, whole-genome sequencing was performed in sporadic late-onset PD samples (1962 patients), as well as 1279 controls. Variants at target GCH1 regions were extracted, and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test. We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset (AAO) in PD patients. RESULTS: For coding variants, we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls (1.2% vs 0.1%, P < 0.0001). In the analysis of possible regulatory variants in GCH1 non-coding regions, rs12323905 (P = 0.001, odds ratio = 1.19, 95%CI 1.07-1.32) was significantly associated with PD, and variant sets in untranslate...