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

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 ofGCH1genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics ofGCH1, 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 ofGCH1variant 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 targetGCH1regions 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 deleteriousGCH1variants with age at onset (AAO) in PD patients. Results: For coding variants, we identified a significant burden ofGCH1deleterious 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 inGCH1non-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 untranslated regions and intron regions,GCH1brain-specific expression quantitative trait loci, and two possible promoter/enhancer (GH14J054857 and GH14J054880) were suggestively associated with PD. Genotype-phenotype correlation analysis revealed that the carriers ofGCH1deleterious variants manifested younger AAO (P < 0.0001), and had milder motor symptoms, milder fatigue symptoms and more autonomic nervous dysfunctions. Meta-analysis of six studies demonstrated 6.4-year earlier onset inGCH1deleterious variant carriers (P = 0.0009). Conclusions: The results highlight the importance of deleterious variants and non-coding variants ofGCH1in PD in Chinese mainland and suggest thatGCH1mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms ofGCH1in the pathogenesis of PD.