Objective: Our aim was to identify the potential role of known genetic components of GCH1, including rare and common variants in coding and non-coding regions, using whole-exome sequencing (WES) or whole-genome sequencing (WGS) technology in two cohorts of PD patients and controls.

Background: Increased burden of predicted deleterious GCH1 mutations in PD patients from exome-wide analysis and the association of polymorphisms in GCH1 locus with PD from genome-wide association studies (GWAS) have been described.However, conflicting results have been reported from different populations, indicating genetic heterogeneity among different populations. Thus, it is of importance to explore whether rare and common GCH1 variants play a role in Chinese mainland PD patients. Furthermore, here is still a lack of studies on GCH1 variants in regulatory regions such as promoter, enhancer and expression quantitative trait loci (eQTLs). In addition to the effect on the risk of PD, genetic variants may also play roles in specific clinical phenotypes.

Method: In this case-control study, we performed whole-exome or whole-genome sequencing on the subjects (3517 cases v.s. 3513 controls). Variants from target GCH1 regions were extracted, and genetic and phenotypic data were analyzed using regression models and sequence kernel association test. We also did a meta-analysis to correlate deleterious GCH1 variants with age at onset in Parkinson’s disease patients.

Results: For coding variants, we identified significant burden of GCH1 deleterious variants in cases (p < 0.0001), see Table 1. For non-coding variants, one common variant (rs12323905, p = 0.0009, odds ratio = 1.19), variants in untranslated regions and intron region (p = 0.04), brain specific expression quantitative trait loci (p = 0.03), and two regulatory regions (GH14J054857, p = 0.04; GH14J054880, p = 0.03) were associated with Parkinson’s disease, see Table 2 and Fig. 1. Genotype-phenotype correlation analysis revealed that GCH1 deleteriousvariant carriers manifested younger age at onset and milder motor symptoms. Meta-analysis of six studies demonstrated 6.4 years earlier onset in GCH1 deleterious variant carriers (p = 0.0009), see Fig. 2.

Conclusion: Our study highlights the importance of deleterious variants and non-coding variants of GCH1 in Parkinson’s disease in Chinese mainland population. Our study will help in exploring the mechanisms of GCH1 in the pathogenesis of Parkinson’s disease.

« Back to MDS Virtual Congress 2020

MDS Abstracts - https://www.mdsabstracts.org/abstract/gch1-variants-contribute-to-risk-and-earlier-age-at-onset-in-parkinsons-disease/