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

Abstract

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 untranslated regions and intron regions, GCH1 brain-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 of GCH1 deleterious 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 in GCH1 deleterious variant carriers ( P = 0.0009). Conclusions The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.

Genotype-Phenotype Correlations in Monogenic Parkinson Disease: A Review on Clinical and Molecular Findings

“…Nigrostriatal degeneration in affected patients was also proved by a reduced tracer uptake in SPECT studies (102). The association between PD phenotype and GCH1 pathogenic variants was confirmed by further studies (103,104). Also, triplet expansion variants in ATXN2 (MIM * 601517), responsible for autosomal dominant cerebellar ataxia type 2 (SCA2, MIM#183090), may cause a form of typical PD with onset after 40 years, good response to levodopa therapy without cognitive impairment, and cerebellar signs.…”

A genetic and transcriptomic assessment of theKTN1gene in Parkinson’s disease risk

“…Of note, one of the 18 genes within the region, GCH1 , has been previously found to be associated with PD 11 . GCH1 encodes the enzyme GTP cyclohydrolase 1, which is necessary for dopamine synthesis in nigrostriatal cells 22,23 and dopamine deficiency in the nigrostriatal region is a core biological feature of PD 24 . However, we found no significant eQTL values for GCH1 .…”

The Association Between Lysosomal Storage Disorder Genes and Parkinson’s Disease: A Large Cohort Study in Chinese Mainland Population

“…Then, the sequencing data were analyzed using the BWA-GATK-ANNOVAR pipeline as follows: the sequencing data were aligned to the human reference genome (hg19 version) using the Burrows-Wheeler Aligner (BWA) ( Li, 2014 ), then variant calling was performed using the Genome Analysis Toolkit (GATK) ( Van Der Auwera et al, 2013 ), subsequent variants were annotated using ANNOVAR ( Wang et al, 2010 ) and Varcards 2 ( Li et al, 2018a ), as described in our previous study ( Zhao et al, 2020 ). Similar to the quality control standards used in our earlier study ( Pan et al, 2020 ), individuals with low genotype rate, ambiguous gender, or cryptic relatedness were excluded from this study.…”