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Parkinsonism Relat Disord ; 84: 29-34, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33548880


INTRODUCTION: A recent study reported that rare variants in NUS1 were associated with Parkinson's disease (PD). We aimed to assess the relative contribution of rare and common coding/non-coding variants of NUS1 to late-onset PD patients (LOPD). METHODS: Whole genome sequencing data were analyzed for target NUS1 regions, derived from a cohort of 1962 cases and 1279 controls. The genetic association analyses were performed using logistic regression analysis and Sequence Kernel association test. Expression quantitative trait loci (eQTL) analysis was conducted to further explore the association of variants with NUS1 expression based on the data from GTEx database. RESULTS: We identified 18 rare coding variants. p.Y131C was first identified in LOPD. However, no significant burden of rare NUS1 coding variants in LOPD was found. The rare variant sets of two regulatory elements (GH06J117605 and GH06J117674) were significantly enriched in LOPD even after Bonferroni correction (adjusted P = 0.013; adjusted P = 0.010). Considering the joint effect of rare and common variants, all variant sets within GH06J117605 and GH06J117674 showed association with LOPD but were no longer significant after Bonferroni correction. None of the common variants within coding/non-coding regions were significant after Bonferroni correction. The eQTL results suggested these variants in GH06J117605 and GH06J117674 could potentially have eQTL effects on the brain tissues. CONCLUSIONS: These findings provide novel insight into the role of NUS1 regulatory regions in the development of LOPD and indicate that the variants in regulatory elements of NUS1 may be associated with LOPD by influencing the gene expression level.

Neurosci Lett ; 740: 135441, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33184037


BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

Transl Neurodegener ; 9(1): 31, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32746945


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.