GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease

Yoshino, Hideaki; Nishioka, Kenya; Li, Yuanzhe; Oji, Yusuke; Oyama, Genko; Hatano, Taku; Machida, Yutaka; Shimo, Yasushi; Hayashida, Arisa; Ikeda, Aya; Mogushi, Kaoru; Shibagaki, Yasuro; Hosaka, Ai; Iwanaga, Hiroshi; Fujitake, Junko; Ohi, Takekazu; Miyazaki, Daigo; Sekijima, Yoshiki; Oki, Mitsuaki; Kusaka, Hirofumi; Fujimoto, Ken’ichi; Ugawa, Yoshikazu; Funayama, Manabu

doi:10.1007/s00415-018-8930-8

Cited by 33 publications

(43 citation statements)

References 28 publications

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“…A total of 51 GCH1 deleterious variant-carriers and 6874 PD patients from six studies (including the present study) were included to analyze the association between GCH1 status and AAO in PD patients. The characteristics of the included studies [ 8 , 9 , 14 , 43 , 44 ] are shown in Fig. 4 b.…”

Section: Resultsmentioning

confidence: 99%

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

Pan

Zhao

Mei

et al. 2020

Transl Neurodegener

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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.

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Section: Resultsmentioning

confidence: 99%

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

Pan

Zhao

Mei

et al. 2020

Transl Neurodegener

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“…We identified 52 positively selected genes (PSGs) in the goose genome based on orthologous genes from the 17 aforementioned species, using a branch-site model and F3 × 4 codon frequencies in Codeml (Codeml, RRID:SCR_004542 ) ( Supplementary Table S8 ). Some of these PSGs, such as GCH1 (GTP-cyclohydrolase I), are associated with Parkinsonism, dystonia, and phenylketonuria disease in humans [ 49 , 50 ]. They also play a role in adaptation to high-altitude environments in humans, where they relate to a lower hemoglobin level, nitric oxide concentration, and oxygen saturation in the blood.…”

Section: Data Descriptionmentioning

confidence: 99%

Pacific Biosciences assembly with Hi-C mapping generates an improved, chromosome-level goose genome

Gao

Lin

et al. 2020

GigaScience

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Background The domestic goose is an economically important and scientifically valuable waterfowl; however, a lack of high-quality genomic data has hindered research concerning its genome, genetics, and breeding. As domestic geese breeds derive from both the swan goose (Anser cygnoides) and the graylag goose (Anser anser), we selected a female Tianfu goose for genome sequencing. We generated a chromosome-level goose genome assembly by adopting a hybrid de novo assembly approach that combined Pacific Biosciences single-molecule real-time sequencing, high-throughput chromatin conformation capture mapping, and Illumina short-read sequencing. Findings We generated a 1.11-Gb goose genome with contig and scaffold N50 values of 1.85 and 33.12 Mb, respectively. The assembly contains 39 pseudo-chromosomes (2n = 78) accounting for ∼88.36% of the goose genome. Compared with previous goose assemblies, our assembly has more continuity, completeness, and accuracy; the annotation of core eukaryotic genes and universal single-copy orthologs has also been improved. We have identified 17,568 protein-coding genes and a repeat content of 8.67% (96.57 Mb) in this genome assembly. We also explored the spatial organization of chromatin and gene expression in the goose liver tissues, in terms of inter-pseudo-chromosomal interaction patterns, compartments, topologically associating domains, and promoter-enhancer interactions. Conclusions We present the first chromosome-level assembly of the goose genome. This will be a valuable resource for future genetic and genomic studies on geese.

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“…Even if not located on a specific common allele, rare variants in GWAS genes may contribute to disease. For example, rare variants in SNCA (Polymeropoulos et al, 1997), GBA (Sidransky et al, 2009;Ran et al, 2016;Emelyanov et al, 2018;Amaral et al, 2019), LRRK2 (Paisan-Ruiz et al, 2004;Khan et al, 2005), VPS13C (Lesage et al, 2016;Jansen et al, 2017;Darvish et al, 2018;Schormair et al, 2018;Rudakou et al, 2020), GCH1 (Mencacci et al, 2014;Guella et al, 2015;Lewthwaite et al, 2015;Xu et al, 2017;Yoshino et al, 2018;Rudakou et al, 2019), all GWAS loci genes, also cause or increase the risk of Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations

Rudakou

Krohn

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5′ UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We ideniified common variants associated with Parkinson′s disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.

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GCH1 mutations in dopa-responsive dystonia and Parkinson’s disease

Cited by 33 publications

References 28 publications

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

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

Pacific Biosciences assembly with Hi-C mapping generates an improved, chromosome-level goose genome

Targeted sequencing of Parkinson’s disease loci genes highlightsSYT11, FGF20and other associations

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