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Neurobiol Aging. 2019 Jan;73:231.e1-231.e6. doi: 10.1016/j.neurobiolaging.2018.09.008. Epub 2018 Sep 15.

Common and rare GCH1 variants are associated with Parkinson's disease.

Author information

1
Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
2
Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada.
3
Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada.
4
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
5
Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary, Alberta, Canada; Cumming School of Medicine, Hotchkiss Brain Institute, Calgary, Alberta, Canada.
6
Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
7
National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France.
8
Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
9
Division of Neurosciences, CHU de Québec, Université Laval, Québec City, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec City, Quebec, Canada.
10
Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address: ziv.gan-or@mcgill.ca.

Abstract

GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed. Three rare GCH1 variants, which were previously reported to be pathogenic in DRD, were found in five patients with PD and not in controls (sequence Kernel association test, p = 0.024). A common haplotype, tagged by rs841, was associated with a reduced risk for PD (OR = 0.71, 95% CI = 0.61-0.83, p = 1.24 × 10-4), and with increased GCH1 expression in brain regions relevant for PD (www.gtexportal.org). Our results support a role for rare, DRD-related variants, and common GCH1 variants in the pathogenesis of PD.

KEYWORDS:

Dopa-responsive dystonia (DRD); GCH1; GTP cyclohydrolase 1 deficiency; Parkinson disease

PMID:
30314816
PMCID:
PMC6251729
[Available on 2020-01-01]
DOI:
10.1016/j.neurobiolaging.2018.09.008

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