Association of Common and Rare GCH1 Variants with Parkinson’s Disease
1.Department of Human Genetics, McGill University, Montréal, QC, Canada; 2.Montreal Neurological Institute, McGill University, Montréal, QC, Canada; 3.Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada; 4.Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; 5. Department of Experimental Medicine, McGill University, Montréal, QC, Canada; 6. National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France; 7.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; 8. Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada; 9.Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada.
Background: GCH1 gene encodes GTP cyclohydrolase 1, an essential enzyme for dopamine synthesis in nigrostriatal cells. Loss-of-function mutations in GCH1 lead to a severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia (DRD). Co-occurrence of DRD and Parkinsonism has been reported in families with GCH1 mutations, and a study on sporadic Parkinson’s disease patients (PD) demonstrated an increased frequency of pathogenic GCH1 mutations that were previously reported to cause DRD. GCH1 is also implicated in genome-wide association studies, but only a few studies examined the role of rare GCH1 variants in PD, and their association with PD is still unclear.
Methods: GCH1 and its 5’ and 3’ untranslated regions were sequenced in 1113 PD patients and 1147 controls. Molecular inversion probes (MIPs) were designed in our lab for the targeted capture of the regions of interest. To examine the association of rare GCH1 variants with PD, burden analysis in R package SKAT was performed. All common variants were analysed with logistic regression.
Results: Three variants (p.R184C, p.M221T and p.K224R) that are considered to be pathogenic in DRD were found in five (~0.5%) PD patients, and none in controls. One variant (p.V204I) that was previously reported to have conflicting interpretation of pathogenicity in DRD was found only in 3 controls (~0.3%). Burden analysis of p.R184C, p.M221T and p.K224R showed significant association with PD risk (p=0.024). Logistic regression showed two common variants to be associated with reduced PD risk in our data: rs841 (OR= 0.71, 95% CI=0.61-0.83, p=1.51x10-5) and rs56130647 (OR=0.79, 95% CI=0.64-0.97, p=0.026).
Conclusions: The significant association between GCH1 variants and an increased risk for the disease reported in this study provides evidence that rare, pathogenic GCH1 variants should be considered as a risk factor for Parkinson’s Disease. Furthermore, common variants in the GCH1 locus also affect the risk for PD, and the mechanism underlying this effect should be further studied.