Common and rare GCH1 variants are associated with Parkinson disease Uladzislau Rudakou 1,2 , Bouchra Ouled Amar Bencheikh 2,3 , Jennifer A. Ruskey 2,4 , Lynne Krohn 1,2 , Sandra B. Laurent 2,4 , Dan Spiegelman 2,4 , Christopher Liong 5 , Stanley Fahn, MD 5 , Cheryl Waters, MD 5 , Oury Monchi 6,7 , Edward A. Fon 2,8 , Yves Dauvilliers 9 , Roy N. Alcalay 4,10 , Nicolas Dupré 11,12 , and Ziv Gan-Or 1,2,4 1. Department of Human Genetics, McGill University, Montréal, QC, Canada 2. Montreal Neurological Institute, McGill University, Montréal, QC, Canada 3. Centre de Recherche, Centre Hospitalier de l’Universite de Montreal, Montreal, QC H2X 0A9, Canada 4. Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada 5. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 6. Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary, Alberta, Canada 7. Cumming School of Medicine, Hotchkiss Brain Institute, Calgary, Alberta, Canada 8. McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada 9. National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de- Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France 10. 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 11. Division of Neurosciences, CHU de Québec, Université Laval, Québec City, QC, Canada 12. Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC, Canada. Abstract GCH1 encodes the enzyme 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 genome-wide association studies in Parkinson disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the current study, GCH1 and its 5’ and 3’ untranslated regions were sequenced in 1,113 PD patients and 1,111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was Corresponding author: Ziv Gan-Or Montreal Neurological Institute, McGill University 1033 Pine Avenue, West, Ludmer Pavilion, room 312 Montreal, QC, H3A 1A1, Phone: +1-514-398-5845 ziv.gan-or@mcgill.ca. HHS Public Access Author manuscript Neurobiol Aging. Author manuscript; available in PMC 2020 January 01. Published in final edited form as: Neurobiol Aging. 2019 January ; 73: 231.e1–231.e6. doi:10.1016/j.neurobiolaging.2018.09.008. Author Manuscript Author Manuscript Author Manuscript Author Manuscript