1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2 Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
3 Department of Physics, Concordia University, Montreal, Quebec, Canada.
4 Centre for Research in Molecular Modeling (CERMM), Concordia University, Montreal, Quebec, Canada.
5 PROTEO, The Quebec Network for Research on Protein Function, Engineering and Applications, Quebec, Quebec, Canada.
6 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
7 Sleep Disorders Unit, Pitié Salpêtrière Hospital, Institute of Brain and Spinal Cord and Sorbonne University, Paris, France.
8 Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.
9 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
10 National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui de Chauliac Hospital, University Hospital Center Montpellier, University of Montpellier, National Institute of Health and Medical Research U1061, Montpellier, France.
11 Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
12 University of Lille Nord de France, Department of Clinical Neurophysiology and Sleep Center, University Hospital Center Lille, Lille, France.
13 Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
14 Scientific Institute for Research and Health Care, Institute of Neurological Sciences of Bologna, Bologna, Italy.
15 Department of Neurological Sciences, Vita-Salute San Raffaele University, Milan, Italy.
16 Institute of Sleep Medicine and Neuromuscular Disorders, University of Münster, Münster, Germany.
17 Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France.
18 EuroMov, University of Montpellier, Montpellier, France.
19 Biologics Structural and Functional Research, Biopharmaceutics Development, Genzyme, Framingham, MA.
20 Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
21 Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
22 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
23 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY.
24 Center for Advanced Research in Sleep Medicine, Sacred Heart Hospital of Montreal, Montreal, Quebec, Canada.
25 Department of Psychology, University of Quebec at Montreal, Montreal, Quebec, Canada.
26 Department of Neurosciences, University of Quebec at Montreal, Montreal, Quebec, Canada.
27 The Movement Disorders Institute, Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel.
28 Department of Psychiatry, University of Montreal, Montreal, Quebec, Canada.
29 Division of Neurosciences, University Hospital Center of Quebec, Laval University, Quebec City, Quebec, Canada.
30 Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
31 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
32 Department of Chemistry, Rutgers University - Camden, Camden, NJ, USA.
33 Center for Computational and Integrative Biology (CCIB), Camden, NY, USA. <

Objective: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications.

Methods: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function.

Results: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants.

Interpretation: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020; 87:139-153.