GBA variation and susceptibility to multiple system atrophy |
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| Institution: | 1. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA;2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA;3. Department of Biology, University of North Florida, Jacksonville, FL, USA;4. Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA;5. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA;6. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA;7. Department of Radiology, Mayo Clinic, Rochester, MN, USA;8. Department of Neurology, Mayo Clinic, Rochester, MN, USA;9. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;10. School of Medicine and Medical Science, University College Dublin, Dublin, Ireland;11. Mayo Graduate School, Mayo Clinic, Jacksonville, FL, USA;1. Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada;2. Department of Human Genetics, McGill University, Montréal, Quebec, Canada;3. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada;4. Centre d''Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, Montréal, Quebec, Canada;5. Department of Psychiatry, Université de Montréal, Montréal, Quebec, Canada;6. Department of Psychiatry, McGill University, Montréal, Quebec, Canada;7. Douglas Mental Health University Institute, Montréal, Quebec, Canada;8. Sleep Disorders Unit, Pitié Salpêtrière Hospital, Centre de Recherche de l''Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, UPMC Paris 6 univ, Paris, France;9. Sleep Unit, National Reference Network for Narcolepsy, Department of Neurology Hôpital-Gui-de Chauliac, CHU Montpellier, INSERM U1061, Montpellier, France;10. Oxford Parkinson''s Disease Centre (OPDC), University of Oxford, Oxford, UK;11. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK;12. Sleep Disorders Clinic, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria;13. Department of Clinical Neurophysiology and Sleep Center, University Lille North of France, CHU Lille, Lille, France;14. Sleep and Neurology Unit, Beau Soleil Clinic, Montpellier, France;15. EuroMov, University of Montpellier, Montpellier, France;p. GRIP, École de psychologie, Université Laval, Québec city, Quebec, Canada;q. Institute of Genetic, Neurobiological and Social Foundations of Child Development, Tomsk State University, Tomsk, Russia;r. Department of Neurological Sciences, Università Vita-Salute San Raffaele, Milan, Italy;s. Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy;t. IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy;u. Department of Sleep Medicine and Neuromuscular Disorders, University of Muenster, Germany;v. Department of Neurosciences, Université de Montréal, Montréal, Quebec, Canada;w. Département de psychologie, Université du Québec à Montréal, Montréal, Quebec, Canada;x. Faculté de Médecine, Université Laval, CHU de Québec (Enfant-Jésus), Québec, Quebec, Canada;y. Department of Neurology, Montreal General Hospital, Montréal, Quebec, Canada;1. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK;2. National Hospital for Neurology and Neurosurgery, Queen Square, London, UK;3. Department of Neurology, Medical and Pharmaceutical State University N. Testemitanu, Chisinau, Moldova;4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway;5. Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France;6. CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France;7. Centre de référence atrophie multisystématisée, CHU de Bordeaux, Bordeaux, France;8. Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, London, UK |
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| Abstract: | IntroductionGenetic variants in the glucocerebrosidase (GBA) gene have been previously associated with susceptibility to synucleinopathies. The risk is well-established in Lewy body disease but is not as confirmed for multiple system atrophy (MSA). We aim to evaluate associations between exonic variants in GBA and risk of neuropathologically-confirmed multiple system atrophy (MSA).MethodsSanger gene sequencing of GBA was performed on 167 pathologically confirmed MSA patients collected at Mayo Clinic Florida Brain Bank, and data were extracted from whole-genome sequencing of 834 clinical controls. Common GBA variants were assessed for association with MSA. Rare GBA variants (and also all GBA variants) were collapsed together and evaluated for association with MSA risk using a gene-burden test.ResultsA total of 17 exonic GBA variants were observed, including a novel p.Q112X variant that is likely pathogenic in a patient with mixed parkinsonism-cerebellar subtype MSA. The more common p.N409S and p.L483P variants that recessively cause Gaucher's disease (GD), and are associated with risk of Lewy body disease, were not observed. When collapsing across all GBA variants, the presence of any GBA variant was significantly more frequent in MSA patients than in controls (OR = 1.90, P = 0.031). However, this association was driven by p.T408M, which had a significantly higher frequency in MSA patients compared to controls (OR = 4.21, P = 0.002). There was no significant association with risk of MSA for the p.E365K variant (OR = 0.79, P = 0.72).ConclusionsOther than the specific GBA p.T408M variant, coding GBA variants are not associated with risk of MSA. |
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| Keywords: | Multiple system atrophy Genetics |
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