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Genome sequence analyses identify novel risk loci for multiple system atrophy.
Chia, Ruth; Ray, Anindita; Shah, Zalak; Ding, Jinhui; Ruffo, Paola; Fujita, Masashi; Menon, Vilas; Saez-Atienzar, Sara; Reho, Paolo; Kaivola, Karri; Walton, Ronald L; Reynolds, Regina H; Karra, Ramita; Sait, Shaimaa; Akcimen, Fulya; Diez-Fairen, Monica; Alvarez, Ignacio; Fanciulli, Alessandra; Stefanova, Nadia; Seppi, Klaus; Duerr, Susanne; Leys, Fabian; Krismer, Florian; Sidoroff, Victoria; Zimprich, Alexander; Pirker, Walter; Rascol, Olivier; Foubert-Samier, Alexandra; Meissner, Wassilios G; Tison, François; Pavy-Le Traon, Anne; Pellecchia, Maria Teresa; Barone, Paolo; Russillo, Maria Claudia; Marín-Lahoz, Juan; Kulisevsky, Jaime; Torres, Soraya; Mir, Pablo; Periñán, Maria Teresa; Proukakis, Christos; Chelban, Viorica; Wu, Lesley; Goh, Yee Y; Parkkinen, Laura; Hu, Michele T; Kobylecki, Christopher; Saxon, Jennifer A; Rollinson, Sara; Garland, Emily; Biaggioni, Italo.
Affiliation
  • Chia R; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
  • Ray A; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Shah Z; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Ding J; Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
  • Ruffo P; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
  • Fujita M; Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
  • Menon V; Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
  • Saez-Atienzar S; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
  • Reho P; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Kaivola K; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Walton RL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Reynolds RH; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK; Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University College London, London, UK; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology,
  • Karra R; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
  • Sait S; Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
  • Akcimen F; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
  • Diez-Fairen M; Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
  • Alvarez I; Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
  • Fanciulli A; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Stefanova N; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Seppi K; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Duerr S; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Leys F; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Krismer F; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Sidoroff V; Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
  • Zimprich A; Department of Neurology, Medical University of Vienna, Vienna, Austria.
  • Pirker W; Department of Neurology, Klinik Ottakring - Wilhelminenspital, Vienna, Austria.
  • Rascol O; MSA French Reference Center and CIC-1436, Department of Clinical Pharmacology and Neurosciences, University of Toulouse, Toulouse, France.
  • Foubert-Samier A; Service de Neurologie des Maladies Neurodégénératives, French Reference Center for MSA, NS-Park/FCRIN Network, CHU Bordeaux, Bordeaux, France.
  • Meissner WG; Service de Neurologie des Maladies Neurodégénératives, French Reference Center for MSA, NS-Park/FCRIN Network, CHU Bordeaux, Bordeaux, France; University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France; Department of Medicine, University of Otago, and the New Zealand Brain Research Institute, Chr
  • Tison F; Service de Neurologie des Maladies Neurodégénératives, French Reference Center for MSA, NS-Park/FCRIN Network, CHU Bordeaux, Bordeaux, France; University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France.
  • Pavy-Le Traon A; French Reference Center for MSA, Department of Neurosciences, Centre d'Investigation Clinique de Toulouse CIC1436, UMR 1048, Institute of Cardiovascular and Metabolic Diseases (I2MC), University Hospital of Toulouse, INSERM, Toulouse, France.
  • Pellecchia MT; Neuroscience Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
  • Barone P; Neuroscience Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
  • Russillo MC; Neuroscience Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
  • Marín-Lahoz J; Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain; Servic
  • Kulisevsky J; Movement Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Torres S; Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Mir P; Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Madrid, Spain; De
  • Periñán MT; Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Seville, Spain; Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University, L
  • Proukakis C; Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
  • Chelban V; Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK; The National Hospital for Neurology and Neurosurgery, London, UK.
  • Wu L; Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
  • Goh YY; Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
  • Parkkinen L; Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
  • Hu MT; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • Kobylecki C; Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.
  • Saxon JA; Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salfort, UK; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
  • Rollinson S; Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
  • Garland E; Autonomic Dysfunction Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Biaggioni I; Autonomic Dysfunction Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Neuron ; 112(13): 2142-2156.e5, 2024 Jul 03.
Article in En | MEDLINE | ID: mdl-38701790
ABSTRACT
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Multiple System Atrophy / Genetic Predisposition to Disease / Genome-Wide Association Study Limits: Aged / Female / Humans / Male / Middle aged Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2024 Document type: Article Affiliation country: Country of publication:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Multiple System Atrophy / Genetic Predisposition to Disease / Genome-Wide Association Study Limits: Aged / Female / Humans / Male / Middle aged Language: En Journal: Neuron Journal subject: NEUROLOGIA Year: 2024 Document type: Article Affiliation country: Country of publication: