. 2024 Jul 3;112(13):2142-2156.e5.

doi: 10.1016/j.neuron.2024.04.002. Epub 2024 May 2.

Genome sequence analyses identify novel risk loci for multiple system atrophy

Ruth Chia¹, Anindita Ray², Zalak Shah², Jinhui Ding³, Paola Ruffo⁴, Masashi Fujita⁵, Vilas Menon⁵, Sara Saez-Atienzar¹, Paolo Reho², Karri Kaivola², Ronald L Walton⁶, Regina H Reynolds⁷, Ramita Karra¹, Shaimaa Sait², Fulya Akcimen¹, Monica Diez-Fairen⁸, Ignacio Alvarez⁸, Alessandra Fanciulli⁹, Nadia Stefanova⁹, Klaus Seppi⁹, Susanne Duerr⁹, Fabian Leys⁹, Florian Krismer⁹, Victoria Sidoroff⁹, Alexander Zimprich¹⁰, Walter Pirker¹¹, Olivier Rascol¹², Alexandra Foubert-Samier¹³, Wassilios G Meissner¹⁴, François Tison¹⁵, Anne Pavy-Le Traon¹⁶, Maria Teresa Pellecchia¹⁷, Paolo Barone¹⁷, Maria Claudia Russillo¹⁷, Juan Marín-Lahoz¹⁸, Jaime Kulisevsky¹⁹, Soraya Torres²⁰, Pablo Mir²¹, Maria Teresa Periñán²², Christos Proukakis²³, Viorica Chelban²⁴, Lesley Wu²⁵, Yee Y Goh²⁵, Laura Parkkinen²⁶, Michele T Hu²⁷, Christopher Kobylecki²⁸, Jennifer A Saxon²⁹, Sara Rollinson³⁰, Emily Garland³¹, Italo Biaggioni³¹, Irene Litvan³², Ileana Rubio³², Roy N Alcalay³³, Kimberly T Kwei³⁴, Steven J Lubbe³⁵, Qinwen Mao³⁶, Margaret E Flanagan³⁷, Rudolph J Castellani³⁸, Vikram Khurana³⁹, Alain Ndayisaba⁴⁰, Andrea Calvo⁴¹, Gabriele Mora⁴², Antonio Canosa⁴¹, Gianluca Floris⁴³, Ryan C Bohannan⁴⁴, Anni Moore³, Lucy Norcliffe-Kaufmann⁴⁵, Jose-Alberto Palma⁴⁵, Horacio Kaufmann⁴⁵, Changyoun Kim⁴⁶, Michiyo Iba⁴⁶, Eliezer Masliah⁴⁶, Ted M Dawson⁴⁷, Liana S Rosenthal⁴⁸, Alexander Pantelyat⁴⁸, Marilyn S Albert⁴⁸, Olga Pletnikova⁴⁹, Juan C Troncoso⁵⁰, Jon Infante⁵¹, Carmen Lage⁵¹, Pascual Sánchez-Juan⁵², Geidy E Serrano⁵³, Thomas G Beach⁵³, Pau Pastor⁵⁴, Huw R Morris⁵⁵, Diego Albani⁵⁶, Jordi Clarimon⁵⁷, Gregor K Wenning⁵⁸, John A Hardy⁵⁹, Mina Ryten⁶⁰, Eric Topol⁶¹, Ali Torkamani⁶¹, Adriano Chiò⁶², David A Bennett⁶³, Philip L De Jager⁵, Philip A Low⁶⁴, Wolfgang Singer⁶⁴, William P Cheshire⁶⁵, Zbigniew K Wszolek⁶⁵, Dennis W Dickson⁶, Bryan J Traynor⁶⁶, J Raphael Gibbs³, Clifton L Dalgard⁶⁷, Owen A Ross⁶⁸, Henry Houlden²⁴, Sonja W Scholz⁶⁹

Affiliations

¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
² Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ 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.
⁵ 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.
⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁷ 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, University College London, London, UK.
⁸ Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
⁹ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹⁰ Department of Neurology, Medical University of Vienna, Vienna, Austria.
¹¹ Department of Neurology, Klinik Ottakring - Wilhelminenspital, Vienna, Austria.
¹² MSA French Reference Center and CIC-1436, Department of Clinical Pharmacology and Neurosciences, University of Toulouse, Toulouse, France.
¹³ Service de Neurologie des Maladies Neurodégénératives, French Reference Center for MSA, NS-Park/FCRIN Network, CHU Bordeaux, Bordeaux, France.
¹⁴ 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, Christchurch, New Zealand.
¹⁵ 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.
¹⁶ 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.
¹⁷ Neuroscience Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
¹⁸ 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; Servicio de Neurología, Hospital Universitario Miguel Servet, Zaragoza, Spain.
¹⁹ 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.
²⁰ Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain.
²¹ 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; Departamento de Medicina Facultad de Medicina, Universidad de Sevilla, Seville, Spain.
²² 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, London, UK.
²³ Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
²⁴ Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK; The National Hospital for Neurology and Neurosurgery, London, UK.
²⁵ Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
²⁶ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
²⁷ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
²⁸ Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.
²⁹ 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.
³⁰ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
³¹ Autonomic Dysfunction Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Neurosciences, University of California, San Diego, San Diego, CA, USA.
³³ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
³⁴ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
³⁵ Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³⁶ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
³⁷ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA; Department of Pathology, UT Health San Antonio, San Antonio, TX, USA.
³⁸ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³⁹ Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
⁴⁰ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴¹ "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
⁴² Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy.
⁴³ Department of Neurology, University Hospital of Cagliari, Cagliari, Italy.
⁴⁴ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
⁴⁵ Department of Neurology, New York University School of Medicine, New York, NY, USA.
⁴⁶ Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴⁷ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA; Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁴⁸ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁴⁹ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA; Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
⁵⁰ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁵¹ Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain.
⁵² Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain; Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain.
⁵³ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁵⁴ Genomics and Transcriptomics of Synucleinopathies, Neurosciences, The Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain; Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
⁵⁵ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵⁶ Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁵⁷ Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁵⁸ Autonomic Unit - Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁵⁹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute of UCL, UCL Institute of Neurology, University College London, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁶⁰ 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.
⁶¹ Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA.
⁶² "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁶³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶⁴ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁶⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁶⁶ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA; RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, Rockville, MD, USA.
⁶⁷ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
⁶⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov.

PMID: 38701790
PMCID: PMC11223971
DOI: 10.1016/j.neuron.2024.04.002

Genome sequence analyses identify novel risk loci for multiple system atrophy

Ruth Chia et al. Neuron. 2024.

. 2024 Jul 3;112(13):2142-2156.e5.

doi: 10.1016/j.neuron.2024.04.002. Epub 2024 May 2.

Authors

Affiliations

¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
² Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
³ Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴ 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.
⁵ 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.
⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
⁷ 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, University College London, London, UK.
⁸ Memory and Movement Disorders Units, Department of Neurology, University Hospital Mutua de Terrassa, Barcelona, Spain.
⁹ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
¹⁰ Department of Neurology, Medical University of Vienna, Vienna, Austria.
¹¹ Department of Neurology, Klinik Ottakring - Wilhelminenspital, Vienna, Austria.
¹² MSA French Reference Center and CIC-1436, Department of Clinical Pharmacology and Neurosciences, University of Toulouse, Toulouse, France.
¹³ Service de Neurologie des Maladies Neurodégénératives, French Reference Center for MSA, NS-Park/FCRIN Network, CHU Bordeaux, Bordeaux, France.
¹⁴ 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, Christchurch, New Zealand.
¹⁵ 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.
¹⁶ 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.
¹⁷ Neuroscience Section, Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
¹⁸ 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; Servicio de Neurología, Hospital Universitario Miguel Servet, Zaragoza, Spain.
¹⁹ 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.
²⁰ Institut d'Investigacions Biomèdiques Sant Pau (IIB-Sant Pau), Centro de Investigación en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain.
²¹ 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; Departamento de Medicina Facultad de Medicina, Universidad de Sevilla, Seville, Spain.
²² 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, London, UK.
²³ Department of Clinical and Movement Neurosciences, University College London Queen Square Institute of Neurology, London, UK.
²⁴ Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK; The National Hospital for Neurology and Neurosurgery, London, UK.
²⁵ Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
²⁶ Nuffield Department of Clinical Neurosciences, Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
²⁷ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
²⁸ Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.
²⁹ 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.
³⁰ Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
³¹ Autonomic Dysfunction Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³² Department of Neurosciences, University of California, San Diego, San Diego, CA, USA.
³³ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
³⁴ Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
³⁵ Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³⁶ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
³⁷ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA; Department of Pathology, UT Health San Antonio, San Antonio, TX, USA.
³⁸ Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
³⁹ Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
⁴⁰ Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria; Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴¹ "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
⁴² Istituti Clinici Scientifici Maugeri, IRCCS, Milan, Italy.
⁴³ Department of Neurology, University Hospital of Cagliari, Cagliari, Italy.
⁴⁴ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
⁴⁵ Department of Neurology, New York University School of Medicine, New York, NY, USA.
⁴⁶ Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
⁴⁷ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA; Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University Medical Center, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁴⁸ Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁴⁹ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA; Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
⁵⁰ Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA.
⁵¹ Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain.
⁵² Neurology Service, University Hospital Marqués de Valdecilla-IDIVAL-UC-CIBERNED, Santander, Spain; Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain.
⁵³ Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁵⁴ Genomics and Transcriptomics of Synucleinopathies, Neurosciences, The Germans Trias i Pujol Research Institute (IGTP), Badalona, Barcelona, Spain; Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
⁵⁵ Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁵⁶ Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
⁵⁷ Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; The Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
⁵⁸ Autonomic Unit - Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
⁵⁹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute of UCL, UCL Institute of Neurology, University College London, London, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
⁶⁰ 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.
⁶¹ Scripps Research Translational Institute, Scripps Research, La Jolla, CA, USA.
⁶² "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁶³ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶⁴ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁶⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
⁶⁶ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA; RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, Rockville, MD, USA.
⁶⁷ Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶⁸ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA.
⁶⁹ Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov.

PMID: 38701790
PMCID: PMC11223971
DOI: 10.1016/j.neuron.2024.04.002

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.

Keywords: GWAS; MSA; TWAS; colocalization; gene-burden analysis; genome-wide association study; multiple system atrophy; pathway analysis; repeat expansion mapping; transcriptome-wide association study; whole genome sequencing.

Published by Elsevier Inc.

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Conflict of interest statement

Declaration of interests T.G.B. is a consultant for Aprinoia Therapeutics, Vivid Genomics, and Avid Radiopharmaceutical and is a scientific advisory board member for Vivid Genomics. J.A.H., H.R.M., B.J.T., and H.R.M. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. B.J.T. and S.W.S. receive research support from Cerevel Therapeutics. B.J.T. is an editorial and advisory board member for Brain, eClinicalMedicine, Journal of Neurology, Neurosurgery, and Psychiatry, and Neurobiology of Aging. H.R.M. reports paid consultancy from Biogen, Biohaven, Lundbeck, UCB, and Denali as well as lecture fees and honoraria from the Wellcome Trust and the Movement Disorders Society. H.R.M. received research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, the Drake Foundation, and the Medical Research Council. H.K. is editor-in-chief of Clinical Autonomic Research, serves as principal investigator (PI) of a clinical trial sponsored by Biogen MA Inc. (TRACK MSA, S19-01846), and received consultancy fees from Lilly USA LLC, Biohaven Pharmaceuticals Inc., Takeda Pharmaceutical Company Ltd., Ono Pharma UK Ltd., Lundbeck LLC, and Theravance Biopharma US Inc. A.F. reports royalties from Springer Verlag; speaker fees and honoraria from Theravance Biopharma, GE Health Care, Broadview Ventures, Austrian Autonomic Society, Stopp-HSP, and Elsevier; and research grants from the FWF-Austrian Science Fund, Medical University of Innsbruck, US MSA Coalition, Dr. Johannes and Hertha Tuba Foundation, and Austrian Exchange Program, outside of the present work. J.-A.P. is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. I.B. received consultancy fees from Theravance Biopharma US Inc., Amenal Pharmaceutics, Regeneron Pharmaceuticals, Takeda Pharmaceuticals, and Neurawell Therapeutics. S.W.S. serves on the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. is an editorial board member for the Journal of Parkinson’s Disease and JAMA Neurology. A.P. serves on the board of directors for CurePSP, has received research grants from the National Institutes of Health and the Michael J. Fox Foundation, and has received consultancy fees from AbbVie Inc., Biogen Inc., SciNeuro Pharmaceuticals, Ono Pharma, and Ferrer Internacional, S.A. A.T. serves on the scientific advisory board for Vivid Genomics. R.H.R. is currently employed by CoSyne Therapeutics; all work performed for this publication was performed on her own time and not as a part of her duties as an employee. Z.K.W. is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals Inc. (BHV4157-206) and Vigil Neuroscience Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for Vigil Neuroscience Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. F.K. received personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, Sanofi, Teva, Vial, and the Austrian Society of Neurology in the past 12 months, and he has ongoing grant support from the Austrian Science Fund (FWF) and the National Institutes of Health outside of the submitted work. W.G.M. has received fees for editorial activities with Elsevier and has served as an advisor for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase, Takeda, and Teva.

Figures

**Figure 1.. Genome-wide and transcriptome-wide association study results in MSA**
(A) Composite figure showing the additive MSA GWAS model (upper panel) with the corresponding TWAS results (lower panel) in 888 cases and 7,128 controls (MAF > 1%). The x-axis denotes the chromosomal position in hg38, and the y-axis shows the association p-values on a negative-log₁₀ scale. Each dot represents a variant (GWAS) or a transcript (TWAS). The TWAS results were generated using GTEx gene expression data (version 8) for the hippocampus (additive model) and the caudate (recessive model). Red dots indicate genome-wide significant variants, while orange dots are sub-significant signals. A red dashed line indicates the Bonferroni threshold for genome-wide significance (5.0 × 10⁻⁸ for the GWAS, 1.38 × 10⁻⁵ for the TWAS in the hippocampus, and 6.77 × 10⁻⁶ for the TWAS in the caudate). The blue dashed line denotes the threshold for declaring variants to be subsignificant (5.0 × 10⁻⁷). The gene(s) closest to the index variant at each locus in the GWAS is listed. In the TWAS plot, the dot with a black diamond outline indicates a colocalization posterior prior probability hypothesis H4 > 0.80. Panel (B) shows the recessive MSA GWAS model with the corresponding TWAS results in the caudate.

**Figure 2.. Bulk RNA-sequencing and colocalization analyses of the MSA loci**
(A) The effect of the 4q31.21 locus index variant, rs55894236-C allele, on *USP38-DT* expression in brain tissues from the GTEx Consortium is shown. Error bars indicate the standard error. (B) The effect of the 7q11.21 locus index variant, rs11766262-C allele, on *KCTD7* expression is depicted. (C) Summary of significant colocalization signals (PPH4 > 0.80) for transcripts at the 4q31.21 and 7q11.21 loci across the GTEx brain tissues. (D) Schematic summary of the GWAS, TWAS, colocalization, and SKAT-O results at the four MSA risk loci. The red squares depict a significant analysis result for the listed gene. The numbers in the red squares show the number of tissues that had a significant colocalization PPH4 signal. Abbreviations: GWAS, genome-wide association study; TWAS, transcriptome-wide association study; coloc, colocalization analysis; PPH4, posterior probability of hypothesis four; and SKAT-O, sequence kernel association test – optimized.

**Figure 3.. Single-nucleus RNA-sequence analyses of common variants at the 4q31.21 and 7q11.21 loci**
(A) Single-nucleus RNA-sequence analyses identified *cis*-eQTLs for rs55894236 for *GAB1* in excitatory neurons, inhibitory neurons, and microglia (p-value threshold < 0.05). This SNP was also a *cis*-eQTL for *INPP4B* in astrocytes, oligodendrocytes, oligodendrocyte precursor cells, and inhibitory cells (B). Additionally, we identified a *cis*-eQTL for rs11766262 regulating *KCTD7* expression in oligodendroglia, microglia, and excitatory neurons (C). Abbreviations: Ast, astrocytes; End, endocytes; Exc, excitatory neurons; Inh, inhibitory neurons; Mic, microglia; Oli, oligodendroglia; OPC, oligodendroglia precursor cells.

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Genes associated with multiple system atrophy.
Fyfe I. Fyfe I. Nat Rev Neurol. 2024 Jul;20(7):379. doi: 10.1038/s41582-024-00986-4. Nat Rev Neurol. 2024. PMID: 38831099 No abstract available.

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Genome sequence analyses identify novel risk loci for multiple system atrophy

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Genome sequence analyses identify novel risk loci for multiple system atrophy

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