Genome sequence analyses identify novel risk loci for multiple system atrophy
Neuron. 2024-05-01; :
DOI: 10.1016/j.neuron.2024.04.002
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Chia R(1), Ray A(2), Shah Z(2), Ding J(3), Ruffo P(4), Fujita M(5), Menon V(5),
Saez-Atienzar S(1), Reho P(2), Kaivola K(2), Walton RL(6), Reynolds RH(7), Karra
R(1), Sait S(2), Akcimen F(1), Diez-Fairen M(8), Alvarez I(8), Fanciulli A(9),
Stefanova N(9), Seppi K(9), Duerr S(9), Leys F(9), Krismer F(9), Sidoroff V(9),
Zimprich A(10), Pirker W(11), Rascol O(12), Foubert-Samier A(13), Meissner
WG(14), Tison F(15), Pavy-Le Traon A(16), Pellecchia MT(17), Barone P(17),
Russillo MC(17), Marín-Lahoz J(18), Kulisevsky J(19), Torres S(20), Mir P(21),
Periñán MT(22), Proukakis C(23), Chelban V(24), Wu L(25), Goh YY(25), Parkkinen
L(26), Hu MT(27), Kobylecki C(28), Saxon JA(29), Rollinson S(30), Garland E(31),
Biaggioni I(31), Litvan I(32), Rubio I(32), Alcalay RN(33), Kwei KT(34), Lubbe
SJ(35), Mao Q(36), Flanagan ME(37), Castellani RJ(38), Khurana V(39), Ndayisaba
A(40), Calvo A(41), Mora G(42), Canosa A(41), Floris G(43), Bohannan RC(44),
Moore A(3), Norcliffe-Kaufmann L(45), Palma JA(45), Kaufmann H(45), Kim C(46),
Iba M(46), Masliah E(46), Dawson TM(47), Rosenthal LS(48), Pantelyat A(48),
Albert MS(48), Pletnikova O(49), Troncoso JC(50), Infante J(51), Lage C(51),
Sánchez-Juan P(52), Serrano GE(53), Beach TG(53), Pastor P(54), Morris HR(55),
Albani D(56), Clarimon J(57), Wenning GK(58), Hardy JA(59), Ryten M(60), Topol
E(61), Torkamani A(61), Chiò A(62), Bennett DA(63), De Jager PL(5), Low PA(64),
Singer W(64), Cheshire WP(65), Wszolek ZK(65), Dickson DW(6), Traynor BJ(66),
Gibbs JR(3), Dalgard CL(67), Ross OA(68), Houlden H(24), Scholz SW(69).
Author information:
(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:
.
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.
Published by Elsevier Inc.
DOI: 10.1016/j.neuron.2024.04.002
PMID: 38701790
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.