BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Service Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer Universitat de Barcelona Barcelona Spain

Banner Sun Health Research Institute Sun City Arizona USA

Basic and Clinical Neuroscience Department Institute of Psychiatry Psychology and Neuroscience King's College London London United Kingdom

Brain Plasticity Group Swammerdam Institute for Life Sciences University of Amsterdam Amsterdam the Netherlands

Brainbank NeuroCEB Neuropathology Network Plateforme de Ressources Biologiques Hôpital de La Pitié Salpêtrière Bâtiment Roger Baillet Paris Cedex France

Center for Neuropathology and Prion Research Ludwig Maximilians Universität Munich Germany

Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona Spain

Department of Anatomical Pathology Alfred Health Melbourne Victoria Australia

Department of Biomedical and Health Informatics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Department of Biomedical Informatics Columbia University Irving Medical Center New York New York USA

Department of Clinical Genomics Mayo Clinic Jacksonville Florida USA

Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Ontario Canada

Department of Neuroimmunology Netherlands Institute for Neuroscience Amsterdam the Netherlands

Department of Neurology Emory University Atlanta Georgia USA

Department of Neurology Hannover Medical School Hannover Germany

Department of Neurology Kiel University Kiel Germany

Department of Neurology Ludwig Maximilians Universität München Munich Germany

Department of Neurology Massachusetts General Hospital Boston Massachusetts USA

Department of Neurology Mayo Clinic Jacksonville Florida USA

Department of Neurology Northwestern University Feinberg School of Medicine Chicago Illinois USA

Department of Neurology Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Neurology School of Medicine Johns Hopkins University Baltimore Maryland USA

Department of Neurology University Medical Center Goettingen Gottingen Germany

Department of Neurology University of Chicago Medicine Chicago Illinois USA

Department of Neurology University of Pennsylvania Perelman School of Medicine Philadelphia Pennsylvania USA

Department of Neuropathology University Hospital of Tübingen Tübingen Germany

Department of Neuropediatrics Children's Hospital University Medical Center Schleswig Holstein University of Kiel Kiel Germany

Department of Neuroscience Mayo Clinic Jacksonville Florida USA

Department of Neurosciences School of Medicine University of California San Diego La Jolla California USA

Department of Neurosurgery University Medical Center Goettingen Goettingen Germany

Department of Pathology 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Pathology and Laboratory Medicine Center for Neurodegenerative Disease Research Perelman School of Medicine Philadelphia Pennsylvania USA

Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis Indiana USA

Department of Pathology and Laboratory Medicine Penn Neurodegeneration Genomics Center Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania USA

Department of Pathology and Laboratory Medicine Translational Neuropathology Research Laboratory Perelman School of Medicine Philadelphia Pennsylvania USA

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

Department of Pathology Massachusetts General Hospital Boston Massachusetts USA

Department of Pathology Northwestern University Chicago Illinois USA

Department of Pathology School of Medicine University of California San Diego La Jolla California USA

Department of Pathology University of British Columbia Vancouver British Columbia Canada

Department of Pathology University of California San Francisco California USA

Department of Pathology University of Sao Paulo Medical School Sao Paulo Brazil

Department of Pathology University of Washington Seattle Washington USA

Department of Pathology Vancouver General Hospital Vancouver British Columbia Canada

Departments of Pathology and Laboratory Medicine and Neurology Emory University School of Medicine Atlanta Georgia USA

Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

Division of Neurology Royal University Hospital University of Saskatchewan Saskatoon Saskatchewan Canada

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna Vienna Austria

DZNE German Center for Neurodegenerative Diseases Munich Germany

Global Health Institute University of California San Francisco California USA

Harvard Medical School Boston Massachusetts USA

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institut de Neurociències Maeztu Center University of Barcelona Barcelona Spain

Institut du Cerveau UMR 7225 Sorbonne Université Paris Brain Institute ICM CNRS AP HP Hôpital de la Pitié Salpêtrière Inserm U1127 DMU Neurosciences Paris France

Institute for Neuropathology University Medical Centre Göttingen Göttingen Germany

Institute of Clinical Molecular Biology Christian Albrechts University of Kiel and University Hospital Schleswig Holstein Kiel Germany

Institute of Clinical Molecular Biology Christian Albrechts University of Kiel Kiel Germany

Institute of Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Human Genetics JLU Gießen Giessen Germany

Institute of Neuropathology University Hospital Zürich Zürich Switzerland

John P Hussman Institute for Human Genomics and Dr John T Macdonald Department of Human Genetics University of Miami Miller School of Medicine Miami Florida USA

Laboratory Medicine Program and Krembil Brain Institute University Health Network Toronto Ontario Canada

Medical University of Vienna Austrian Reference Center for Human Prion Diseases Vienna Austria

Memory and Aging Center Weill Institute for Neurosciences Department of Neurology University of California San Francisco San Francisco California USA

Mesulam Center for Cognitive Neurology and Alzheimer's Disease Northwestern University Feinberg School of Medicine Chicago Illinois USA

Molecular Neuropathology of Neurodegenerative Diseases German Center for Neurodegenerative Diseases Tübingen Germany

Munich Cluster for Systems Neurology Munich Germany

Neurological Tissue Bank Biobanc Hospital Clínic IDIBAPS Barcelona Spain

Neurology Department Hospital Clinic IDIBAPS Barcelona Spain

Neuropathology Department CIEN Foundation Alzheimer's Centre Queen Sofía Foundation Madrid Spain

Paracelsus Elena Klinik Kassel Germany

Parkinson's Disease and Movement Disorders Unit Department of Neurology Hospital Clinic of Barcelona Barcelona Spain

Pathology University of Texas Southwestern Medical Center Dallas Texas USA

Saskatchewan Movement Disorders Program Saskatchewan Health Authority University of Saskatchewan Saskatoon Saskatchewan Canada

Section of Neurology Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Servicio de Neurología Hospital Ramón y Cajal de Madrid Madrid Spain

The Epilepsy NeuroGenetics Initiative Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

The University of Sydney School of Medical Sciences and Brain and Mind Centre Sydney New South Wales Australia

Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne United Kingdom

Zentrum für Systemische Neurowissenschaften Hannover Germany

See more in PubMed

Fanciulli A, Stankovic I, Krismer F, Seppi K, Levin J, Wenning GK. Multiple system atrophy. Int Rev Neurobiol 2019;149:137–192. PubMed

Gilman S, Wenning GK, Low PA, et al.. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71(9): 670–676. PubMed PMC

Schrag A, Wenning GK, Quinn N, Ben-Shlomo Y. Survival in multiple system atrophy. Mov Disord 2008;23(2):294–296. PubMed

Klockgether T, Ludtke R, Kramer B, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain 1998;121(Pt 4):589–600. PubMed

Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013;12(3):264–274. PubMed PMC

Rohrer G, Hoglinger GU, Levin J. Symptomatic therapy of multiple system atrophy. Auton Neurosci 2018;211:26–30. PubMed

Walsh RR, Krismer F, Galpern WR, et al. Recommendations of the global multiple system atrophy research roadmap meeting. Neurology 2018;90(2):74–82. PubMed PMC

Jellinger KA, Lantos PL. Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathol 2010; 119(6):657–667. PubMed

Jellinger KA, Seppi K, Wenning GK. Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 2005;20(Suppl 12):S29–S36. PubMed

Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 2004;127(Pt 12):2657–2671. PubMed

Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med 2015;372(3):249–263. PubMed

Chrysostome V, Tison F, Yekhlef F, Sourgen C, Baldi I, Dartigues JF. Epidemiology of multiple system atrophy: a prevalence and pilot risk factor study in Aquitaine, France. Neuroepidemiology 2004;23(4):201–208. PubMed

Nee LE, Gomez MR, Dambrosia J, Bale S, Eldridge R, Polinsky RJ. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res 1991;1(1):9–13. PubMed

Vanacore N, Bonifati V, Fabbrini G, et al. Case-control study of multiple system atrophy. Mov Disord 2005;20(2):158–163. PubMed

Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet 2009;41(12):1308–1312. PubMed PMC

Schottlaender LV, Houlden H. Multiple-system atrophy brain Bank C. mutant COQ2 in multiple-system atrophy. N Engl J Med 2014; 371(1):81 PubMed

Chen Y, Wei QQ, Ou R, et al. Genetic variants of SNCA are associated with susceptibility to Parkinson’s disease but not amyotrophic lateral sclerosis or multiple system atrophy in a Chinese population. PLoS One 2015;10(7):e0133776 PubMed PMC

Labbe C, Heckman MG, Lorenzo-Betancor O, et al. MAPT haplotype diversity in multiple system atrophy. Parkinsonism Relat Disord 2016;30:40–45. PubMed PMC

Labbe C, Ogaki K, Lorenzo-Betancor O, et al. Role for the microtubule-associated protein tau variant p.A152T in risk of alpha-synucleinopathies. Neurology 2015;85(19):1680–1686. PubMed PMC

Ronchi D, Di Biase E, Franco G, et al. Mutational analysis of COQ2 in patients with MSA in Italy. Neurobiol Aging 2016;45:213 e211–213 e212. PubMed

Sailer A, Scholz SW, Nalls MA, et al. A genome-wide association study in multiple system atrophy. Neurology 2016;87(15):1591–1598. PubMed PMC

Koga S, Aoki N, Uitti RJ, et al. When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 2015; 85(5):404–412. PubMed PMC

Trojanowski JQ, Revesz T. Neuropathology working group on MSA. Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 2007;33(6):615–620. PubMed

Wichmann HE, Gieger C, Illig T, Group MKS. KORA-gen–resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 2005;67(Suppl 1):S26–S30. PubMed

Nothlings U, Krawczak M. PopGen. A population-based biobank with prospective follow-up of a control group. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2012;55(6–7):831–835. PubMed

Kunkle BW, Grenier-Boley B, Sims R, et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet 2019;51(3): 414–430. PubMed PMC

Team RC. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2019.

Auton A, Abecasis GR, Altshuler DM, et al. A global reference for human genetic variation. Nature 2015;526(7571):68–74. PubMed PMC

Taliun D, Harris DN, Kessler MD, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Nature 2021; 590(7845):290–299. PubMed PMC

Loh PR, Danecek P, Palamara PF, et al. Reference-based phasing using the haplotype reference consortium panel. Nat Genet 2016; 48(11):1443–1448. PubMed PMC

Brown DW, Myers TA, Machiela MJ. PCAmatchR: a flexible R package for optimal case–control matching using weighted principal components. Bioinformatics 2020;37(8):1178–1181. PubMed PMC

Pruim RJ, Welch RP, Sanna S, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010; 26(18):2336–2337. PubMed PMC

Consortium GT, Laboratory DA, Coordinating Center -Analysis Working G et al. Genetic effects on gene expression across human tissues. Nature 2017;550(7675):204–213. PubMed PMC

Nalls MA, Blauwendraat C, Vallerga CL, et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 2019;18(12):1091–1102. PubMed PMC

Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns WB, Millen KJ. Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet 2004; 36(10):1053–1055. PubMed

Blank MC, Grinberg I, Aryee E, et al. Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. Development 2011;138(6): 1207–1216. PubMed PMC

Bataller L, Wade DF, Fuller GN, Rosenfeld MR, Dalmau J. Cerebellar degeneration and autoimmunity to zinc-finger proteins of the cerebellum. Neurology 2002;59(12):1985–1987. PubMed

Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004;62(5):778–782. PubMed PMC

Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol 2009;65(5):610–614. PubMed PMC

Kouri N, Ross OA, Dombroski B, et al. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun 2015;6:7247. PubMed PMC

Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347(6220): 1260419. PubMed

Ali RG, Bellchambers HM, Arkell RM. Zinc fingers of the cerebellum (Zic): transcription factors and co-factors. Int J Biochem Cell Biol 2012;44(11):2065–2068. PubMed

Ogura H, Aruga J, Mikoshiba K. Behavioral abnormalities of Zic1 and Zic2 mutant mice: implications as models for human neurological disorders. Behav Genet 2001;31(3):317–324. PubMed

Tohyama J, Kato M, Kawasaki S, et al. Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: report of a new patient. Am J Med Genet A 2011;155A(1):130–133. PubMed

Bettencourt C, Piras IS, Foti SC, et al. Epigenomics and transcriptomics analyses of multiple system atrophy brain tissue supports a role for inflammatory processes in disease pathogenesis. Acta Neuropathol Commun 2020;8(1):71. PubMed PMC

Rydbirk R, Folke J, Busato F, et al. Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients. Acta Neuropathol Commun 2020;8(1):29. PubMed PMC