ArticleMovement disorders : official journal of the Movement Disorder Society2022
Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.
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Article in Movement disorders : official journal of the Movement Disorder Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 15 citations in OpenAlex.
- Multiple system atrophy: cure and care.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Prolonged Anti-Zic4 Antibody-Positive Cerebellar Degeneration Following COVID-19 Infection.Neuropsychopharmacology reports · 2026Article
- Multiple system atrophy: integrating clinical phenotypes and multimodal biomarkers for early diagnosis.Frontiers in aging neuroscience · 2026Review
- Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis.European journal of neurology · 2024Article
- Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.Movement disorders : official journal of the Movement Disorder Society · 2024Article
- Prioritizing disease-related rare variants by integrating gene expression data.PLoS genetics · 2024Article
- Article
- Prioritizing disease-related rare variants by integrating gene expression data.Research square · 2024Article
- Does Spinocerebellar ataxia 27B mimic cerebellar multiple system atrophy?Journal of neurology · 2024Article
- Prioritizing disease-related rare variants by integrating gene expression data.bioRxiv : the preprint server for biology · 2024Article
- Multiple system atrophy: at the crossroads of cellular, molecular and genetic mechanisms.Nature reviews. Neuroscience · 2023Review
- Blood based biomarkers for movement disorders.Acta neurologica Scandinavica · 2022Review
- Disease modification in Parkinsonism: obstacles and ways forward.Journal of neural transmission (Vienna, Austria : 1996) · 2022Review
- A multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson's disease with dementia.Brain communications · 2022Article
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Authors and funding
73 authors at 20 institutions in 14 countries.
Franziska Hopfner *Department of Neurology Hannover Medical School, Hannover, Germany.ORCID 0000-0001-6524-0281
Anja K TietzDepartment of Neurology, Kiel University, Kiel, Germany.
Viktoria C RufCenter for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.
Owen A RossDepartment of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.ORCID 0000-0003-4813-756X
Shunsuke KogaDepartment of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, Florida, USA.ORCID 0000-0001-8868-9700
Dennis DicksonDepartment of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, Florida, USA.
Adriano AguzziInstitute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
Johannes AttemsTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Thomas BeachBanner Sun Health Research Institute, Sun City, Arizona, USA.
Allison BellerDepartment of Pathology, University of Washington, Seattle, Washington, USA.
William P CheshireDepartment of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Vivianna van DeerlinDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Paula DesplatsDepartment of Neurosciences, School of Medicine University of California San Diego, La Jolla, California, USA.
Günther DeuschlDepartment of Neurology, Kiel University, Kiel, Germany.ORCID 0000-0002-4176-9196
Charles DuyckaertsInstitut du Cerveau, UMR 7225, Sorbonne Université, Paris Brain Institute-ICM, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, Inserm U1127 DMU Neurosciences, Paris, France.
David EllinghausInstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel & University Hospital Schleswig-Holstein, Kiel, Germany.
Valentin EvsyukovDepartment of Neurology Hannover Medical School, Hannover, Germany.
Margaret Ellen FlanaganMesulam Center for Cognitive Neurology and Alzheimer's Disease Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Andre FrankeInstitute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel & University Hospital Schleswig-Holstein, Kiel, Germany.
Matthew P FroschDepartment of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Marla GearingDepartments of Pathology and Laboratory Medicine and Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
Ellen GelpiDivision of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.ORCID 0000-0003-2948-4187
Jay A van GerpenDepartment of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Bernardino GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Jonathan D GlassDepartment of Neurology, Emory University, Atlanta, Georgia, USA.
Lea T GrinbergMemory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Glenda HallidayThe University of Sydney, School of Medical Sciences, and Brain & Mind Centre, Sydney, New South Wales, Australia.ORCID 0000-0003-0422-8398
Ingo HelbigDepartment of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
Matthias HöllerhageDepartment of Neurology Hannover Medical School, Hannover, Germany.
Inge HuitingaDepartment of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
David John IrwinDepartment of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.ORCID 0000-0002-5599-5098
Dirk C KeeneDepartment of Pathology, University of Washington, Seattle, Washington, USA.
Gabor G KovacsDivision of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.
Edward B LeeDepartment of Pathology and Laboratory Medicine, Translational Neuropathology Research Laboratory Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Johannes LevinDZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
Maria J MartíParkinson's Disease and Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain.
Ian MackenzieDepartment of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
Ian McKeithTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Catriona McleanDepartment of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia.
Brit MollenhauerParacelsus-Elena-Klinik, Kassel, Germany.ORCID 0000-0001-8437-3645
Manuela NeumannMolecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany.
Kathy L NewellDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Alex PantelyatDepartment of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.ORCID 0000-0002-6427-7485
Manuela PendziwiatDepartment of Neuropediatrics, Children's Hospital, University Medical Center Schleswig-Holstein, University of Kiel, Kiel, Germany.
Annette PetersInstitute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Laura Molina PorcelNeurology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain.
Alberto RabanoNeuropathology Department, CIEN Foundation, Alzheimer's Centre Queen Sofía Foundation, Madrid, Spain.
Radoslav MatějDepartment of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic.
Alex RajputDivision of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Ali RajputSaskatchewan Movement Disorders Program, Saskatchewan Health Authority/University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Regina ReimannInstitute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
William K ScottJohn 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.
William SeeleyMemory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Sashika SelvackaduncoBasic and Clinical Neuroscience Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Tanya SimuniDepartment of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Christine StadelmannInstitute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany.
Per SvenningssonSection of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.ORCID 0000-0001-6727-3802
Alan ThomasTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
Claudia TrenkwalderParacelsus-Elena-Klinik, Kassel, Germany.
Claire TroakesBasic and Clinical Neuroscience Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
John Q TrojanowskiDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Ryan J UittiDepartment of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Charles L WhitePathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Zbigniew K WszolekDepartment of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
Tao XieDepartment of Neurology, University of Chicago Medicine, Chicago, Illinois, USA.
Teresa XimelisAlzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Justo YebenesNeurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
Alzheimer's Disease Genetics Consortium
Ulrich MüllerInstitute of Human Genetics, JLU-Gießen, Giessen, Germany.
Gerard D SchellenbergDepartment of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jochen HermsCenter for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.
Gregor KuhlenbäumerDepartment of Neurology, Kiel University, Kiel, Germany.
Günter HöglingerDepartment of Neurology Hannover Medical School, Hannover, Germany.ORCID 0000-0001-7587-6187
Jacksonville College · USChristian-Albrechts-Universität zu Kiel · DEGerman Center for Neurodegenerative Diseases · DEMedizinische Hochschule Hannover · DENewcastle University · GBUniversity of Pennsylvania · USEmory University · USIndiana University School of MedicineKing's College London · GBNorthwestern University · USParacelsus Elena Klinik Kassel · DESaskatchewan Health Authority · CAUniversity Hospital of Zurich · CHUniversity of Washington · USAlfred Health · AUBanc de Sang i Teixits · ESBanner Sun Health Research Institute · USBiomedical Research Networking Center on Neurodegenerative Diseases · ESCentre National de la Recherche Scientifique · FRCharles University · CZ
Funding
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8MNATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8MAlzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4MTHERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI GRABOWSKI, THOMAS J. · 1985 to 2019
$57.2MTHE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITEU24AG041689 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LI-SAN WANG · 2012 to 2026
$42.3MUPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI VAN DEERLIN, VIVIANNA M · 1991 to 2020
$35.1MUniversity of Washington Alzheimer's Disease Research CenterP30AG066509 · NIA · UNIVERSITY OF WASHINGTON · PI Amanda D. Boyd · 2020 to 2026
$29.0MResearch Education Core FP30AG072977 · NIA · NORTHWESTERN UNIVERSITY AT CHICAGO · PI ROBERT J VASSAR · 2021 to 2026
$26.3MResearch Education ComponentP30AG072979 · NIA · UNIVERSITY OF PENNSYLVANIA · PI DAVID A WOLK · 2021 to 2026
$24.8MProject IV: "Alpha-Synuclein Strains & Diverse Synucleinopathies"P50NS053488 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI TROJANOWSKI, JOHN Q. · 2007 to 2017
$20.9MUnderstanding Environmental Contributions to Heterogeneity in bvFTD.P01AG066597 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Sharon Xiangwen Xie · 2020 to 2026
$18.8MProject IV "Tackling Heterogeneity of Cognitive Trajectory in LBD"U19AG062418 · NIA · UNIVERSITY OF PENNSYLVANIA · PI CHEN-PLOTKIN, ALICE S · 2019 to 2023
$18.1MMedical Research Council MR/L016451/1NIA NIH HHS K08 AG065463NIA NIH HHS P01 AG066597NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG066509NIA NIH HHS P30 AG072977NIA NIH HHS P30 AG072979NIA NIH HHS P50 AG005136NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG032984NIA NIH HHS U19 AG062418NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG041689NINDS NIH HHS P50 NS053488NINDS NIH HHS U24 NS120854NINDS NIH HHS U54 NS110435
Abstract
backgroundMultiple 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.
objectiveSince 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.
methodsWe studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898).
resultsThe 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
interpretationSince 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.
Indexed as
Multiple System AtrophyOlivopontocerebellar AtrophiesStriatonigral Degenerationalpha-SynucleinAutoantibodiesAutopsyGenome-Wide Association StudyHumansNerve Tissue ProteinsTranscription Factorsalpha-SynucleinAutoantibodiesNerve Tissue ProteinsTranscription FactorsZIC1 protein, humanZIC4 protein, humanautopsy-confirmedgenome-wide association studymultiple system atrophyZIC1ZIC4
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