Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

doi:10.1002/mds.29164

. 2022 Oct;37(10):2110-2121.

doi: 10.1002/mds.29164. Epub 2022 Aug 23.

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

Franziska Hopfner^#¹, Anja K Tietz², Viktoria C Ruf³, Owen A Ross^{4

5}, Shunsuke Koga⁶, Dennis Dickson⁶, Adriano Aguzzi⁷, Johannes Attems⁸, Thomas Beach⁹, Allison Beller¹⁰, William P Cheshire¹¹, Vivianna van Deerlin¹², Paula Desplats^{13

14}, Günther Deuschl², Charles Duyckaerts^{15

16}, David Ellinghaus¹⁷, Valentin Evsyukov¹, Margaret Ellen Flanagan^{18

19}, Andre Franke¹⁷, Matthew P Frosch^{20

21

22}, Marla Gearing²³, Ellen Gelpi^{24

25}, Jay A van Gerpen¹¹, Bernardino Ghetti²⁶, Jonathan D Glass²⁷, Lea T Grinberg^{28

29

30

31}, Glenda Halliday³², Ingo Helbig^{33

34

35

36

37}, Matthias Höllerhage¹, Inge Huitinga^{38

39}, David John Irwin⁴⁰, Dirk C Keene¹⁰, Gabor G Kovacs^{24

41

42}, Edward B Lee⁴³, Johannes Levin^{44

45

46}, Maria J Martí^{47

48

49

50}, Ian Mackenzie^{51

52}, Ian McKeith⁸, Catriona Mclean⁵³, Brit Mollenhauer^{54

55}, Manuela Neumann^{56

57}, Kathy L Newell²⁶, Alex Pantelyat⁵⁸, Manuela Pendziwiat^{59

60}, Annette Peters⁶¹, Laura Molina Porcel⁶², Alberto Rabano⁶³, Radoslav Matěj^{64

65}, Alex Rajput⁶⁶, Ali Rajput⁶⁷, Regina Reimann⁷, William K Scott⁶⁸, William Seeley^{28

29

30}, Sashika Selvackadunco⁶⁹, Tanya Simuni⁷⁰, Christine Stadelmann⁷¹, Per Svenningsson⁷², Alan Thomas⁸, Claudia Trenkwalder^{54

73}, Claire Troakes⁶⁹, John Q Trojanowski⁷⁴, Ryan J Uitti¹¹, Charles L White⁷⁵, Zbigniew K Wszolek¹¹, Tao Xie⁷⁶, Teresa Ximelis⁷⁷, Justo Yebenes^{78

79}; Alzheimer's Disease Genetics Consortium; Ulrich Müller⁸⁰, Gerard D Schellenberg¹², Jochen Herms^{3

44

45}, Gregor Kuhlenbäumer², Günter Höglinger^{1

44

81}

Affiliations

¹ Department of Neurology Hannover Medical School, Hannover, Germany.
² Department of Neurology, Kiel University, Kiel, Germany.
³ Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.
⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
⁵ Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida, USA.
⁶ Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, Florida, USA.
⁷ Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
⁸ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
⁹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁰ Department of Pathology, University of Washington, Seattle, Washington, USA.
¹¹ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹² Department of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Neurosciences, School of Medicine University of California San Diego, La Jolla, California, USA.
¹⁴ Department of Pathology, School of Medicine University of California San Diego, La Jolla, California, USA.
¹⁵ 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.
¹⁶ Brainbank NeuroCEB Neuropathology Network: Plateforme de Ressources Biologiques, Hôpital de La Pitié-Salpêtrière, Bâtiment Roger Baillet, Paris Cedex, France.
¹⁷ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel & University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁸ Mesulam Center for Cognitive Neurology and Alzheimer's Disease Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁹ Department of Pathology, Northwestern University, Chicago, Illinois, USA.
²⁰ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²¹ Harvard Medical School, Boston, Massachusetts, USA.
²² Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²³ Departments of Pathology and Laboratory Medicine and Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁴ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.
²⁵ Medical University of Vienna, Austrian Reference Center for Human Prion Diseases (OERPE), Vienna, Austria.
²⁶ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁷ Department of Neurology, Emory University, Atlanta, Georgia, USA.
²⁸ Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
²⁹ Global Health Institute, University of California, San Francisco, California, USA.
³⁰ Department of Pathology, University of California, San Francisco, California, USA.
³¹ Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil.
³² The University of Sydney, School of Medical Sciences, and Brain & Mind Centre, Sydney, New South Wales, Australia.
³³ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
³⁴ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁵ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁶ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁷ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁸ Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
³⁹ Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
⁴⁰ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴¹ Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁴² Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁴³ Department of Pathology and Laboratory Medicine, Translational Neuropathology Research Laboratory Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴⁴ DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
⁴⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁶ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
⁴⁷ Parkinson's Disease and Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain.
⁴⁸ Institut de Neurociències, Maeztu Center, University of Barcelona, Barcelona, Spain.
⁴⁹ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁵⁰ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
⁵¹ Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
⁵² Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
⁵³ Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia.
⁵⁴ Paracelsus-Elena-Klinik, Kassel, Germany.
⁵⁵ Department of Neurology, University Medical Center Goettingen, Gottingen, Germany.
⁵⁶ Molecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany.
⁵⁷ Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
⁵⁸ Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁵⁹ Department of Neuropediatrics, Children's Hospital, University Medical Center Schleswig-Holstein, University of Kiel, Kiel, Germany.
⁶⁰ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
⁶¹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶² Neurology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain.
⁶³ Neuropathology Department, CIEN Foundation, Alzheimer's Centre Queen Sofía Foundation, Madrid, Spain.
⁶⁴ Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic.
⁶⁵ Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic.
⁶⁶ Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶⁷ Saskatchewan Movement Disorders Program, Saskatchewan Health Authority/University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶⁸ 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.
⁶⁹ Basic and Clinical Neuroscience Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁷⁰ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁷¹ Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany.
⁷² Section of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷³ Department of Neurosurgery, University Medical Center Goettingen, Goettingen, Germany.
⁷⁴ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷⁵ Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁷⁶ Department of Neurology, University of Chicago Medicine, Chicago, Illinois, USA.
⁷⁷ Alzheimer'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.
⁷⁸ Neurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁷⁹ Servicio de Neurología, Hospital Ramón y Cajal de Madrid, Madrid, Spain.
⁸⁰ Institute of Human Genetics, JLU-Gießen, Giessen, Germany.
⁸¹ Zentrum für Systemische Neurowissenschaften, Hannover, Germany.

^# Contributed equally.

PMID: 35997131
PMCID: PMC10052809
DOI: 10.1002/mds.29164

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

Franziska Hopfner et al. Mov Disord. 2022 Oct.

. 2022 Oct;37(10):2110-2121.

doi: 10.1002/mds.29164. Epub 2022 Aug 23.

Authors

Affiliations

¹ Department of Neurology Hannover Medical School, Hannover, Germany.
² Department of Neurology, Kiel University, Kiel, Germany.
³ Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Munich, Germany.
⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
⁵ Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida, USA.
⁶ Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, Florida, USA.
⁷ Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
⁸ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
⁹ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁰ Department of Pathology, University of Washington, Seattle, Washington, USA.
¹¹ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹² Department of Pathology and Laboratory Medicine, Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Neurosciences, School of Medicine University of California San Diego, La Jolla, California, USA.
¹⁴ Department of Pathology, School of Medicine University of California San Diego, La Jolla, California, USA.
¹⁵ 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.
¹⁶ Brainbank NeuroCEB Neuropathology Network: Plateforme de Ressources Biologiques, Hôpital de La Pitié-Salpêtrière, Bâtiment Roger Baillet, Paris Cedex, France.
¹⁷ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel & University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁸ Mesulam Center for Cognitive Neurology and Alzheimer's Disease Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁹ Department of Pathology, Northwestern University, Chicago, Illinois, USA.
²⁰ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²¹ Harvard Medical School, Boston, Massachusetts, USA.
²² Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
²³ Departments of Pathology and Laboratory Medicine and Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
²⁴ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.
²⁵ Medical University of Vienna, Austrian Reference Center for Human Prion Diseases (OERPE), Vienna, Austria.
²⁶ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²⁷ Department of Neurology, Emory University, Atlanta, Georgia, USA.
²⁸ Memory and Aging Center, Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
²⁹ Global Health Institute, University of California, San Francisco, California, USA.
³⁰ Department of Pathology, University of California, San Francisco, California, USA.
³¹ Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil.
³² The University of Sydney, School of Medical Sciences, and Brain & Mind Centre, Sydney, New South Wales, Australia.
³³ Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, New York, USA.
³⁴ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁵ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁶ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³⁷ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁸ Department of Neuroimmunology, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.
³⁹ Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
⁴⁰ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴¹ Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁴² Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁴³ Department of Pathology and Laboratory Medicine, Translational Neuropathology Research Laboratory Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴⁴ DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
⁴⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴⁶ Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
⁴⁷ Parkinson's Disease and Movement Disorders Unit, Department of Neurology, Hospital Clinic of Barcelona, Barcelona, Spain.
⁴⁸ Institut de Neurociències, Maeztu Center, University of Barcelona, Barcelona, Spain.
⁴⁹ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁵⁰ Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
⁵¹ Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada.
⁵² Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
⁵³ Department of Anatomical Pathology, Alfred Health, Melbourne, Victoria, Australia.
⁵⁴ Paracelsus-Elena-Klinik, Kassel, Germany.
⁵⁵ Department of Neurology, University Medical Center Goettingen, Gottingen, Germany.
⁵⁶ Molecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany.
⁵⁷ Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
⁵⁸ Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁵⁹ Department of Neuropediatrics, Children's Hospital, University Medical Center Schleswig-Holstein, University of Kiel, Kiel, Germany.
⁶⁰ Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
⁶¹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
⁶² Neurology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain.
⁶³ Neuropathology Department, CIEN Foundation, Alzheimer's Centre Queen Sofía Foundation, Madrid, Spain.
⁶⁴ Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Prague, Czech Republic.
⁶⁵ Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University, Thomayer University Hospital, Prague, Czech Republic.
⁶⁶ Division of Neurology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶⁷ Saskatchewan Movement Disorders Program, Saskatchewan Health Authority/University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶⁸ 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.
⁶⁹ Basic and Clinical Neuroscience Department, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁷⁰ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁷¹ Institute for Neuropathology, University Medical Centre Göttingen, Göttingen, Germany.
⁷² Section of Neurology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷³ Department of Neurosurgery, University Medical Center Goettingen, Goettingen, Germany.
⁷⁴ Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷⁵ Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁷⁶ Department of Neurology, University of Chicago Medicine, Chicago, Illinois, USA.
⁷⁷ Alzheimer'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.
⁷⁸ Neurological Tissue Bank, Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain.
⁷⁹ Servicio de Neurología, Hospital Ramón y Cajal de Madrid, Madrid, Spain.
⁸⁰ Institute of Human Genetics, JLU-Gießen, Giessen, Germany.
⁸¹ Zentrum für Systemische Neurowissenschaften, Hannover, Germany.

^# Contributed equally.

PMID: 35997131
PMCID: PMC10052809
DOI: 10.1002/mds.29164

Abstract

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.

Keywords: ZIC1; ZIC4; autopsy-confirmed; genome-wide association study; multiple system atrophy.

PubMed Disclaimer

Conflict of interest statement

Relevant conflicts of interest/financial disclosures: Nothing to report.

Figures

**FIG. 1.**
Flowchart sample quality control. SD, standard deviation. [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 2.**
Association plots for multiple system atrophy (MSA). (A) QQ (quantile-quantile) plot based on 8,109,760 variants after imputation. (B) Manhattan plot showing –log10 P values from logistic regression on imputed variants with sex and two principal components as covariates plotted against their chromosomal position. The red and blue lines indicate the genome-wide significance threshold of 5 × 10^–8 and threshold for suggestive associations of 5 × 10^–6, respectively. (C) Regional plot for the association between MSA and variants on chromosome 3 in the genomic region from 147.4 to 148.6 Mb. A circle represents a genotyped variant and a plus symbol an imputed variant. The r² metric displays the pairwise linkage-disequilibrium (LD) between the leading and the respective variant. The bottom part shows gene positions. (D) Regional plot for associations on chromosome 8 in the genomic region from 22.7 to 23.9 Mb. (E) Regional plot for associations on chromosome 4 in the genomic region from 32.8 to 34.0 Mb. (F) Regional plot for associations on chromosome 5 in the genomic region from 149.0 to 150.2 Mb. [Color figure can be viewed at wileyonlinelibrary.com]

**FIG. 3.**
ZIC4 immunohistochemical staining of multiple system atrophy (MSA) patients and control brains. Representative ZIC4 immunohistochemical stainings of different brain regions (antibodies binding specifically to antigens in biological tissues, eg, brain tissue) of a control without neurodegenerative disease (**A, D, G**) and two MSA patients with striatonigral degeneration (SND) (**B, E, H**) and mixed subtype (**C, F, I**), respectively. (**A–C**) Nuclear and cytoplasmic expression of ZIC4 (brown staining) was detected in a comparable manner in the frontal cortex of healthy controls and patients with MSA. In the cerebellar dentate nucleus (dotted lines in D–I) of healthy controls and patients with SND, a constant subset of neurons stained strongly positive for ZIC4, whereas in patients with olivopontocerebellar atrophy (OPCA) or mixed subtype, only weak staining could be observed, and the number of ZIC4-positive neurons was clearly reduced **(D–I**, with higher magnification in **G–I)**. (J) Quantification of ZIC4-immunoreactive neurons in relation to the total number of neurons of the dentate nucleus depicted on the entire slide showed significantly reduced fractions of ZIC4-immunoreactive neurons in patients with either mixed subtype (light blue) or OPCA (dark blue) compared with SND or controls without neurodegenerative disease, while no difference was seen between patients with SND and healthy controls. Scale bars: 100 μm (A–C), 200 μm (D–F), 50 μm (G–I). [Color figure can be viewed at wileyonlinelibrary.com]

See this image and copyright information in PMC

Cited by

Multiple system atrophy: at the crossroads of cellular, molecular and genetic mechanisms.
Stefanova N, Wenning GK. Stefanova N, et al. Nat Rev Neurosci. 2023 Jun;24(6):334-346. doi: 10.1038/s41583-023-00697-7. Epub 2023 Apr 21. Nat Rev Neurosci. 2023. PMID: 37085728 Review.
Prioritizing disease-related rare variants by integrating gene expression data.
Guo H, Urban AE, Wong WH. Guo H, et al. PLoS Genet. 2024 Sep 30;20(9):e1011412. doi: 10.1371/journal.pgen.1011412. eCollection 2024 Sep. PLoS Genet. 2024. PMID: 39348415 Free PMC article.
A multiplex pedigree with pathologically confirmed multiple system atrophy and Parkinson's disease with dementia.
Fanciulli A, Leys F, Lehner F, Sidoroff V, Ruf VC, Raccagni C, Mahlknecht P, Kuipers DJS, van IJcken WFJ, Stockner H, Musacchio T, Volkmann J, Monoranu CM, Stankovic I, Breedveld G, Ferraro F, Fevga C, Windl O, Herms J, Kiechl S, Poewe W, Seppi K, Stefanova N, Scholz SW, Bonifati V, Wenning GK. Fanciulli A, et al. Brain Commun. 2022 Jul 4;4(4):fcac175. doi: 10.1093/braincomms/fcac175. eCollection 2022. Brain Commun. 2022. PMID: 35855480 Free PMC article.
Genome sequence analyses identify novel risk loci for multiple system atrophy.
Chia R, Ray A, Shah Z, Ding J, Ruffo P, Fujita M, Menon V, Saez-Atienzar S, Reho P, Kaivola K, Walton RL, Reynolds RH, Karra R, Sait S, Akcimen F, Diez-Fairen M, Alvarez I, Fanciulli A, Stefanova N, Seppi K, Duerr S, Leys F, Krismer F, Sidoroff V, Zimprich A, Pirker W, Rascol O, Foubert-Samier A, Meissner WG, Tison F, Pavy-Le Traon A, Pellecchia MT, Barone P, Russillo MC, Marín-Lahoz J, Kulisevsky J, Torres S, Mir P, Periñán MT, Proukakis C, Chelban V, Wu L, Goh YY, Parkkinen L, Hu MT, Kobylecki C, Saxon JA, Rollinson S, Garland E, Biaggioni I, Litvan I, Rubio I, Alcalay RN, Kwei KT, Lubbe SJ, Mao Q, Flanagan ME, Castellani RJ, Khurana V, Ndayisaba A, Calvo A, Mora G, Canosa A, Floris G, Bohannan RC, Moore A, Norcliffe-Kaufmann L, Palma JA, Kaufmann H, Kim C, Iba M, Masliah E, Dawson TM, Rosenthal LS, Pantelyat A, Albert MS, Pletnikova O, Troncoso JC, Infante J, Lage C, Sánchez-Juan P, Serrano GE, Beach TG, Pastor P, Morris HR, Albani D, Clarimon J, Wenning GK, Hardy JA, Ryten M, Topol E, Torkamani A, Chiò A, Bennett DA, De Jager PL, Low PA, Singer W, Cheshire WP, Wszolek ZK, Dickson DW, Traynor BJ, Gibbs JR, Dalgard CL, Ross OA, Houlden H, Scholz SW. Chia R, et al. Neuron. 2024 Jul 3;112(13):2142-2156.e5. doi: 10.1016/j.neuron.2024.04.002. Epub 2024 May 2. Neuron. 2024. PMID: 38701790
An update on multiple system atrophy.
Stankovic I, Kuijpers M, Kaufmann H. Stankovic I, et al. Curr Opin Neurol. 2024 Aug 1;37(4):400-408. doi: 10.1097/WCO.0000000000001285. Epub 2024 Jun 3. Curr Opin Neurol. 2024. PMID: 38828714 Review.

See all "Cited by" articles

References

1. Fanciulli A, Stankovic I, Krismer F, Seppi K, Levin J, Wenning GK. Multiple system atrophy. Int Rev Neurobiol 2019;149:137–192. - PubMed
1. Gilman S, Wenning GK, Low PA, et al.. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71(9): 670–676. - PMC - PubMed
1. Schrag A, Wenning GK, Quinn N, Ben-Shlomo Y. Survival in multiple system atrophy. Mov Disord 2008;23(2):294–296. - PubMed
1. 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
1. 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. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources

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

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

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

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

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

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

[7] 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

[8] 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

[9] 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. - PMC - PubMed

[10] 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. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

Affiliations

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources