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

• Type of Material: Article
• Authors: Franziska Hopfner, Hannover Medical School; Anja K Tietz, Kiel University; Viktoria C Ruf, Ludwig-Maximilians-Universität; Shunsuke Koga, Mayo Clinic, Jacksonville, Florida; Dennis Dickson, Mayo Clinic, Jacksonville, Florida; Marla Gearing, Emory University; Jonathan D Glass, Emory University; Günter Höglinger, Hannover Medical School
• Language: English
• Date: 2022-08-23
• Publisher: Wiley Periodicals LLC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1002%2Fmds.29164
• Title of Journal or Parent Work: Movement Disorders
• Volume: 37
• Issue: 10
• Start Page: 2110
• End Page: 2121
• Grant/Funding Information: This study received support from the Deutsche Parkinson Gesellschaft; the Else-Kröner-Fresenius-Stiftung; the CurePSP foundation; the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site, Alzheimer’s Disease Genetics Consortium (ADGC) National Institute on Aging (NIA) grant U01AG032984; the National Alzheimer’s Coordinating Center (NACC) NIA grant U01 AG016976; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198); the Hannover Cluster RESIST (EXC 2155, ID 390874280) and the Kiel Cluster (EXC2167, Precision Medicine in Chronic Inflammation [PMI]); DFG grant HO2402/18-1; VolkswagenStiftung (Niedersächsisches Vorab); Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies); ERARE18-124 (MSA-omics) under the frame of E-Rare-3; and the ERA-Net for Research on Rare Diseases. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (NIA grant U24-AG041689). Samples from the KORA biobank have been included in this study. The KORA study was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is supported by the German Federal Ministry of Education and Research (BMBF) and the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Max-imilians-Universität, as part of LMUinnovativ. Samples from the National Cell Repository for Alzheimer’s Disease, which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the NIA, were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. A part of the samples was collected at the Mayo Clinic. The Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and is supported by a Lewy Body Dementia Center Without Walls grant U54NS110435 (to D.D. and O.A.R.). The brain bank was supported, in part, by the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic. The London Neurodegenerative Diseases Brain Bank, King’s College London was supported by the MRC (Medical Research Council, UK) and the Brains for Dementia Research project (jointly funded by the Alzheimer’s Society and Alzheimer’s Research UK). Data were contributed to this study by the Center on Alpha-synuclein Strains in Alzheimer Disease & Related Dementias at the University of Pennsylvania Perelman School of Medicine (grant U19 AG062418 to J.Q.T., principal investigator); the former Morris K. Udall Center at the University of Pennsylvania Perelman School of Medicine (grant P50 NS053488 to J.Q.T., principal investigator); and the NIA (grants P01-AG066597 and AG072979; formerly AG010124). Parts of the samples were provided by the University of Washington Alzheimer’s Disease Research Center (NIH P50 AG005136 and P30 AG066509) and BioRepository and Integrated Neuropathology Laboratory, with support from the Nancy and Buster Alvord Endowment (C.D. K.). Open Access funding enabled and organized by Projekt DEAL.
• Keywords: autopsy-confirmed; ZIC4; multiple system atrophy; ZIC1; genome-wide association study
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Pathology

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.