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

The Alzheimer’s Disease Genetics Consortium

doi:10.1002/mds.29164

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

The Alzheimer’s Disease Genetics Consortium

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2110-2121
Number of pages	12
Journal	Movement Disorders
Volume	37
Issue number	10
DOIs	https://doi.org/10.1002/mds.29164
State	Published - Oct 2022

Funding

We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. 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‐Maximilians‐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. F.H. received grants from the Deutsche Parkinson Gesellschaft, the Else‐Kröner‐Fresenius‐Stiftung, and the CurePSP foundation. V.C.R. has received speaker's honoraria from AURIKAMED and research grants from the Friedrich Baur‐Stiftung. B.M. has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced research company. B.M. is member of the executive steering committee of the Parkinson Progression Marker Initiative and principal investigator (PI) of the Systemic Synuclein Sampling Study of The Michael J. Fox Foundation for Parkinson's Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, and The Michael J. Fox Foundation for Parkinson's Research. G.D. has received lecture fees from UCB, Medtronic, and Desitin and has been serving as a consultant for Medtronic, Sapiens, Boston Scientific, and Britannica; he received royalties from Thieme publishers; receives support through institution funding for his research from the German Research Council, the German Ministry of Education and Health, and Medtronic. G.K. receives research support from the German Research Council (DFG) and the Christian‐Albrechts‐University Kiel. C. Trenkwalder was supported by The Michael J. Fox foundation and by EU Horizon 2010; she receives honoraria or consultation fees from UCB, Gruenenthal, and Orion. C. Trenkwalder has received speaker's honoraria from Roche and Britannia. Günter Höglinger was supported by the German Federal Ministry of Education and Research (BMBF: 01KU1403A EpiPD), 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), DFG grants (HO2402/6‐2, HO2402/18‐1 MSAomics), the NOMIS foundation (FTLD project), and the EU/EFPIA/Innovative Medicines Initiative, Joint Undertaking (IMPRIND grant 116,060). The other authors report no disclosures. All authors are government employees. No sponsor had access to the data or participated in the writing of the manuscript. We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. 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.

Keywords

ZIC1
ZIC4
autopsy-confirmed
genome-wide association study
multiple system atrophy

ASJC Scopus subject areas

Neurology
Clinical Neurology

Access to Document

10.1002/mds.29164

Cite this

@article{d0fdcfe31d57484f94e718d414060c81,

title = "Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy",

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.",

keywords = "ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy",

author = "{The Alzheimer{\textquoteright}s Disease Genetics Consortium} and Franziska Hopfner and Tietz, {Anja K.} and Ruf, {Viktoria C.} and Ross, {Owen A.} and Shunsuke Koga and Dennis Dickson and Adriano Aguzzi and Johannes Attems and Thomas Beach and Allison Beller and Cheshire, {William P.} and {van Deerlin}, Vivianna and Paula Desplats and G{\"u}nther Deuschl and Charles Duyckaerts and David Ellinghaus and Valentin Evsyukov and Flanagan, {Margaret Ellen} and Andre Franke and Frosch, {Matthew P.} and Marla Gearing and Ellen Gelpi and {van Gerpen}, {Jay A.} and Bernardino Ghetti and Glass, {Jonathan D.} and Grinberg, {Lea T.} and Glenda Halliday and Ingo Helbig and Matthias H{\"o}llerhage and Inge Huitinga and Irwin, {David John} and Keene, {Dirk C.} and Kovacs, {Gabor G.} and Lee, {Edward B.} and Johannes Levin and Mart{\'i}, {Maria J.} and Ian Mackenzie and Ian McKeith and Catriona Mclean and Brit Mollenhauer and Manuela Neumann and Newell, {Kathy L.} and Alex Pantelyat and Manuela Pendziwiat and Annette Peters and {Molina Porcel}, Laura and Alberto Rabano and Radoslav Mat{\v e}j and Alex Rajput and Tanya Simuni",

note = "Funding Information: We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. This study received support from the Deutsche Parkinson Gesellschaft; the Else‐Kr{\"o}ner‐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 (Nieders{\"a}chsisches Vorab); Petermax‐M{\"u}ller 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 M{\"u}nchen – 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‐Maximilians‐Universit{\"a}t, 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{\textquoteright}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. Funding Information: F.H. received grants from the Deutsche Parkinson Gesellschaft, the Else‐Kr{\"o}ner‐Fresenius‐Stiftung, and the CurePSP foundation. V.C.R. has received speaker's honoraria from AURIKAMED and research grants from the Friedrich Baur‐Stiftung. B.M. has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced research company. B.M. is member of the executive steering committee of the Parkinson Progression Marker Initiative and principal investigator (PI) of the Systemic Synuclein Sampling Study of The Michael J. Fox Foundation for Parkinson's Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, and The Michael J. Fox Foundation for Parkinson's Research. G.D. has received lecture fees from UCB, Medtronic, and Desitin and has been serving as a consultant for Medtronic, Sapiens, Boston Scientific, and Britannica; he received royalties from Thieme publishers; receives support through institution funding for his research from the German Research Council, the German Ministry of Education and Health, and Medtronic. G.K. receives research support from the German Research Council (DFG) and the Christian‐Albrechts‐University Kiel. C. Trenkwalder was supported by The Michael J. Fox foundation and by EU Horizon 2010; she receives honoraria or consultation fees from UCB, Gruenenthal, and Orion. C. Trenkwalder has received speaker's honoraria from Roche and Britannia. G{\"u}nter H{\"o}glinger was supported by the German Federal Ministry of Education and Research (BMBF: 01KU1403A EpiPD), 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), DFG grants (HO2402/6‐2, HO2402/18‐1 MSAomics), the NOMIS foundation (FTLD project), and the EU/EFPIA/Innovative Medicines Initiative, Joint Undertaking (IMPRIND grant 116,060). The other authors report no disclosures. All authors are government employees. No sponsor had access to the data or participated in the writing of the manuscript. Funding Information: We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. This study received support from the Deutsche Parkinson Gesellschaft; the Else-Kr{\"o}ner-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 (Nieders{\"a}chsisches Vorab); Petermax-M{\"u}ller 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. Publisher Copyright: {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.",

year = "2022",

month = oct,

doi = "10.1002/mds.29164",

language = "English (US)",

volume = "37",

pages = "2110--2121",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley and Sons Inc.",

number = "10",

}

TY - JOUR

T1 - Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy

AU - The Alzheimer’s Disease Genetics Consortium

AU - Hopfner, Franziska

AU - Tietz, Anja K.

AU - Ruf, Viktoria C.

AU - Ross, Owen A.

AU - Koga, Shunsuke

AU - Dickson, Dennis

AU - Aguzzi, Adriano

AU - Attems, Johannes

AU - Beach, Thomas

AU - Beller, Allison

AU - Cheshire, William P.

AU - van Deerlin, Vivianna

AU - Desplats, Paula

AU - Deuschl, Günther

AU - Duyckaerts, Charles

AU - Ellinghaus, David

AU - Evsyukov, Valentin

AU - Flanagan, Margaret Ellen

AU - Franke, Andre

AU - Frosch, Matthew P.

AU - Gearing, Marla

AU - Gelpi, Ellen

AU - van Gerpen, Jay A.

AU - Ghetti, Bernardino

AU - Glass, Jonathan D.

AU - Grinberg, Lea T.

AU - Halliday, Glenda

AU - Helbig, Ingo

AU - Höllerhage, Matthias

AU - Huitinga, Inge

AU - Irwin, David John

AU - Keene, Dirk C.

AU - Kovacs, Gabor G.

AU - Lee, Edward B.

AU - Levin, Johannes

AU - Martí, Maria J.

AU - Mackenzie, Ian

AU - McKeith, Ian

AU - Mclean, Catriona

AU - Mollenhauer, Brit

AU - Neumann, Manuela

AU - Newell, Kathy L.

AU - Pantelyat, Alex

AU - Pendziwiat, Manuela

AU - Peters, Annette

AU - Molina Porcel, Laura

AU - Rabano, Alberto

AU - Matěj, Radoslav

AU - Rajput, Alex

AU - Simuni, Tanya

N1 - Funding Information: We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. 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‐Maximilians‐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. Funding Information: F.H. received grants from the Deutsche Parkinson Gesellschaft, the Else‐Kröner‐Fresenius‐Stiftung, and the CurePSP foundation. V.C.R. has received speaker's honoraria from AURIKAMED and research grants from the Friedrich Baur‐Stiftung. B.M. has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced research company. B.M. is member of the executive steering committee of the Parkinson Progression Marker Initiative and principal investigator (PI) of the Systemic Synuclein Sampling Study of The Michael J. Fox Foundation for Parkinson's Research and has received research funding from the Deutsche Forschungsgemeinschaft (DFG), EU (Horizon2020), Parkinson Fonds Deutschland, Deutsche Parkinson Vereinigung, and The Michael J. Fox Foundation for Parkinson's Research. G.D. has received lecture fees from UCB, Medtronic, and Desitin and has been serving as a consultant for Medtronic, Sapiens, Boston Scientific, and Britannica; he received royalties from Thieme publishers; receives support through institution funding for his research from the German Research Council, the German Ministry of Education and Health, and Medtronic. G.K. receives research support from the German Research Council (DFG) and the Christian‐Albrechts‐University Kiel. C. Trenkwalder was supported by The Michael J. Fox foundation and by EU Horizon 2010; she receives honoraria or consultation fees from UCB, Gruenenthal, and Orion. C. Trenkwalder has received speaker's honoraria from Roche and Britannia. Günter Höglinger was supported by the German Federal Ministry of Education and Research (BMBF: 01KU1403A EpiPD), 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), DFG grants (HO2402/6‐2, HO2402/18‐1 MSAomics), the NOMIS foundation (FTLD project), and the EU/EFPIA/Innovative Medicines Initiative, Joint Undertaking (IMPRIND grant 116,060). The other authors report no disclosures. All authors are government employees. No sponsor had access to the data or participated in the writing of the manuscript. Funding Information: We thank all those who contributed toward our research, particularly the patients and families who donated brain tissue—without their donation this study would not have been possible. We thank Vanessa Boll and Lena Jaschkowitz for excellent technical assistance. 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. Publisher Copyright: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - ZIC1

KW - ZIC4

KW - autopsy-confirmed

KW - genome-wide association study

KW - multiple system atrophy

UR - http://www.scopus.com/inward/record.url?scp=85131795499&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85131795499&partnerID=8YFLogxK

U2 - 10.1002/mds.29164

DO - 10.1002/mds.29164

M3 - Article

C2 - 35997131

AN - SCOPUS:85131795499

SN - 0885-3185

VL - 37

SP - 2110

EP - 2121

JO - Movement Disorders

JF - Movement Disorders

IS - 10

ER -

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

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