Common Variants Near ZIC1 and ZIC4 in Autopsy‐Confirmed Multiple System Atrophy
Authors: Hopfner Franziska , Tietz Anja K. , Ruf Viktoria C. , Ross Owen A. , Koga Shunsuke , Dickson Dennis , Aguzzi Adriano , Attems Johannes , Beach Thomas , Beller Allison , Cheshire William P. , van Deerlin Vivianna , Desplats Paula , Deuschl Günther , Duyckaerts Charles , Ellinghaus David , Evsyukov Valentin , Flanagan Margaret Ellen , Franke Andre , Frosch Matthew P. , Gearing Marla , Gelpi Ellen , van Gerpen Jay A. , Ghetti Bernardino , Glass Jonathan D. , Grinberg Lea T. , Halliday Glenda , Helbig Ingo , Höllerhage Matthias , Huitinga Inge , Irwin David John , Keene Dirk C. , Kovacs Gabor G. , Lee Edward B. , Levin Johannes , Martí Maria J. , Mackenzie Ian , McKeith Ian , Mclean Catriona , Mollenhauer Brit , Neumann Manuela , Newell Kathy L. , Pantelyat Alex , Pendziwiat Manuela , Peters Annette , Molina Porcel Laura , Rabano Alberto , Matěj Radoslav , Rajput Alex , Rajput Ali , Reimann Regina , Scott William K. , Seeley William , Selvackadunco Sashika , Simuni Tanya , Stadelmann Christine , Svenningsson Per , Thomas Alan , Trenkwalder Claudia , Troakes Claire , Trojanowski John Q. , Uitti Ryan J. , White Charles L. , Wszolek Zbigniew K. , Xie Tao , Ximelis Teresa , Yebenes Justo ,   the Alzheimer's Disease Genetics Consortium, Müller Ulrich , Schellenberg Gerard D. , Herms Jochen , Kuhlenbäumer Gregor , Höglinger Günter 
Published: August 2022

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