Genome-wide association study of autopsy-confirmed Multiple System Atrophy identifies common variants near ZIC1 and ZIC4
Authors: Hopfner Franziska , Tietz Anja K. , Ruf Viktoria , Ross Owen A. , Koga Shunsuke , Dickson Dennis , Aguzzi Adriano , Attems Johannes , Beach Thomas , Beller Allison , 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 , 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 , Porcel Laura Molina , 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. , White Charles L. , Xie Tao , Ximelis Teresa , Yebenes Justo ,   the Alzheimer’s Disease Genetics Consortium, Müller Ulrich , Schellenberg Gerard D. , Herms Jochen , Kuhlenbäumer Gregor , Höglinger Günter 
Published: November 2021

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. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898).

The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 × 10−7, odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 × 10−6, OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 × 10−6, OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 × 10−5. 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).

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 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy.

These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.