Genome-wide association study of autopsy-confirmed Multiple System Atrophy identifies common variants near ZIC1 and ZIC4
| Autor: | Manuela Pendziwiat, Margaret E. Flanagan, Marla Gearing, Catriona McLean, Regina Reimann, Günter U. Höglinger, Günther Deuschl, Alan J. Thomas, David Ellinghaus, María José Martí, Allison Beller, Johannes Levin, Ian R. A. Mackenzie, Viktoria Ruf, John Q. Trojanowski, Jonathan D. Glass, Brit Mollenhauer, Franziska Hopfner, Justo Yebenes, Adriano Aguzzi, Lea T. Grinberg, Claire Troakes, Glenda M. Halliday, William K. Scott, Johannes Attems, Charles L. White, Ali H. Rajput, Kathy L. Newell, Owen A. Ross, Ulrich Müller, Charles Duyckaerts, Paula Desplats, Tao Xie, David J. Irwin, Inge Huitinga, Gerard D. Schellenberg, Valentin Evsyukov, Sashika Selvackadunco, Bernardino Ghetti, Per Svenningsson, Ian G. McKeith, Alex Rajput, Manuela Neumann, Ingo Helbig, Edward B. Lee, Ellen Gelpi, Jochen Herms, Tanya Simuni, Matthias Höllerhage, Matthew P. Frosch, Gregor Kuhlenbäumer, Andre Franke, Thomas G. Beach, Annette Peters, Dennis W. Dickson, Shunsuke Koga, Laura Molina Porcel, Vivianna M. Van Deerlin, Dirk C. Keene, Anja K. Tietz, Christine Stadelmann, Claudia Trenkwalder, Teresa Ximelis, William W. Seeley, Radoslav Matěj, Alexander Pantelyat, Alberto Rabano, Gabor G. Kovacs |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Pathology medicine.medical_specialty Cerebellum Cerebellar ataxia business.industry Striatonigral Degeneration Genome-wide association study medicine.disease 3. Good health 03 medical and health sciences 0302 clinical medicine Olivopontocerebellar atrophy Dentate nucleus medicine.anatomical_structure Atrophy Chromosome 3 medicine medicine.symptom business 030217 neurology & neurosurgery 030304 developmental biology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|