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Shadrin, A.A.* ; Mucha, S.* ; Ellinghaus, D.* ; Makarious, M.B.* ; Blauwendraat, C.* ; Sreelatha, A.A.K.* ; Heras-Garvin, A.* ; Ding, J.* ; Hammer, M.* ; Foubert-Samier, A.* ; Meissner, W.G.* ; Rascol, O.* ; Pavy-Le Traon, A.* ; Frei, O.* ; O’Connell, K.S.* ; Bahrami, S.* ; Schreiber, S.* ; Lieb, W.* ; Müller-Nurasyid, M. ; Schminke, U.* ; Homuth, G.* ; Schmidt, C.O.* ; Nöthen, M.M.* ; Hoffmann, P.* ; Gieger, C. ; Wenning, G.* ; Gibbs, J.R.* ; Franke, A.* ; Hardy, J.* ; Stefanova, N.* ; Gasser, T.* ; Singleton, A.* ; Houlden, H.* ; Scholz, S.W.* ; Andreassen, O.A.* ; Sharma, M.*

Shared genetics of multiple system atrophy and inflammatory bowel disease.

Mov. Disord. 36, 449-459 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Background Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of alpha-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.Methods Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.Results We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.Conclusion Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Multiple System Atrophy ; Inflammatory Bowel Disease ; Genetic Overlap ; Conjunctional False Discovery Rate; Genome-wide Association; Parkinsons-disease; Alzheimers-disease; Common Variants; Risk; Gwas; Pleiotropy; Schizophrenia; Heritability; Metaanalysis
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Zeitschrift Movement Disorders
Quellenangaben Band: 36, Heft: 2, Seiten: 449-459 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Förderungen Wellcome Trust
Austrian Science Fund
KG Jebsen Stiftelsen
South-East Norway Health Authority
Research Council of Norway
German Research Council
Michael J Fox Foundation, USA Genetic Diversity in PD Program: GAP-India
Medical Research Council UK
Michael J. Fox Foundation for Parkinson's Research
National Institute on Aging
Intramural Research Programs of the National Institute of Neurological Disorders and Stroke
German Research Foundation under Germany's Excellence Strategy -EXC
EU Joint Program-Neurodegenerative diseases (COURAGE-PD)
German Federal Ministry of Education and Research
MSA Coalition USA