期刊
MOVEMENT DISORDERS
卷 36, 期 2, 页码 449-459出版社
WILEY
DOI: 10.1002/mds.28338
关键词
multiple system atrophy; inflammatory bowel disease; genetic overlap; conjunctional false discovery rate
资金
- MSA Coalition USA
- Michael J Fox Foundation, USA Genetic Diversity in PD Program: GAP-India [17473]
- German Research Council [DFG/SH 599/6-1]
- Research Council of Norway [223273, 225989, 248778]
- South-East Norway Health Authority [2016-064, 2017-004]
- KG Jebsen Stiftelsen [SKGJ-Med-008]
- Austrian Science Fund [F4414]
- German Federal Ministry of Education and Research [01ZX1606A, 01ZX1709, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03IS2061A, 03Z1CN22]
- EU Joint Program-Neurodegenerative diseases (COURAGE-PD) [FKZ 01ED1604]
- German Research Foundation under Germany's Excellence Strategy -EXC [2167-390884018]
- Intramural Research Programs of the National Institute of Neurological Disorders and Stroke [1ZIA NS003154]
- National Institute on Aging [Z01-AG000949]
- Michael J. Fox Foundation for Parkinson's Research
- Medical Research Council UK [MR/N026004/1]
- Wellcome Trust [202903/Z/16/Z]
- MRC [MR/N026004/1] Funding Source: UKRI
The study revealed a significant genetic overlap between multiple system atrophy (MSA) and inflammatory bowel disease, with shared genetic loci including the C7 gene. The C7 gene was found to play an important role in both phenotypes, suggesting the involvement of immune and gut dysfunction in the pathophysiology of MSA.
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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