Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease

Advanced search
Browse by:

Department | Year

UCL Theses | Latest

Deposit your research

Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease

Shadrin, AA; Mucha, S; Ellinghaus, D; Makarious, MB; Blauwendraat, C; Sreelatha, AAK; Heras-Garvin, A; ... Sharma, M; + view all (2020) Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease. Movement Disorders 10.1002/mds.28338. (In press). Green open access

Preview

Text
mds.28338.pdf - Published Version
Download (1MB) | Preview

Abstract

BACKGROUND: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-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. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

Type:	Article
Title:	Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease
Location:	United States
Open access status:	An open access version is available from UCL Discovery
DOI:	10.1002/mds.28338
Publisher version:	http://dx.doi.org/10.1002/mds.28338
Language:	English
Additional information:	© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords:	conjunctional false discovery rate, genetic overlap, inflammatory bowel disease, multiple system atrophy
UCL classification:	UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI:	https://discovery.ucl.ac.uk/id/eprint/10114149