Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease.

Alexey Shadrin ,Christian Gieger,Wassilios G Meissner,Markus M Nöthen,Stefan Schreiber,Wolfgang Lieb,Sören Mucha,Cornelis Blauwendraat,Mary B Makarious,Sonja W Scholz,Alexandra Foubert‐Samier,Oleksandr Frei,J Raphael Gibbs,Monia Hammer,Manu Sharma,David Ellinghaus,Nadia Stefanova,Henry Houlden,Jinhui Ding,Shahram Bahrami,Olivier Rascol,Ole A Andreassen,John Hardy,Martina Müller‐Nurasyid,Anne Pavy‐Le Traon,Per Hoffmann,Ulf Schminke,Georg Homuth,Thomas Gasser,Ashwin Ashok Kumar Sreelatha ,Antonio Heras-Garvín ,Carsten Oliver Schmidt ,Kevin O’connell ,Andrew Singleton ,Gregor K Wenning ,André Franke

doi:10.1002/mds.28338

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.

Highlights

The role of immune dysfunction in neurodegenerative diseases has long been debated
One of the earlier studies using autopsy-confirmed PD cases showed a higher level of microglial activation within the substantia nigra, and this increase in microglial activity was identified by human leukocyte antigen (HLA) DR.[9]
The present study provides evidence of shared genetic etiology between Inflammatory bowel disease (IBD)/Crohn’s disease (CD) and Multiple system atrophy (MSA), using a genome-wide genetic pleiotropy-informed approach

Summary

Introduction

The role of immune dysfunction in neurodegenerative diseases has long been debated. For example, one of the earlier studies using autopsy-confirmed PD cases showed a higher level of microglial activation within the substantia nigra, and this increase in microglial activity was identified by human leukocyte antigen (HLA) DR.[9].

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Results

Conclusion