Shared Genetics of Multiple System Atrophy and Inflammatory Bowel Disease
Mov Disord. 2020-10-27; 36(2): 449-459
DOI: 10.1002/mds.28338
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Shadrin AA(1), Mucha S(#)(2), Ellinghaus D(#)(2), Makarious MB(3), Blauwendraat
C(4), Sreelatha AAK(5), Heras-Garvin A(6), Ding J(4), Hammer M(4), Foubert-Samier
A(7)(8), Meissner WG(7)(9), Rascol O(10)(11), Pavy-Le Traon A(12), Frei O(1),
O’Connell KS(1), Bahrami S(1), Schreiber S(2)(13), Lieb W(14), Müller-Nurasyid
M(15)(16)(17), Schminke U(18), Homuth G(19), Schmidt CO(20), Nöthen MM(21),
Hoffmann P(21), Gieger C(22), Wenning G(6); European Multiple System Atrophy
Study Group, Gibbs JR(4), Franke A(2), Hardy J(23), Stefanova N(6), Gasser
T(24)(25), Singleton A(4), Houlden H(23), Scholz SW(3)(26), Andreassen OA(1),
Sharma M(5).
Author information:
(1)NORMENT, Institute of Clinical Medicine, University of Oslo and Division of
Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
(2)Institute of Clinical Molecular Biology, Christian-Albrechts-University of
Kiel, Kiel, Germany.
(3)Neurodegenerative Diseases Research Unit, National Institute of Neurological
Disorders and, Stroke, National Institutes of Health, Bethesda, Maryland, USA.
(4)Laboratory of Neurogenetics, National Institute on Aging, National Institutes
of Health, Bethesda, Maryland, USA.
(5)Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and
Applied Biometry, University of Tübingen, Tübingen, Germany.
(6)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
(7)Service de Neurologie, CRMR Atrophie Multisystématisée, CHU Bordeaux,
Bordeaux, France.
(8)Inserm, UMR1219, Bordeaux Population Health Research Center, Bordeaux
University, ISPED, Bordeaux, France.
(9)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, CNRS,
Bordeaux, France.
(10)Centre de Reference Maladie Rare Atrophie MultiSystématisée, Centre
d’Investigation, Clinique CIC 1436, Services de Pharmacologie Clinique et
Neurosciences, NeuroToul COEN Center, Toulouse, France.
(11)Centre Hospitalo-Universitaire de Toulouse, 3, INSERM, Toulouse, France.
(12)Neurology Department, French Reference Centre for MSA, University Hospital of
Toulouse and INSERM U 1048, Institute of Cardiovascular and Metabolic Diseases,
Toulouse, France.
(13)First Medical Department, University Hospital Schleswig-Holstein, Kiel,
Germany.
(14)Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University
of Kiel, Kiel, Germany.
(15)Institute of Genetic Epidemiology, Helmholtz Zentrum München – German
Research Center for Environmental Health, Neuherberg, Germany.
(16)Chair of Genetic Epidemiology, IBE, Faculty of Medicine,
Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
(17)Department of Internal Medicine I (Cardiology), Hospital of the
Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
(18)Department of Neurology, University Medicine Greifswald, Greifswald, Germany.
(19)Department of Functional Genomics, Interfaculty Institute for Genetics and
Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University
Greifswald, Greifswald, Germany.
(20)Institute for Community Medicine, Study of Health in Pomerania/KEF,
University Medicine Greifswald, Greifswald, Germany.
(21)Institute of Human Genetics, University of Bonn, Bonn, Germany.
(22)Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz
Zentrum München-German Research Center for Environmental Health, Neuherberg,
Germany.
(23)Rita Lila Weston Institute, University College London, London, UK.
(24)German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
(25)Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain
Research, University of Tübingen, Tübingen, Germany.
(26)Department of Neurology, Johns Hopkins University Medical Center, Baltimore,
Maryland, USA.
(#)Contributed equally
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.
© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on
behalf of International Parkinson and Movement Disorder Society.