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A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease

Alexey A Shadrin, Sören Mucha, David Ellinghaus, Mary B Makarious, Cornelis Blauwendraat, Ashwin A Sreelatha, Antonio Heras-Garvin, View ORCID ProfileJinhui Ding, Monia Hammer, Alexandra Foubert-Samier, Wassilios G Meissner, Olivier Rascol, Anne Pavy-Le Traon, Oleksandr Frei, Kevin S O’Connell, Shahram Bahrami, Stefan Schreiber, Wolfgang Lieb, Martina Müller-Nurasyid, Andreas Arnold, Georg Homuth, Carsten O. Schmidt, View ORCID ProfileMarkus M. Nöthen, Per Hoffmann, Christian Gieger, European Multiple System Atrophy Study Group, J Raphael Gibbs, View ORCID ProfileAndre Franke, John Hardy, Gregor Wenning, Nadia Stefanova, Thomas Gasser, Andrew Singleton, Henry Houlden, Sonja W Scholz, Ole A. Andreassen, Manu Sharma
doi: https://doi.org/10.1101/751354
Alexey A Shadrin
1NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway
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Sören Mucha
2Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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David Ellinghaus
2Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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Mary B Makarious
3Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
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Cornelis Blauwendraat
4Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Ashwin A Sreelatha
5Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
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Antonio Heras-Garvin
6Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Jinhui Ding
4Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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  • ORCID record for Jinhui Ding
Monia Hammer
4Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Alexandra Foubert-Samier
7Service de Neurologie, CRMR Atrophie Multisystématisée, CHU Bordeaux, 33000 Bordeaux, France
8Inserm, UMR1219, Bordeaux Population Health Research Center, Bordeaux University, ISPED, 33000 Bordeaux, France
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Wassilios G Meissner
9Service de Neurologie, CRMR Atrophie Multisystématisée, CHU Bordeaux, 33000 Bordeaux, France
10Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, CNRS, 33000 Bordeaux, France
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Olivier Rascol
11Centre de Reference Maladie Rare Atrophie MultiSystématisée, Centre d’Investigation Clinique CIC 1436, Services de Pharmacologie Clinique et Neurosciences, NeuroToul COEN Center
12Centre Hospitalo-Universitaire de Toulouse, Université de Toulouse 3, INSERM, Toulouse, France
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Anne Pavy-Le Traon
13Neurology department, French Reference Centre for MSA, University Hospital of Toulouse and INSERM U 1048, Institute of Cardiovascular and Metabolic Diseases, Toulouse, France
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Oleksandr Frei
1NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway
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Kevin S O’Connell
1NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway
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Shahram Bahrami
1NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway
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Stefan Schreiber
14Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
15First Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany
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Wolfgang Lieb
16Institute of Epidemiology and Biobank PopGen, Christian-Albrechts-University of Kiel, Kiel, Germany
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Martina Müller-Nurasyid
17Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
18Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Germany
19Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
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Andreas Arnold
20Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany
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Georg Homuth
21Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
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Carsten O. Schmidt
22Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany
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Markus M. Nöthen
23Institute of Human Genetics, University of Bonn, Bonn, Germany
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Per Hoffmann
23Institute of Human Genetics, University of Bonn, Bonn, Germany
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Christian Gieger
24Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München- German Research Center for Environmental Health, Neuherberg, Germany
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J Raphael Gibbs
4Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Andre Franke
2Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
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John Hardy
25Rita Lila Weston Institute, University College London, London, England
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Gregor Wenning
6Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Nadia Stefanova
6Department of Neurology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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Thomas Gasser
26German Center for Neurodegenerative Diseases (DZNE), Tübingen
27Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
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Andrew Singleton
4Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
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Henry Houlden
25Rita Lila Weston Institute, University College London, London, England
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Sonja W Scholz
3Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
28Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
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Ole A. Andreassen
1NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407 Oslo, Norway
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Manu Sharma
5Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
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  • For correspondence: manu.sharma@uni-tuebingen.de
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ABSTRACT

We aimed to identify shared genetic background between multiple system atrophy (MSA) and autoimmune diseases by using the conjFDR approach. Our study showed significant genetic overlap between MSA and inflammatory bowel disease and identified DENND1B, C7, and RSP04 loci, which are linked to significant changes in methylation or expression levels of adjacent genes. We obtained evidence of enriched heritability involving immune/digestive categories. Finally, an MSA mouse model showed dysregulation of the C7 gene in the degenerating midbrain compared to wildtype mice. The results identify novel molecular mechanisms and implicate immune and gut dysfunction in MSA pathophysiology.

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Posted August 31, 2019.
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A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease
Alexey A Shadrin, Sören Mucha, David Ellinghaus, Mary B Makarious, Cornelis Blauwendraat, Ashwin A Sreelatha, Antonio Heras-Garvin, Jinhui Ding, Monia Hammer, Alexandra Foubert-Samier, Wassilios G Meissner, Olivier Rascol, Anne Pavy-Le Traon, Oleksandr Frei, Kevin S O’Connell, Shahram Bahrami, Stefan Schreiber, Wolfgang Lieb, Martina Müller-Nurasyid, Andreas Arnold, Georg Homuth, Carsten O. Schmidt, Markus M. Nöthen, Per Hoffmann, Christian Gieger, European Multiple System Atrophy Study Group, J Raphael Gibbs, Andre Franke, John Hardy, Gregor Wenning, Nadia Stefanova, Thomas Gasser, Andrew Singleton, Henry Houlden, Sonja W Scholz, Ole A. Andreassen, Manu Sharma
bioRxiv 751354; doi: https://doi.org/10.1101/751354
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A genome-wide genetic pleiotropy approach identified shared loci between multiple system atrophy and inflammatory bowel disease
Alexey A Shadrin, Sören Mucha, David Ellinghaus, Mary B Makarious, Cornelis Blauwendraat, Ashwin A Sreelatha, Antonio Heras-Garvin, Jinhui Ding, Monia Hammer, Alexandra Foubert-Samier, Wassilios G Meissner, Olivier Rascol, Anne Pavy-Le Traon, Oleksandr Frei, Kevin S O’Connell, Shahram Bahrami, Stefan Schreiber, Wolfgang Lieb, Martina Müller-Nurasyid, Andreas Arnold, Georg Homuth, Carsten O. Schmidt, Markus M. Nöthen, Per Hoffmann, Christian Gieger, European Multiple System Atrophy Study Group, J Raphael Gibbs, Andre Franke, John Hardy, Gregor Wenning, Nadia Stefanova, Thomas Gasser, Andrew Singleton, Henry Houlden, Sonja W Scholz, Ole A. Andreassen, Manu Sharma
bioRxiv 751354; doi: https://doi.org/10.1101/751354

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