Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Till F. M. Andlauer(Munich Cluster for Systems Neurology), Dorothea Buck(TUM Klinikum), Gisela Antony(Philipps University of Marburg), Antonios Bayas(University Hospital Augsburg), Lukas Bechmann(Leipzig University), Achim Berthele(TUM Klinikum), Andrew T. Chan(University of Bern), Christiane Gasperi(TUM Klinikum), Ralf Gold(St. Josef-Hospital), Christiane Graetz(Johannes Gutenberg University Mainz), Jürgen Haas(Heidelberg University), Michael Hecker(University of Rostock), Carmen Infante‐Duarte(Max Delbrück Center), Matthias Knop(Max Planck Institute of Psychiatry), Tania Kümpfel(Institute of Neuroimmunology of the Slovak Academy of Sciences), Volker Limmroth(Lungenklinik Köln-Merheim), Ralf A. Linker(Universitätsklinikum Erlangen), Verena Loleit(TUM Klinikum), Felix Luessi(Johannes Gutenberg University Mainz), Sven G. Meuth(University of Münster), Mark Mühlau(TUM Klinikum), Sandra Nischwitz(Max Planck Institute of Psychiatry), Friedemann Paul(Max Delbrück Center), Michael Pütz(Philipps University of Marburg), Tobias Ruck(University of Münster), Anke Salmen(University of Bern), Martin Stangel(Medizinische Hochschule Hannover), Jan‐Patrick Stellmann(Universität Hamburg), Klarissa Hanja Stürner(Universität Hamburg), Björn Tackenberg(Philipps University of Marburg), Florian Then Bergh(University Hospital Leipzig), Hayrettin Tumani(Universität Ulm), Clemens Warnke(Heinrich Heine University Düsseldorf), Frank Weber(Max Planck Institute of Psychiatry), Heinz Wiendl(University of Münster), Brigitte Wildemann(Heidelberg University), Uwe K. Zettl(University of Rostock), Ulf Ziemann(Hertie Institute for Clinical Brain Research), Frauke Zipp(Johannes Gutenberg University Mainz), Janine Arloth(Helmholtz Zentrum München), Peter Weber(Max Planck Institute of Psychiatry), Milena Radivojkov‐Blagojevic(Helmholtz Zentrum München), Markus O. Scheinhardt(University Hospital Schleswig-Holstein), Theresa Dankowski(University Hospital Schleswig-Holstein), Thomas Bettecken(Max Planck Institute of Psychiatry), Peter Lichtner(Helmholtz Zentrum München), Darina Czamara(Max Planck Institute of Psychiatry), Tania Carrillo‐Roa(Max Planck Institute of Psychiatry), Elisabeth B. Binder(Emory University), Klaus Berger(University of Münster), Lars Bertram(Institute for Integrative and Experimental Genomics), André Franke(Christian-Albrechts-Universität zu Kiel), Christian Gieger(Helmholtz Zentrum München), Stefan Herms(University of Bonn), Georg Homuth(Universität Greifswald), Marcus Ising(Max Planck Institute of Psychiatry), Karl‐Heinz Jöckel(Essen University Hospital), Tim Kacprowski(Universität Greifswald), Stefan Kloiber(Max Planck Institute of Psychiatry), Matthias Laudes(Christian-Albrechts-Universität zu Kiel), Wolfgang Lieb(Hochschule für Angewandte Wissenschaften Kiel), Christina M. Lill(Johannes Gutenberg University Mainz), Susanne Lucae(Max Planck Institute of Psychiatry), Thomas Meitinger(Helmholtz Zentrum München), Susanne Moebus(Essen University Hospital), Martina Müller‐Nurasyid(Helmholtz Zentrum München), Markus M. Nöthen(University of Bonn), Astrid Petersmann(Universitätsmedizin Greifswald), Rajesh Rawal(Helmholtz Zentrum München), Ulf Schminke(Universitätsmedizin Greifswald), Konstantin Strauch(Zimmer Biomet (Netherlands)), Henry Völzke(Universitätsmedizin Greifswald), Mélanie Waldenberger(Helmholtz Zentrum München), Jürgen Wellmann(University of Münster), Eleonora Porcu(Institute of Genetic and Biomedical Research), Antonella Mulas(University of Sassari), Maristella Pitzalis(Institute of Genetic and Biomedical Research), Carlo Sidore(Institute of Genetic and Biomedical Research), Ilenia Zara(Center for Advanced Studies Research and Development in Sardinia), Francesco Cucca(University of Sassari), Magdalena Żołędziewska(University of Sassari), Andreas Ziegler(University Hospital Schleswig-Holstein), Bernhard Hemmer(TUM Klinikum), Bertram Müller‐Myhsok(University of Liverpool)
Science Advances
June 3, 2016
10.1126/sciadv.1501678
Cited by 182Open Access
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Abstract

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

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