title: Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.
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.
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
authors.forename: Till F M
authors.identifier: 0000-0002-2917-5889
authors.initials: TF
authors.lastname: Andlauer
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.affiliation: Central Information Office KKNMS, Philipps University Marburg, 35043 Marburg, Germany.
authors.forename: Gisela
authors.identifier: 0000-0002-5367-6069
authors.initials: G
authors.lastname: Antony
authors.affiliation: Department of Neurology, Klinikum Augsburg, 86156 Augsburg, Germany.
authors.forename: Antonios
authors.initials: A
authors.lastname: Bayas
authors.affiliation: Department of Neurology, University of Leipzig, 04103 Leipzig, Germany.; Institute of Medical Microbiology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bechmann
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.affiliation: Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.; Department of Neurology, University Hospital Bern and University of Bern, 3010 Bern, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Gasperi
authors.affiliation: Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn ), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Graetz
authors.affiliation: Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.affiliation: Department of Neurology, University of Rostock, 18147 Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hecker
authors.affiliation: NeuroCure Clinical Research Center, Department of Neurology, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, and Charité University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Duarte
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Knop
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, 81377 Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel
authors.affiliation: Department of Neurology, Hospital Köln-Merheim, 51109 Köln, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Limmroth
authors.affiliation: Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
authors.affiliation: Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Loleit
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn ), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Mühlau
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Nischwitz
authors.affiliation: NeuroCure Clinical Research Center, Department of Neurology, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, and Charité University Medicine Berlin, 10117 Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pütz
authors.affiliation: Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.affiliation: Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.; Department of Neurology, University Hospital Bern and University of Bern, 3010 Bern, Switzerland.
authors.forename: Anke
authors.initials: A
authors.lastname: Salmen
authors.affiliation: Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
authors.affiliation: Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
authors.forename: Jan-Patrick
authors.identifier: 0000-0003-2565-2833
authors.initials: JP
authors.lastname: Stellmann
authors.affiliation: Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
authors.forename: Klarissa H
authors.identifier: 0000-0003-2199-3315
authors.initials: KH
authors.lastname: Stürner
authors.affiliation: Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Tackenberg
authors.affiliation: Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Then Bergh
authors.affiliation: Department of Neurology, University of Ulm, 89081 Ulm, Germany.; Neurological Clinic Dietenbronn, 88477 Schwendi, Germany.
authors.forename: Hayrettin
authors.initials: H
authors.lastname: Tumani
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Warnke
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Neurological Clinic, Medical Park, 65520 Bad Camberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.affiliation: Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wildemann
authors.affiliation: Department of Neurology, University of Rostock, 18147 Rostock, Germany.
authors.forename: Uwe K
authors.initials: UK
authors.lastname: Zettl
authors.affiliation: Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.
authors.forename: Ulf
authors.identifier: 0000-0001-8372-3615
authors.initials: U
authors.lastname: Ziemann
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn ), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Arloth
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Milena
authors.identifier: 0000-0001-5834-5122
authors.initials: M
authors.lastname: Radivojkov-Blagojevic
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
authors.forename: Markus O
authors.initials: MO
authors.lastname: Scheinhardt
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Dankowski
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bettecken
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Berger
authors.affiliation: Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, 23562 Lübeck, Germany.; School of Public Health, Faculty of Medicine, Imperial College London, SW7 2AZ London, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.; Department of Biomedicine, Division of Medical Genetics, University of Basel, 4031 Basel, Switzerland.
authors.forename: Stefan
authors.identifier: 0000-0002-2786-8200
authors.initials: S
authors.lastname: Herms
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Georg
authors.identifier: 0000-0001-6839-0605
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Tim
authors.identifier: 0000-0002-5393-2413
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.affiliation: Department I of Internal Medicine, Kiel University, 24105 Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Laudes
authors.affiliation: Institute of Epidemiology and Biobank popgen, Kiel University, 24105 Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.; Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lill
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Moebus
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Department of Medicine I, Ludwig-Maximilians-Universität, 81377 Munich, Germany.; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Petersmann
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Rajesh
authors.identifier: 0000-0002-1465-0317
authors.initials: R
authors.lastname: Rawal
authors.affiliation: Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schminke
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Strauch
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wellmann
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Pitzalis
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
authors.forename: Carlo
authors.identifier: 0000-0001-7504-7477
authors.initials: C
authors.lastname: Sidore
authors.affiliation: Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, 09010 Cagliari, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Zara
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.; Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
authors.forename: Magdalena
authors.identifier: 0000-0002-3033-6133
authors.initials: M
authors.lastname: Zoledziewska
authors.affiliation: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.; Zentrum für Klinische Studien, Universität zu Lübeck, 23562 Lübeck, Germany.; School of Mathematics, Statistics, and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville 3209, South Africa.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.; Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000235:genetics; D000071230:Transcriptional Regulator ERG / Q000235:genetics; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; C502190:L3MBTL3 protein, human; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; C076035:c-MYC-associated zinc finger protein; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human
keywords: DLEU1; DNA methylation; ERG; L3MBTL3; MAZ; Multiple sclerosis; SHMT1; genome-wide association study