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Sci Adv. 2016 Jun 17;2(6):e1501678. doi: 10.1126/sciadv.1501678. eCollection 2016 Jun.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Author information

1
Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
2
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
3
Central Information Office KKNMS, Philipps University Marburg, 35043 Marburg, Germany.
4
Department of Neurology, Klinikum Augsburg, 86156 Augsburg, Germany.
5
Department of Neurology, University of Leipzig, 04103 Leipzig, Germany.; Institute of Medical Microbiology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
6
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.
7
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
8
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.
9
Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
10
Department of Neurology, University of Rostock, 18147 Rostock, Germany.
11
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.
12
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
13
Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, 81377 Munich, Germany.
14
Department of Neurology, Hospital Köln-Merheim, 51109 Köln, Germany.
15
Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
16
Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
17
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
18
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
19
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
20
Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
21
Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany.
22
Department of Neurology, University of Ulm, 89081 Ulm, Germany.; Neurological Clinic Dietenbronn, 88477 Schwendi, Germany.
23
Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
24
Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Neurological Clinic, Medical Park, 65520 Bad Camberg, Germany.
25
Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.
26
Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
27
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
28
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
29
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
30
Max Planck Institute of Psychiatry, 80804 Munich, Germany.; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
31
Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
32
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.
33
Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
34
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.; Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
35
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.; Department of Biomedicine, Division of Medical Genetics, University of Basel, 4031 Basel, Switzerland.
36
Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
37
Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
38
Department I of Internal Medicine, Kiel University, 24105 Kiel, Germany.
39
Institute of Epidemiology and Biobank popgen, Kiel University, 24105 Kiel, Germany.
40
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.
41
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.
42
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
43
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
44
Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany.
45
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.
46
Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
47
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
48
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.
49
Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, 09010 Cagliari, Italy.
50
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.
51
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.

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.

KEYWORDS:

DLEU1; DNA methylation; ERG; L3MBTL3; MAZ; Multiple sclerosis; SHMT1; genome-wide association study

PMID:
27386562
PMCID:
PMC4928990
DOI:
10.1126/sciadv.1501678
[Indexed for MEDLINE]
Free PMC Article

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