Research ArticleNEUROLOGICAL DISORDERS
Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation
- Till F. M. Andlauer1,2,*,
- Dorothea Buck3,*,
- Gisela Antony4,
- Antonios Bayas5,
- Lukas Bechmann6,7,
- Achim Berthele3,
- Andrew Chan8,56,
- Christiane Gasperi3,
- Ralf Gold8,
- Christiane Graetz9,
- Jürgen Haas10,
- Michael Hecker11,
- Carmen Infante-Duarte12,
- Matthias Knop1,
- Tania Kümpfel13,
- Volker Limmroth14,
- Ralf A. Linker15,
- Verena Loleit3,
- Felix Luessi9,
- Sven G. Meuth16,
- Mark Mühlau2,3,
- Sandra Nischwitz1,
- Friedemann Paul12,
- Michael Pütz17,
- Tobias Ruck16,
- Anke Salmen8,56,
- Martin Stangel18,
- Jan-Patrick Stellmann19,
- Klarissa H. Stürner19,
- Björn Tackenberg17,
- Florian Then Bergh20,
- Hayrettin Tumani21,22,
- Clemens Warnke23,
- Frank Weber1,24,
- Heinz Wiendl16,
- Brigitte Wildemann10,
- Uwe K. Zettl11,
- Ulf Ziemann25,
- Frauke Zipp9,
- Janine Arloth1,26,
- Peter Weber1,
- Milena Radivojkov-Blagojevic27,
- Markus O. Scheinhardt28,
- Theresa Dankowski28,
- Thomas Bettecken1,
- Peter Lichtner27,29,
- Darina Czamara1,
- Tania Carrillo-Roa1,
- Elisabeth B. Binder1,30,
- Klaus Berger31,
- Lars Bertram32,33,
- Andre Franke34,
- Christian Gieger35,36,
- Stefan Herms37,38,
- Georg Homuth39,
- Marcus Ising1,
- Karl-Heinz Jöckel40,
- Tim Kacprowski39,
- Stefan Kloiber1,
- Matthias Laudes41,
- Wolfgang Lieb42,
- Christina M. Lill9,32,
- Susanne Lucae1,
- Thomas Meitinger27,29,
- Susanne Moebus40,
- Martina Müller-Nurasyid43,44,45,
- Markus M. Nöthen37,
- Astrid Petersmann46,
- Rajesh Rawal35,36,
- Ulf Schminke47,
- Konstantin Strauch43,48,
- Henry Völzke49,
- Melanie Waldenberger35,36,
- Jürgen Wellmann31,
- Eleonora Porcu50,
- Antonella Mulas50,51,
- Maristella Pitzalis50,
- Carlo Sidore50,
- Ilenia Zara52,
- Francesco Cucca50,51,
- Magdalena Zoledziewska50,51,
- Andreas Ziegler28,53,54,
- Bernhard Hemmer2,3,*,† and
- Bertram Müller-Myhsok1,2,55,*,†
- 1Max Planck Institute of Psychiatry, 80804 Munich, Germany.
- 2Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
- 3Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
- 4Central Information Office KKNMS, Philipps University Marburg, 35043 Marburg, Germany.
- 5Department of Neurology, Klinikum Augsburg, 86156 Augsburg, Germany.
- 6Department of Neurology, University of Leipzig, 04103 Leipzig, Germany.
- 7Institute of Medical Microbiology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
- 8Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
- 9Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
- 10Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
- 11Department of Neurology, University of Rostock, 18147 Rostock, Germany.
- 12NeuroCure 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.
- 13Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, 81377 Munich, Germany.
- 14Department of Neurology, Hospital Köln-Merheim, 51109 Köln, Germany.
- 15Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
- 16Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
- 17Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
- 18Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
- 19Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
- 20Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany.
- 21Department of Neurology, University of Ulm, 89081 Ulm, Germany.
- 22Neurological Clinic Dietenbronn, 88477 Schwendi, Germany.
- 23Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
- 24Neurological Clinic, Medical Park, 65520 Bad Camberg, Germany.
- 25Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.
- 26Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
- 27Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
- 28Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
- 29Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
- 30Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
- 31Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
- 32Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, 23562 Lübeck, Germany.
- 33School of Public Health, Faculty of Medicine, Imperial College London, SW7 2AZ London, UK.
- 34Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
- 35Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
- 36Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
- 37Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
- 38Department of Biomedicine, Division of Medical Genetics, University of Basel, 4031 Basel, Switzerland.
- 39Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
- 40Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
- 41Department I of Internal Medicine, Kiel University, 24105 Kiel, Germany.
- 42Institute of Epidemiology and Biobank popgen, Kiel University, 24105 Kiel, Germany.
- 43Institute of Genetic Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
- 44Department of Medicine I, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
- 45DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
- 46Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
- 47Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany.
- 48Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
- 49Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
- 50Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
- 51Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, 07100 Sassari, Italy.
- 52Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, 09010 Cagliari, Italy.
- 53Zentrum für Klinische Studien, Universität zu Lübeck, 23562 Lübeck, Germany.
- 54School of Mathematics, Statistics, and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, Scottsville 3209, South Africa.
- 55Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
- 56Department of Neurology, University Hospital Bern and University of Bern, 3010 Bern, Switzerland.
- ↵†Corresponding author. Email: hemmer{at}tum.de (B.H.); bmm{at}psych.mpg.de (B.M.-M.)
↵* These authors contributed equally to this work.
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Science Advances 17 Jun 2016:
Vol. 2, no. 6, e1501678
DOI: 10.1126/sciadv.1501678
Vol. 2, no. 6, e1501678
DOI: 10.1126/sciadv.1501678
Till F. M. Andlauer
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Dorothea Buck
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Gisela Antony
Central Information Office KKNMS, Philipps University Marburg, 35043 Marburg, Germany.
Antonios Bayas
Department of Neurology, Klinikum Augsburg, 86156 Augsburg, Germany.
Lukas Bechmann
Department of Neurology, University of Leipzig, 04103 Leipzig, Germany.
Institute of Medical Microbiology, Otto-von-Guericke University, 39120 Magdeburg, Germany.
Achim Berthele
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Andrew Chan
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.
Christiane Gasperi
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Ralf Gold
Department of Neurology, St. Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
Christiane Graetz
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Jürgen Haas
Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Michael Hecker
Department of Neurology, University of Rostock, 18147 Rostock, Germany.
Carmen Infante-Duarte
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.
Matthias Knop
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Tania Kümpfel
Institute of Clinical Neuroimmunology, Ludwigs-Maximilians-Universität, 81377 Munich, Germany.
Volker Limmroth
Department of Neurology, Hospital Köln-Merheim, 51109 Köln, Germany.
Ralf A. Linker
Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
Verena Loleit
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Felix Luessi
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Sven G. Meuth
Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
Mark Mühlau
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Sandra Nischwitz
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Friedemann Paul
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.
Michael Pütz
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
Tobias Ruck
Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
Anke Salmen
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.
Martin Stangel
Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
Jan-Patrick Stellmann
Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
Klarissa H. Stürner
Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
Björn Tackenberg
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.
Florian Then Bergh
Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, 04103 Leipzig, Germany.
Hayrettin Tumani
Department of Neurology, University of Ulm, 89081 Ulm, Germany.
Neurological Clinic Dietenbronn, 88477 Schwendi, Germany.
Clemens Warnke
Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
Frank Weber
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Neurological Clinic, Medical Park, 65520 Bad Camberg, Germany.
Heinz Wiendl
Department of Neurology, Klinik für Allgemeine Neurologie, University of Münster, 48149 Münster, Germany.
Brigitte Wildemann
Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Uwe K. Zettl
Department of Neurology, University of Rostock, 18147 Rostock, Germany.
Ulf Ziemann
Department of Neurology and Stroke, and Hertie Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany.
Frauke Zipp
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Janine Arloth
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Peter Weber
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Milena Radivojkov-Blagojevic
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Markus O. Scheinhardt
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
Theresa Dankowski
Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
Thomas Bettecken
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Peter Lichtner
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
Darina Czamara
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Tania Carrillo-Roa
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Elisabeth B. Binder
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
Klaus Berger
Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
Lars Bertram
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.
Andre Franke
Institute of Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany.
Christian Gieger
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Stefan Herms
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Department of Biomedicine, Division of Medical Genetics, University of Basel, 4031 Basel, Switzerland.
Georg Homuth
Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
Marcus Ising
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Karl-Heinz Jöckel
Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Tim Kacprowski
Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University and University Medicine Greifswald, 17475 Greifswald, Germany.
Stefan Kloiber
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Matthias Laudes
Department I of Internal Medicine, Kiel University, 24105 Kiel, Germany.
Wolfgang Lieb
Institute of Epidemiology and Biobank popgen, Kiel University, 24105 Kiel, Germany.
Christina M. Lill
Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), 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.
Susanne Lucae
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Thomas Meitinger
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
Susanne Moebus
Institute of Medical Informatics, Biometry, and Epidemiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Martina Müller-Nurasyid
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.
Markus M. Nöthen
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Astrid Petersmann
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
Rajesh Rawal
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Ulf Schminke
Department of Neurology, University Medicine Greifswald, 17475 Greifswald, Germany.
Konstantin Strauch
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.
Henry Völzke
Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
Melanie Waldenberger
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Jürgen Wellmann
Institut für Epidemiologie und Sozialmedizin der Universität Münster, 48149 Münster, Germany.
Eleonora Porcu
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
Antonella Mulas
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.
Maristella Pitzalis
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
Carlo Sidore
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, 09042 Cagliari, Italy.
Ilenia Zara
Center for Advanced Studies, Research and Development in Sardinia (CRS4), Pula, 09010 Cagliari, Italy.
Francesco Cucca
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.
Magdalena Zoledziewska
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.
Andreas Ziegler
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.
Bernhard Hemmer
Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Bertram Müller-Myhsok
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.
