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dc.contributor.authorKular, Lara
dc.contributor.authorLiu, Yun
dc.contributor.authorRuhrmann, Sabrina
dc.contributor.authorZheleznyakova, Galina
dc.contributor.authorMarabita, Francesco
dc.contributor.authorGomez-Cabrero, David
dc.contributor.authorJames, Tojo
dc.contributor.authorEwing, Ewoud
dc.contributor.authorLindén, Magdalena
dc.contributor.authorGórnikiewicz, Bartosz
dc.contributor.authorAeinehband, Shahin
dc.contributor.authorStridh, Pernilla
dc.contributor.authorLink, Jenny
dc.contributor.authorAndlauer, Till F. M.
dc.contributor.authorGasperi, Christiane
dc.contributor.authorWiendl, Heinz
dc.contributor.authorZipp, Frauke
dc.contributor.authorGold, Ralf
dc.contributor.authorTackenberg, Björn
dc.contributor.authorWeber, Frank
dc.contributor.authorHemmer, Bernhard
dc.contributor.authorStrauch, Konstantin
dc.contributor.authorHeilmann-Heimbach, Stefanie
dc.contributor.authorRawal, Rajesh
dc.contributor.authorSchminke, Ulf
dc.contributor.authorSchmidt, Carsten O.
dc.contributor.authorKacprowski, Tim
dc.contributor.authorFranke, Andre
dc.contributor.authorLaudes, Matthias
dc.contributor.authorDilthey, Alexander T.
dc.contributor.authorCelius, Elisabeth G.
dc.contributor.authorSøndergaard, Helle B.
dc.contributor.authorTegner, Jesper
dc.contributor.authorHarbo, Hanne F.
dc.contributor.authorOturai, Annette B.
dc.contributor.authorOlafsson, Sigurgeir
dc.contributor.authorEggertsson, Hannes P.
dc.contributor.authorHalldorsson, Bjarni V.
dc.contributor.authorHjaltason, Haukur
dc.contributor.authorOlafsson, Elias
dc.contributor.authorJonsdottir, Ingileif
dc.contributor.authorStefansson, Kari
dc.contributor.authorOlsson, Tomas
dc.contributor.authorPiehl, Fredrik
dc.contributor.authorEkström, Tomas J.
dc.contributor.authorKockum, Ingrid
dc.contributor.authorFeinberg, Andrew P.
dc.contributor.authorJagodic, Maja
dc.date.accessioned2018-09-03T13:23:44Z
dc.date.available2018-09-03T13:23:44Z
dc.date.issued2018-06-19
dc.identifier.citationKular L, Liu Y, Ruhrmann S, Zheleznyakova G, Marabita F, et al. (2018) DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nature Communications 9. Available: http://dx.doi.org/10.1038/s41467-018-04732-5.
dc.identifier.issn2041-1723
dc.identifier.doi10.1038/s41467-018-04732-5
dc.identifier.urihttp://hdl.handle.net/10754/628438
dc.description.abstractThe human leukocyte antigen (HLA) haplotype DRB1 15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1 15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1 15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1 15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1 15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
dc.description.sponsorshipThis work was supported by grants from the Swedish Research Council, the Swedish Association for Persons with Neurological Disabilities, the Swedish Brain Foundation, the Swedish MS Foundation, Petrus and Augusta Hedlunds Foundation, the Swedish AFA Insurance, Knut and Alice Wallenberg Foundation, the Stockholm County Council (ALF project), and AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration). A.P.F. received grant support from NIH (DP1 ES022579). L.K. was supported by fellowship from the Margaretha af Ugglas Foundation. D.G.-C. and J.T. were supported by EU FP7 306000 STATegra. Y.L. was supported in part by the National Natural Science Foundation (grant no. 31471212). We acknowledge the International Multiple Sclerosis Genetics Consortium (IMSGC) for providing SNP genotypes used in this study and BEA core facility (Karolinska Institutet) for processing 450K array data on monocytes. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX). The Norwegian MS Registry and Biobank and the MS research group in Oslo are acknowledged for access to data from Norwegian MS patients. B.H. was supported by the German research foundation in the framework of the Collaborative research group TR128, the German MS competence network, and the EU project MultipleMS. This work was supported by the German Ministry for Education and Research (BMBF) as part of the “German Competence Network Multiple Sclerosis” (KKNMS) (grant nos. 01GI0916 and 01GI0917). F.Z., H.W., and R.G. were supported by the German research foundation in the framework of the Collaborative research group TR128, the German MS competence network. The KORA study was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the BMBF and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The collection of probands in the Heinz Nixdorf RECALL Study (HNR) (PIs: K.-H. Jöckel, R. Erbel) was supported by the Heinz Nixdorf Foundation. The genotyping of HNR probands was financed through a grant of the BMBF to M. M. Nöthen. The Dortmund Health Study was supported by the German Migraine and Headache Society (DMKG) and unrestricted grants of equal share from Almirall, AstraZeneca, Berlin-Chemie, Boehringer, Boots Healthcare, GlaxoSmithKline (GSK), Janssen-Cilag, McNeil Pharma, Merck Sharp & Dohme (MSD), and Pfizer to the University of Münster. Blood collection was done through funds from the Institute of Epidemiology and Social Medicine, University of Münster (K. Berger and J. Wellmann), genotyping was supported by the BMBF (grant no. 01ER0816). SHIP is part of the Community Medicine Research Network of the University Medicine Greifswald, Germany (www.community-medicine.de), which was initiated and funded by the BMBF (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania; genome-wide data have been supported by the BMBF (grant no. 03ZIK012). The FoCus study was supported by the BMBF (grant no. 0315540A).
dc.publisherSpringer Nature
dc.relation.urlhttp://link.springer.com/article/10.1038/s41467-018-04732-5
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleDNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.contributor.departmentBioscience Program
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.identifier.journalNature Communications
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 171 77, , Sweden
dc.contributor.institutionKey Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, 200032, , , China
dc.contributor.institutionCenter for Epigenetics, Departments of Medicine, Biomedical Engineering and Mental Health, Johns Hopkins University, Baltimore, MD, 21205, , United States
dc.contributor.institutionUnit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, 171 77, , Sweden
dc.contributor.institutionGerman Competence Network Multiple Sclerosis (KKNMS), Klinikum Rechts der Isar, Technische Universität München, Munich, 81675, , , Germany
dc.contributor.institutionDepartment of Neurology, Klinikum Rechts der Isar, School of Medicine, Technische Universität München, Munich, 81675, , , Germany
dc.contributor.institutionMax Planck Institute of Psychiatry, Munich, 80804, , Germany
dc.contributor.institutionDepartment of Neurology, Institute of Translational Neurology, University of Münster, D-Münster, 48149, , Germany
dc.contributor.institutionDepartment of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Mainz, 55122, , , Germany
dc.contributor.institutionDepartment of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, 44801, , , Germany
dc.contributor.institutionNeuroimmunology Center, Marburg University, Marburg, 35037, , Germany
dc.contributor.institutionMunich Cluster for Systems Neurology (SyNergy), Munich, 81377, , Germany
dc.contributor.institutionInstitute of Medical Informatics, Biometry, and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, 80539, , Germany
dc.contributor.institutionInstitute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, , Germany
dc.contributor.institutionInstitute of Human Genetics, University Hospital Bonn, Division of Genomics, Life and Brain Research Centre, University of Bonn School of Medicine, Bonn, 53113, , , Germany
dc.contributor.institutionInstitute of Epidemiology and Social Medicine, University of Münster, D-Münster, 48149, , Germany
dc.contributor.institutionDepartment of Neurology, University Medicine Greifswald, Greifswald, 17489, , Germany
dc.contributor.institutionInstitute for Community Medicine, University Medicine Greifswald, Greifswald, 17489, , Germany
dc.contributor.institutionInterfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University, University Medicine Greifswald, Greifswald, 17489, , Germany
dc.contributor.institutionInstitute of Clinical Molecular Biology, Kiel University, Kiel, 24105, , Germany
dc.contributor.institutionDepartment i of Internal Medicine, Kiel University, Kiel, 24105, , Germany
dc.contributor.institutionInstitute of Medical Microbiology, Hospital Hygiene Heinrich-Heine-University Düsseldorf, Düsseldorf, 40225, , Germany
dc.contributor.institutionWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, , , United Kingdom
dc.contributor.institutionInstitute of Health and Society, Faculty of Medicine, University of Oslo, Olso, 0450, , Norway
dc.contributor.institutionDepartment of Neurology, Oslo University Hospital, Oslo, 0372, , Norway
dc.contributor.institutionDanish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, 2100, , , Denmark
dc.contributor.institutionInstitute of Clinical Medicine, University of Oslo, Oslo, 0450, , Norway
dc.contributor.institutionDeCODE Genetics/Amgen Inc, Reykjavik, 101, , Iceland
dc.contributor.institutionSchool of Science and Engineering, Reykjavik University, Reykjavik, 101, , Iceland
dc.contributor.institutionFaculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, 101, , Iceland
dc.contributor.institutionDepartment of Neurology, Landspitali, National University of Iceland, Reykjavik, 101, , Iceland
dc.contributor.institutionDepartment of Immunology, Landspitali, National University Hospital of Iceland, Reykjavik, 101, , Iceland
kaust.personTegner, Jesper
refterms.dateFOA2018-09-06T12:49:29Z
dc.date.published-online2018-06-19
dc.date.published-print2018-12


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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.