Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

• Type of Material: Article
• Authors: Till F. M. Andlauer, Max Planck Institute of Psychiatry; Dorothea Buck, Technical University of Munich; Gisela Antony, Philipps University Marburg; Antonios Bayas, Klinikum Augsburg; Lukas Bechmann, University of Leipzig; Achim Berthele, Technical University of Munich; Andrew Chan, Ruhr-University Bochum; Christiane Gasperi, Technical University of Munich; Ralf Gold, Ruhr-University Bochum; Christiane Graetz, University Medical Center of the Johannes Gutenberg University Mainz; Elisabeth Binder, Emory University
• Language: English
• Date: 2016-06-17
• Publisher: American Association for the Advancement of Science: Science Advances
• Publication Version: Final Published Version
• Copyright Statement: © 2016, The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.1501678
• Title of Journal or Parent Work: Science Advances
• ISSN: 2375-2548
• Volume: 2
• Issue: 6
• Start Page: e1501678
• End Page: e1501678
• Grant/Funding Information: 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) and the Munich Cluster for Systems Neurology (SyNergy).; 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 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 Heinz Nixdorf Recall study was supported by the Heinz Nixdorf Foundation Germany, the BMBF, and the DFG (ER 155/6-1 and ER 155/6-2).; The collection of sociodemographic and clinical data in 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.; D.B., B.H., F.Z., and H.W. were supported by the German Research Foundation (DFG) (grant no. CRC128).; The FoCus study was supported by the BMBF (grant no. 0315540A).; Blood collection in the Dortmund Health Study was done through funds from the Institute of Epidemiology and Social Medicine University of Münster; genotyping was supported by the BMBF (grant no. 01ER0816).; SHIP is part of the Community Medicine Research Network of the University Medicine Greifswald (www.community-medicine.de), which was initiated and funded by the BMBF and the State of Mecklenburg-Pomerania; genome-wide data have been supported by the BMBF (grant no. 03ZIK012).; Funding for the WTCCC project was provided by the Wellcome Trust under awards 076113 and 085475.; The PopGen 2.0 network is supported by a grant from the BMBF (grant no. 01EY1103).
• Keywords: ERG; MAZ; Multiple sclerosis; L3MBTL3; DNA methylation; SHMT1; DLEU1; Genome-wide association study
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Epidemiology

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.