Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Authors:
Till F M Andlauer, Dorothea Buck, Gisela Antony, Antonios Bayas, Lukas Bechmann, Achim Berthele, Andrew Chan, Christiane Gasperi, Ralf Gold, Christiane Graetz, Jürgen Haas, Michael Hecker, Carmen Infante-Duarte, Matthias Knop, Tania Kümpfel, Volker Limmroth, Ralf A Linker, Verena Loleit, Felix Luessi, Sven G Meuth, Mark Mühlau, Sandra Nischwitz, Friedemann Paul, Michael Pütz, Tobias Ruck, Anke Salmen, Martin Stangel, Jan-Patrick Stellmann, Klarissa H Stürner, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Clemens Warnke, Frank Weber, Heinz Wiendl, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Frauke Zipp, Janine Arloth, Peter Weber, Milena Radivojkov-Blagojevic, Markus O Scheinhardt, Theresa Dankowski, Thomas Bettecken, Peter Lichtner, Darina Czamara, Tania Carrillo-Roa, Elisabeth B Binder, Klaus Berger, Lars Bertram, Andre Franke, Christian Gieger, Stefan Herms, Georg Homuth, Marcus Ising, Karl-Heinz Jöckel, Tim Kacprowski, Stefan Kloiber, Matthias Laudes, Wolfgang Lieb, Christina M Lill, Susanne Lucae, Thomas Meitinger, Susanne Moebus, Martina Müller-Nurasyid, Markus M Nöthen, Astrid Petersmann, Rajesh Rawal, Ulf Schminke, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Jürgen Wellmann, Eleonora Porcu, Antonella Mulas, Maristella Pitzalis, Carlo Sidore, Ilenia Zara, Francesco Cucca, Magdalena Zoledziewska, Andreas Ziegler, Bernhard Hemmer, Bertram Müller-Myhsok
Year of publication:
2016
Volume:
2
Issue:
6
Issn:
2375-2548
Journal title abbreviated:
Sci Adv
Journal title long:
Science advances
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.