Novel Multiple Sclerosis Genetic Risk Factors Are Involved in Epigenetic Regulation

Objective: To further unravel the genetic contribution to disease susceptibility in Multiple Sclerosis by analyzing a population with limited substructure.Background: The known genetic variants affecting susceptibility of Multiple Sclerosis account for about 25 [percnt] of disease heritability.Methods: We conducted a genome-wide association study (GWAS) on multiple sclerosis susceptibility in two German cohorts with overall 4.888 cases and 10.395 controls.Results: The MHC locus and 15 non-MHC loci, of whom 5 have not been established so far, reached genome-wide significance. Two of the novel variants replicated in an independent Sardinian cohort of 2.093 cases and 2.880 controls. The five novel loci map to the genes L3MBTL3, MAZ, ERG, DLEU1, and SHMT1. The first four novel genes play important roles in immune cell regulation and intersect with epigenetic pathways. SHMT1 catalyzes the transfer of a carbon unit in the folate cycle, a reaction required for regulation of methylation homeostasis, important for establishment and maintenance of epigenetic signatures.Conclusions: Our GWAS approach in a defined population with limited substructure allowed identification of associations not found in larger, more heterogeneous cohorts, and thus provides new clues to the pathogenesis of MS. Disclosure: Dr. Buck has nothing to disclose. Dr. Andlauer has nothing to disclose. Dr. Bayas has received personal compensation for activities with Merck Serono, Biogen-Idec, Novartis and Sanofi/Genzyme as a speaker/consultant. Dr. Berger has received research support from the German Migraine and Headache Society. Dr. Berthele has nothing to disclose. Dr. Binder has nothing to disclose. Dr. Dankwoski has nothing to disclose. Dr. Franke has nothing to disclose. Dr. Gold has received research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Herms has nothing to disclose. Dr. Homuth has nothing to disclose. Dr. Joeckel has nothing to disclose. Dr. Kacprowski has nothing to disclose. Dr. Kieseier holds stock and/or stock options in Biogen, which sponsored research in which Dr. Kieseier was involved as an investigator. Dr Kumpfel has received personal compensation for activities with Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis Pharma, Sanofi-Aventis, Genzyme, and Biogen-Idec. Dr. Laudes has nothing to disclose. Dr. Lieb has nothing to disclose. Dr. Limmroth has received personal compensation for activities with Bayer Pharmaceuticals Inc., Biogen Idec, Novartis, Roche Diagnostics Corp., Sanofi-Aventis Pharmaceuticals Inc., and Teva Neuroscience. Dr. Linker has nothing to disclose. Dr. Moebus has nothing to disclose. Dr. Mueller-Nurasyid has nothing to disclose. Dr. Mulas has nothing to disclose. Dr. Noethen has nothing to disclose. Dr. Paul has received personal compensation for activities with Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Bayer Schering Pharma, Merck Serono, Biogen Idec, Medimmune, and Novartis. Dr. Stangel has received personal compensation for activities with Bayer HealthCare. Dr. Stellmann has nothing to disclose. Dr. Strauch has nothing to disclose. Dr. Tackenberg has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Tackenberg has received research support. Dr. Then Bergh has received personal compensation for activities with Biogen Idec, Novartis, Merck Serono, and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker and/or advisory board member. Dr. Tumani has received personal compensation for activities with Bayer Pharmaceuticals, Inc., Biogen Idec, Merck Serono, Teva Neuroscience, Roche Diagnostics Corporation, Genzyme Corporation, and Virotech. Dr. Weber has received personal compensation for activities with Genzyme, Novartis, and Merck-Serono. Dr. Weber has nothing to disclose. Dr. Wiendl has received research support from Bayer HealthCare, Biogen Idec, the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, and the Else Kroner Fresenius Foundation. Dr. Wildemann has received personal compensation for activities with Biogen Idec, Merck Serono, Teva Neuroscience, and Genzyme Corporation. Dr. Zettl has received personal compensation for activities with Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi, Almirall, and Teva. Dr. Ziegler has nothing to disclose. Dr. Ziemann has nothing to disclose. Dr. Zipp has received personal compensation for activities with Teva, Novartis, Merck Serono, Bayer, Johnson u0026 Johnson, Ono Pharma, Octapharma, and Sanofi. Dr. Cucca has nothing to disclose. Dr. Muller-Myhsok has nothing to disclose. Dr. Hemmer has received personal compensation for activities with Roche, Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai, Micromet and Genzyme Corporation as a scientific advisory board member.