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For a full list of authors please see publication

Email: hemmer@tum.de (B.H.)

Email:bmm@psych.mpg.de (B.M.-M.)

Conception and design: T.F.M.A., D.B., A.Z., B.H., and B.M.-M.

Recruitment of German cases: D.B., G.A., A. Bayas, L. Bechmann, A. Berthele, A.C., C. Gasperi, R.G., C. Graetz, J.H., M.H., C.I.-D., M.K., T. Kümpfel, V. Limmroth, R.A.L., V. Loleit, F.L., S.G. Meuth, M.M., S.N., F.P., M. Pütz, T.R., A.S., M. Stangel, J.-P.S., K.H. Stürner, B.T., F.T.B., H.T., C.W., F.W., H.W., B.W., U.K. Zettl, U. Ziemann, F.Z., and B.H.

Acquisition of genotype or expression data of German cases (DE1): P.W., M.R.-B., P.L., T.B., and F.W.

German control cohorts: K.B., L. Bertram, A.F., C. Gieger, S.H., G.H., M.I., K.-H.J., S.K., T. Kacprowski, M.L., W.L., C.L., S.L., T.M., S. Moebus, M.M.-N, M.N., A.P., R.R., K. Strauch, U.S., H.V., M.W., and J.W.

Provided replication data (Sardinian cohort): A.M., M. Pitzalis, E.P., C.S., I.Z., F.C., and M.Z.

Analysis and interpretation of data: T.F.M.A., D.B., J.A., M.O.S., T.D., A.Z., D.C., T.C.-R., E.B., B.H., and B.M.-M

Drafting or revising the manuscript: T.F.M.A., D.B., F.C., M.Z., B.H., and B.M.-M.

We thank V. Grummel, J. Hornung, and N. Miksch for technical assistance as well as N. Provençal and S. Ripke for scientific discussions.

This study makes use of data generated by the WTCCC.

A full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk.

For full list of Competing Interests, please see Publication.

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Research Funding:

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).

D.B., B.H., F.Z., and H.W. were supported by the German Research Foundation (DFG) (grant no. CRC128).

Funding for the WTCCC project was provided by the Wellcome Trust under awards 076113 and 085475.

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.

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).

The FoCus study was supported by the BMBF (grant no. 0315540A).

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 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 PopGen 2.0 network is supported by a grant from the BMBF (grant no. 01EY1103).

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).

Keywords:

  • DLEU1
  • DNA methylation
  • ERG
  • L3MBTL3
  • MAZ
  • Multiple sclerosis
  • SHMT1
  • Genome-wide association study

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

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Journal Title:

Science Advances

Volume:

Volume 2, Number 6

Publisher:

, Pages e1501678-e1501678

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2016, The Authors

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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