Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Sci Adv. 2016 Jun 17;2(6):e1501678. doi: 10.1126/sciadv.1501678. eCollection 2016 Jun.


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.

Keywords: DLEU1; DNA methylation; ERG; L3MBTL3; MAZ; Multiple sclerosis; SHMT1; genome-wide association study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Case-Control Studies
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic*
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Glycine Hydroxymethyltransferase / genetics
  • Humans
  • Male
  • Middle Aged
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology
  • Quantitative Trait Loci
  • Transcription Factors / genetics
  • Transcriptional Regulator ERG / genetics
  • Young Adult


  • DNA-Binding Proteins
  • ERG protein, human
  • L3MBTL3 protein, human
  • Transcription Factors
  • Transcriptional Regulator ERG
  • c-MYC-associated zinc finger protein
  • Glycine Hydroxymethyltransferase
  • SHMT protein, human