Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

Nat Genet. 2009 Jul;41(7):776-82. doi: 10.1038/ng.401. Epub 2009 Jun 14.

Abstract

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / genetics*
  • Antigens, Differentiation, T-Lymphocyte / genetics*
  • Case-Control Studies
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Multiple Sclerosis / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Receptors, Tumor Necrosis Factor, Type I / genetics*

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD6 antigen
  • Interferon Regulatory Factors
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • interferon regulatory factor-8