PLoS Genetics (Nov 2013)

Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.

  • Nikolaos A Patsopoulos,
  • Lisa F Barcellos,
  • Rogier Q Hintzen,
  • Catherine Schaefer,
  • Cornelia M van Duijn,
  • Janelle A Noble,
  • Towfique Raj,
  • IMSGC,
  • ANZgene,
  • Pierre-Antoine Gourraud,
  • Barbara E Stranger,
  • Jorge Oksenberg,
  • Tomas Olsson,
  • Bruce V Taylor,
  • Stephen Sawcer,
  • David A Hafler,
  • Mary Carrington,
  • Philip L De Jager,
  • Paul I W de Bakker

DOI
https://doi.org/10.1371/journal.pgen.1003926
Journal volume & issue
Vol. 9, no. 11
p. e1003926

Abstract

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The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.