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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.

Original publication

DOI

10.1371/journal.pgen.1003926

Type

Journal article

Journal

PLoS genetics

Publication Date

21/11/2013

Volume

9

Addresses

Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America ; Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America ; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

Keywords

IMSGC, ANZgene, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Membrane Proteins, Receptors, Tumor Necrosis Factor, Type I, Histocompatibility Antigens Class I, Chromosome Mapping, Major Histocompatibility Complex, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Genome-Wide Association Study, HLA-DRB1 Chains, HLA-DP beta-Chains