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

• Published in: PLoS genetics Vol. 9; no. 11; p. e1003926
• Main Authors: Patsopoulos, Nikolaos A, Barcellos, Lisa F, Hintzen, Rogier Q, Schaefer, Catherine, van Duijn, Cornelia M, Noble, Janelle A, Raj, Towfique, Gourraud, Pierre-Antoine, Stranger, Barbara E, Oksenberg, Jorge, Olsson, Tomas, Taylor, Bruce V, Sawcer, Stephen, Hafler, David A, Carrington, Mary, De Jager, Philip L, de Bakker, Paul I W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-11-2013; Public Library of Science (PLoS)
• Subjects: Alleles; Amino acids; Biomedical research; Chromosome Mapping; Councils; Genetic aspects; Genetic Predisposition to Disease; Genetic screening; Genome-Wide Association Study; Genomes; Haplotypes; Health aspects; Histocompatibility antigens; Histocompatibility Antigens Class I - genetics; HLA histocompatibility antigens; HLA-DP beta-Chains - genetics; HLA-DRB1 Chains - genetics; Humans; Intracellular Signaling Peptides and Proteins; Linkage Disequilibrium; Major histocompatibility complex; Major Histocompatibility Complex - genetics; Medical research; Medicin och hälsovetenskap; Membrane Proteins - genetics; Methods; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Physiological aspects; Polymorphism, Single Nucleotide; Receptors, Tumor Necrosis Factor, Type I - genetics; Studies; Netherlands
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003926

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.