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, International Multiple Sclerosis Genetics Consortium, Australian and New Zealand Multiple Sclerosis Genetics Consortium (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

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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 languageEnglish
Article numbere1003926
JournalPloS Genetics
Issue number11
Publication statusPublished - 1 Nov 2013

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