Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

NA Patsopoulos, LF Barcellos, Rogier Hintzen, C Schaefer, Cornelia Duijn, JA Noble, T Raj, PA Gourraud, BE Stranger, J Oksenberg, T Olsson, BV Taylor, S Sawcer, DA Hafler, M Carrington, PL De Jager, PIW de Bakker

Research output: Contribution to journalArticleAcademicpeer-review

191 Citations (Scopus)
3 Downloads (Pure)

Abstract

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLADRB1* 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 languageUndefined/Unknown
JournalPLoS Genetics (print)
Volume9
Issue number11
DOIs
Publication statusPublished - 2013

Cite this