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

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., ANZgene and Brown, Matthew A. (2013) Fine-mapping the genetic association of the major histocompatibility complex in Multiple sclerosis: HLA and non-HLA effects. PLoS Genetics, 9 11: . doi:10.1371/journal.pgen.1003926


Author 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.
ANZgene
Brown, Matthew A.
Title Fine-mapping the genetic association of the major histocompatibility complex in Multiple sclerosis: HLA and non-HLA effects
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
1553-7404
Publication date 2013-11-21
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1003926
Open Access Status DOI
Volume 9
Issue 11
Total pages 10
Place of publication San Francisco, United States
Publisher Public Library of Science
Language eng
Formatted abstract
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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