TY - JOUR
T1 - Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis
T2 - HLA and Non-HLA Effects
AU - Patsopoulos, Nikolaos A.
AU - Barcellos, Lisa F.
AU - Hintzen, Rogier Q.
AU - Schaefer, Catherine
AU - van Duijn, Cornelia M.
AU - Noble, Janelle A.
AU - Raj, Towfique
AU - International Multiple Sclerosis Genetics Consortium
AU - Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene)
AU - Gourraud, Pierre Antoine
AU - Stranger, Barbara E.
AU - Oksenberg, Jorge
AU - Olsson, Tomas
AU - Taylor, Bruce V.
AU - Sawcer, Stephen
AU - Hafler, David A.
AU - Carrington, Mary
AU - De Jager, Philip L.
AU - de Bakker, Paul I.W.
AU - Bernardinelli, Luisa
AU - Booth, David R.
AU - Comabella, Manuel
AU - Compston, Alastair
AU - D'Alfonso, Sandra
AU - Fontaine, Bertrand
AU - Goris, An
AU - Haines, Jonathan
AU - Harbo, Hanne
AU - Hauser, Steve
AU - Hawkins, Clive
AU - Hemmer, Bernhard
AU - Ivinson, Adrian
AU - Lill, Christina
AU - Martin, Roland
AU - Martinelli-Boneschi, Filippo
AU - Oturai, Annette
AU - Palotie, Aarno
AU - PericakVance, Margaret
AU - Saarela, Janna
AU - Stewart, Graeme
AU - Zipp, Frauke
AU - Scott, Rodney J.
AU - Lechner-Scott, Jeannette
AU - Moscato, Pablo
AU - Booth, David R.
AU - Stewart, Graeme J.
AU - Heard, Robert N.
AU - Mason, Deborah
AU - Griffiths, Lyn
AU - Broadley, Simon
AU - Brown, Matthew A.
AU - Slee, Mark
AU - Foote, Simon J.
AU - Stankovich, Jim
AU - Wiley, James
AU - Bahlo, Melanie
AU - Perreau, Victoria
AU - Field, Judith
AU - Butzkueven, Helmut
AU - Kilpatrick, Trevor J.
AU - Rubio, Justin
AU - Marriott, Mark
AU - Carroll1, William M.
AU - Kermode, Allan G.
N1 - Unless otherwise indicated, articles and accompanying materials published by PLOS on the PLOS Sites, including peer reviews, are licensed by the respective authors for use and distribution by you subject to citation of the original source in accordance with the Creative Commons Attribution (CC BY) license.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84888231843&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003926
DO - 10.1371/journal.pgen.1003926
M3 - Article
C2 - 24278027
AN - SCOPUS:84888231843
SN - 1553-7390
VL - 9
JO - PloS Genetics
JF - PloS Genetics
IS - 11
M1 - e1003926
ER -