PMID- 24278027 OWN - NLM STAT- MEDLINE DCOM- 20140514 LR - 20220311 IS - 1553-7404 (Electronic) IS - 1553-7390 (Print) IS - 1553-7390 (Linking) VI - 9 IP - 11 DP - 2013 Nov TI - Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PG - e1003926 LID - 10.1371/journal.pgen.1003926 [doi] LID - e1003926 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. FAU - Patsopoulos, Nikolaos A AU - Patsopoulos NA AD - Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham & Women's Hospital, Boston, Massachusetts, United States of America ; Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Harvard Medical School, Boston, Massachusetts, United States of America ; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. FAU - Barcellos, Lisa F AU - Barcellos LF FAU - Hintzen, Rogier Q AU - Hintzen RQ FAU - Schaefer, Catherine AU - Schaefer C FAU - van Duijn, Cornelia M AU - van Duijn CM FAU - Noble, Janelle A AU - Noble JA FAU - Raj, Towfique AU - Raj T CN - IMSGC CN - ANZgene FAU - Gourraud, Pierre-Antoine AU - Gourraud PA FAU - Stranger, Barbara E AU - Stranger BE FAU - Oksenberg, Jorge AU - Oksenberg J FAU - Olsson, Tomas AU - Olsson T FAU - Taylor, Bruce V AU - Taylor BV FAU - Sawcer, Stephen AU - Sawcer S FAU - Hafler, David A AU - Hafler DA FAU - Carrington, Mary AU - Carrington M FAU - De Jager, Philip L AU - De Jager PL FAU - de Bakker, Paul I W AU - de Bakker PI LA - eng GR - R01 NS049477/NS/NINDS NIH HHS/United States GR - R01 AI076544/AI/NIAID NIH HHS/United States GR - R01NS026799/NS/NINDS NIH HHS/United States GR - R01 NS049510/NS/NINDS NIH HHS/United States GR - NIH/NINDS R01NS049510/NS/NINDS NIH HHS/United States GR - R01NS049477/NS/NINDS NIH HHS/United States GR - HHSN261200800001E/CA/NCI NIH HHS/United States GR - NIH/NIAID R01AI076544/PHS HHS/United States GR - R01NS0495103/NS/NINDS NIH HHS/United States GR - HHSN261200800001C/RC/CCR NIH HHS/United States GR - R01 NS026799/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131121 PL - United States TA - PLoS Genet JT - PLoS genetics JID - 101239074 RN - 0 (HLA-DP beta-Chains) RN - 0 (HLA-DPB1 antigen) RN - 0 (HLA-DRB1 Chains) RN - 0 (Histocompatibility Antigens Class I) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (LST1 protein, human) RN - 0 (MICB antigen) RN - 0 (Membrane Proteins) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (TNFRSF1A protein, human) SB - IM MH - Alleles MH - Chromosome Mapping MH - Genetic Predisposition to Disease MH - *Genome-Wide Association Study MH - HLA-DP beta-Chains/genetics MH - HLA-DRB1 Chains/*genetics MH - Haplotypes MH - Histocompatibility Antigens Class I/genetics MH - Humans MH - Intracellular Signaling Peptides and Proteins MH - Linkage Disequilibrium MH - Major Histocompatibility Complex/*genetics MH - Membrane Proteins/genetics MH - Multiple Sclerosis/*genetics/pathology MH - Polymorphism, Single Nucleotide MH - Receptors, Tumor Necrosis Factor, Type I/genetics PMC - PMC3836799 COIS- The authors have declared that no competing interests exist. FIR - Barcellos, Lisa IR - Barcellos L FIR - Bernardinelli, Luisa IR - Bernardinelli L FIR - Booth, David IR - Booth D FIR - Comabella, Manuel IR - Comabella M FIR - Compston, Alastair IR - Compston A FIR - D'Alfonso, Sandra IR - D'Alfonso S FIR - De Jager, Philip IR - De Jager P FIR - Fontaine, Bertrand IR - Fontaine B FIR - Goris, An IR - Goris A FIR - Hafler, David IR - Hafler D FIR - Haines, Jonathan IR - Haines J FIR - Harbo, Hanne IR - Harbo H FIR - Hauser, Steve IR - Hauser S FIR - Hawkins, Clive IR - Hawkins C FIR - Hemmer, Bernhard IR - Hemmer B FIR - Hintzen, Rogier IR - Hintzen R FIR - Ivinson, Adrian IR - Ivinson A FIR - Lill, Christina IR - Lill C FIR - Martin, Roland IR - Martin R FIR - Martinelli-Boneschi, Filippo IR - Martinelli-Boneschi F FIR - Oksenberg, Jorge IR - Oksenberg J FIR - Olsson, Tomas IR - Olsson T FIR - Oturai, Annette IR - Oturai A FIR - Palotie, Aarno IR - Palotie A FIR - Pericak-Vance, Margaret IR - Pericak-Vance M FIR - Saarela, Janna IR - Saarela J FIR - Sawcer, Stephen IR - Sawcer S FIR - Stewart, Graeme IR - Stewart G FIR - Taylor, Bruce IR - Taylor B FIR - Zipp, Frauke IR - Zipp F FIR - Scott, Rodney J IR - Scott RJ FIR - Lechner-Scott, Jeannette IR - Lechner-Scott J FIR - Moscato, Pablo IR - Moscato P FIR - Booth, David R IR - Booth DR FIR - Stewart, Graeme J IR - Stewart GJ FIR - Heard, Robert N IR - Heard RN FIR - Mason, Deborah IR - Mason D FIR - Griffiths, Lyn IR - Griffiths L FIR - Broadley, Simon IR - Broadley S FIR - Brown, Matthew A IR - Brown MA FIR - Slee, Mark IR - Slee M FIR - Foote, Simon J IR - Foote SJ FIR - Stankovich, Jim IR - Stankovich J FIR - Taylor, Bruce V IR - Taylor BV FIR - Wiley, James IR - Wiley J FIR - Bahlo, Melanie IR - Bahlo M FIR - Perreau, Victoria IR - Perreau V FIR - Field, Judith IR - Field J FIR - Butzkueven, Helmut IR - Butzkueven H FIR - Kilpatrick, Trevor J IR - Kilpatrick TJ FIR - Rubio, Justin IR - Rubio J FIR - Marriott, Mark IR - Marriott M FIR - Carroll, William M IR - Carroll WM FIR - Kermode, Allan G IR - Kermode AG EDAT- 2013/11/28 06:00 MHDA- 2014/05/16 06:00 PMCR- 2013/11/01 CRDT- 2013/11/27 06:00 PHST- 2013/04/23 00:00 [received] PHST- 2013/09/13 00:00 [accepted] PHST- 2013/11/27 06:00 [entrez] PHST- 2013/11/28 06:00 [pubmed] PHST- 2014/05/16 06:00 [medline] PHST- 2013/11/01 00:00 [pmc-release] AID - PGENETICS-D-13-01062 [pii] AID - 10.1371/journal.pgen.1003926 [doi] PST - ppublish SO - PLoS Genet. 2013 Nov;9(11):e1003926. doi: 10.1371/journal.pgen.1003926. Epub 2013 Nov 21.