title: Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects.
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.
authors.affiliation: 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.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Lisa F
authors.initials: LF
authors.lastname: Barcellos
authors.forename: Rogier Q
authors.initials: RQ
authors.lastname: Hintzen
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaefer
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Noble
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.forename: Jorge
authors.initials: J
authors.lastname: Oksenberg
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Bruce V
authors.initials: BV
authors.lastname: Taylor
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059868:HLA-DP beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; C093604:LST1 protein, human; C098080:MICB antigen; D008565:Membrane Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human