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Cited by 312Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyPsoriasis: Treatment and Pathogenesis

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

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Patsopoulos, Nikolaos A., Barcellos, Lisa F., Hintzen, Rogier Q., Schaefer, Catherine, van Duijn, Cornelia M., Noble, Janelle A., Raj, Towfique, IMSGC, ANZgene, 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.·2013·PLoS Genetics
DOI 10.1371/journal.pgen.1003926PMC PMC3836799
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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.

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Figure 1 Association plots for the analyzed variants and HLA genes. Panels on the left are regional association plots for all variants in the MHC region; each diamond is a polymorphism evaluated in the analysis (SNP, HLA type, amino acid). The index variant that best captures the effect of each locus is highlighted with a larger diamond. Variants that are in LD with the index variant are colored, with the intensity of the color being proportional to the extent of LD. The panels on the right plot the −log10(p-value) of the eight analyzed HLA genes. The order of the genes is based on their position on chromosome 6. The rows represent univariate analysis (A, B), conditioning on six HLA-DRB1 alleles (*15:01, *03:01, *13:03, *04:04, *04:01, and *14:01) (C, D), conditioning on the above and HLA-A*02:01 (E, F), conditioning on the above and the DPB1 effect (G, H), conditioning on the above and rs2516489 (I, J), conditioning on the above and B*37:01 (K, L), conditioning on the above and B*38:01 (M, N). In panels M and N the solid black line marks the threshold of statistical significance in the study.
Figure 1 Association plots for the analyzed variants and HLA genes. Panels on the left are regional association plots for all variants in the MHC region; each diamond is a polymorphism evaluated in the analysis (SNP, HLA type, amino acid). The index variant that best captures the effect of each locus is highlighted with a larger diamond. Variants that are in LD with the index variant are colored, with the intensity of the color being proportional to the extent of LD. The panels on the right plot the −log10(p-value) of the eight analyzed HLA genes. The order of the genes is based on their position on chromosome 6. The rows represent univariate analysis (A, B), conditioning on six HLA-DRB1 alleles (*15:01, *03:01, *13:03, *04:04, *04:01, and *14:01) (C, D), conditioning on the above and HLA-A*02:01 (E, F), conditioning on the above and the DPB1 effect (G, H), conditioning on the above and rs2516489 (I, J), conditioning on the above and B*37:01 (K, L), conditioning on the above and B*38:01 (M, N). In panels M and N the solid black line marks the threshold of statistical significance in the study.CC0 · PubMed Central
Figure 2 3D ribbon models for HLA DR, HLA A, HLA DP and HLA B. All structures are positioned to accommodate the view of the peptide-binding groove and the associated amino acid residues. The Protein Data Bank entries 3pdo, 1a1m, 3lqz, and 2bvp were used to produce the 3D structures, respectively, using UCSF Chimera [49].
Figure 2 3D ribbon models for HLA DR, HLA A, HLA DP and HLA B. All structures are positioned to accommodate the view of the peptide-binding groove and the associated amino acid residues. The Protein Data Bank entries 3pdo, 1a1m, 3lqz, and 2bvp were used to produce the 3D structures, respectively, using UCSF Chimera [49].CC0 · PubMed Central
Figure 3 Functional annotation of the MICB-LST1. The first 6 rows are H3K4me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line (B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Barr Virus). The next 5 rows display H3K27ac (blue) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line, respectively. Then there are the H3K36me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line. The chomatin states displayed are for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line. The DNase hypersensitivity sites are for CD4 primary cells, CD8 primary cells, CD14+ monocytes, Treg, Th1, Th2, Th17 and GM12878 cell line, respectively. The detailed colorscheme of the chromatin states is listed in the Supplementary material. Briefly, red corresponds to transcription start sites (TSSs) and/or active promoters, orange/yellow to enhancers, green to transcription, and white/grey to heterochromain. All data are publicly available data from ENCODE and NIH Roadmap. The last row displays the −log10(p) of the SNPs in the LD block after adjustment with the HLA-DRB1*15:01 effect.
Figure 3 Functional annotation of the MICB-LST1. The first 6 rows are H3K4me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line (B-lymphocyte, lymphoblastoid, International HapMap Project - CEPH/Utah - European Caucasion, Epstein-Barr Virus). The next 5 rows display H3K27ac (blue) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line, respectively. Then there are the H3K36me3 (green) data for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, Treg primary cells, and GM12878 cell line. The chomatin states displayed are for CD4 memory primary cells, CD4 naïve primary cells, CD8 memory primary cells, CD8 naïve primary cells, and GM12878 cell line. The DNase hypersensitivity sites are for CD4 primary cells, CD8 primary cells, CD14+ monocytes, Treg, Th1, Th2, Th17 and GM12878 cell line, respectively. The detailed colorscheme of the chromatin states is listed in the Supplementary material. Briefly, red corresponds to transcription start sites (TSSs) and/or active promoters, orange/yellow to enhancers, green to transcription, and white/grey to heterochromain. All data are publicly available data from ENCODE and NIH Roadmap. The last row displays the −log10(p) of the SNPs in the LD block after adjustment with the HLA-DRB1*15:01 effect.CC0 · PubMed Central

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Metadata

Authors
Patsopoulos, N. A., Barcellos, L. F., Hintzen, R. Q., Schaefer, C., van Duijn, C. M., Noble, J. A., Raj, T., IMSGC, ANZgene, Gourraud, P.-A., Stranger, B. E., Oksenberg, J., Olsson, T., Taylor, B. V., Sawcer, S., Hafler, D. A., Carrington, M., De Jager, P. L., & de Bakker, P. I. W.
Affiliations
  • Broad Institute (US)
  • Kaiser Permanente (US)
  • Erasmus MC (NL)
  • University of California, San Francisco (US)
  • University of Chicago (US)
  • Karolinska Institutet (SE)
  • University of Tasmania (AU)
  • University of Cambridge (GB)
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2013-11-21
Volume
9
Issue
11
Pages
e1003926
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1003926
PMC
PMC3836799
OpenAlex
W2164021954
Cited by
312
References
50
Citations by year
2026: 19 · 2025: 14 · 2024: 23 · 2023: 19 · 2022: 17 · 2021: 32 · 2020: 30 · 2019: 32 · 2018: 26 · 2017: 21 · 2016: 27 · 2015: 28 · 2014: 22 · 2013: 1
FWCI
19.49
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (acceptedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, other-oa)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • eCite Digital Repository (University of Tasmania) (submittedVersion, public-domain)
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  • Murdoch University Research Portal (submittedVersion)
  • Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, public-domain)
  • Figshare (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • University of Chicago
Funders
  • U.S. Department of Health and Human Services (HHSN261200800001E)
  • National Multiple Sclerosis Society (JF2138A1)
  • John T. Reid Charitable Trusts
  • Frederick National Laboratory for Cancer Research (HHSN261200800001E.)
  • National Institute for Health and Care Research (NF-SI-0508-10335)
  • Multiple Sclerosis Society
  • Multiple Sclerosis Australia
  • Forskningsrådet för Arbetsliv och Socialvetenskap
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.126.354)
  • Stockholms Läns Landsting (562183)
  • Vetenskapsrådet
  • Trish Multiple Sclerosis Research Foundation
  • National Institutes of Health (Contract No. HHSN261200800001E., #HHSN261200800001E, HHSN261200800001C)
  • U.S. Public Health Service (NIH/NIAID R01AI076544)
  • Australian Research Council (LP0776744)
  • National Cancer Institute (HHSN261200800001E))
  • National Institute of Allergy and Infectious Diseases (HHSN261200800001E, R01AI076544)
  • National Institute of Neurological Disorders and Stroke (R01 NS0495103, R01NS026799, R01NS049510, NIH/NINDS R01NS049510, R01NS049477)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
multiple sclerosis, major histocompatibility complex, HLA-DRB1*1501, TNF-α, TNFRSF1A, disease susceptibility, fine mapping
MeSH terms
Alleles, Chromosome Mapping, Haplotypes, Humans, Major Histocompatibility Complex, Membrane Proteins, Multiple Sclerosis, Histocompatibility Antigens Class I, Linkage Disequilibrium, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Type I, Intracellular Signaling Peptides and Proteins, Genome-Wide Association Study, HLA-DRB1 Chains, HLA-DP beta-Chains

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