Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
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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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The nature of the interaction may be more complicated than expected, with multiple different amino acid-level alleles demonstrating consistent interaction with HLA-DRB1*15:01, in addition to the HLA-DQA1*01:01 allele.
“However, the nature of the interaction may be more complicated than expected, with multiple different amino acid‐level alleles demonstrating consistent interaction with HLA‐DRB1*15:01, in addition to the HLA‐DQA1*01:01 allele.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [51]
The Results section on amino acid residues in DRβ1 identifies several associated amino acid positions, and the Discussion says the DRB1 effect is more complex than a single amino acid model can explain. But these passages do not demonstrate consistent interactions between amino acid-level alleles and DRB1*15:01. The Results section on multi-allelic association discusses DQA1*01:02, not the claimed DQA1*01:01, and says its effect could be explained by DRB1*15:01 (page numbers unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe DR15 haplotype and its component alleles also associate with protection against diabetes, a high risk for multiple sclerosis, and risk or protective effects with many other immune-mediated diseases.
“the DR15 haplotype and its component alleles also associate with protection against diabetes108, a high risk for multiple sclerosis109,110, and risk or protective effects with many other immune-mediated diseases”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [109]
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Self-citation
- 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
- 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 · 2012: 1
- FWCI
- 19.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- 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)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- 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 › Pathology and Forensic Medicine › 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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