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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Open accessAbstract
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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“The role of the adaptive arm of the immune system, particularly its CD4+ T cell component has become clearer, with multiple different T cell subsets being implicated.(4)”
From Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility (2019) · cites this paper as [4]
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“the role of B cells, dendritic cells and natural killer cells has emerged more clearly, broadening the prior narrative of T cell dysregulation that emerged from earlier studies.(4)”
From Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility (2019) · cites this paper as [4]
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“published efforts to systematically interrogate severity have, thus far, only involved modest numbers of cases, and unanimously fall short of identifying any convincingly associated genetic variants5,10,11.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [5]
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“refinement of the associations in the HLA region showed that just four variants are sufficient to account for the risk previously attributed to extended haplotype alleles spanning hundreds of kilobases (kb) and many tens of genes.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [43]
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“the GWAS enrichment studies all point to risk being mediated by gene regulation in CD4+ T cells43”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [43]
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“Several studies have explored the genetic basis of clinical course, age of onset and severity, although no genome‐wide significant associations have been discovered.36, 37, 43, 74, 75, 76, 77”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [43]
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“Although these risk variants have been found to reduce the age at onset5, it is notable that they do not appear to have any impact on disease severity6.”
From Locus for severity implicates CNS resilience in progression of multiple sclerosis (2023) · cites this paper as [5]
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“A further expansion of the IMSGC resulted in a collaborative GWAS of 9772 cases and 17 376 controls, again of European descent, in 2011.43 This study replicated 23 of 26 previously identified associations and identified 29 novel risk loci.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [43]
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“it became evident that these loci are strongly enriched for genes acting in T‐cell activation and proliferation pathways.”
From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [43]
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Metadata
- Authors
- The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2
- Venue
- Nature
- Published
- 2011-08
- Volume
- 476
- Issue
- 7359
- Pages
- 214-219
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3182531
- OpenAlex
- W2040547343
- Cited by
- 2,697
- References
- 26
- Citations by year
- 2026: 72 · 2025: 101 · 2024: 112 · 2023: 111 · 2022: 136 · 2021: 155 · 2020: 167 · 2019: 173 · 2018: 178 · 2017: 215 · 2016: 220 · 2015: 273 · 2014: 244 · 2013: 279 · 2012: 223
- FWCI
- 175.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Keele Research Repository (Keele University) (submittedVersion, cc-by)
- PEARL (University of Plymouth) (submittedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Griffith Research Online (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Faculty of Health; Institute of Health and Biomedical Innovation
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Susan G. Komen for the Cure
- Biogen
- Kaiser Permanente
- Children's Hospital of Philadelphia
- Fondazione CRT
- Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques
- Institute of Clinical and Translational Sciences
- Scleroseforeningen
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Wellcome Trust (085475/Z/08/Z, 068545/Z/02), 085475, G0000934, 075491, 068545, 075491/Z/04,, 090532, 085475/B/08/Z, 084702)
- National Institute for Health and Care Research (G0000934, NF-SI-0507-10379, PDA/02/06/016)
- Parkinson's UK (G0909, J‐0804)
- Multiple Sclerosis Society (898/08)
- Multiple Sclerosis Australia
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche (ANR-10-INBS-0001)
- Institut National de la Santé et de la Recherche Médicale
- Forskningsrådet för Arbetsliv och Socialvetenskap
- Academy of Finland
- Fonds Wetenschappelijk Onderzoek
- Ministero della Salute (502/92, D.lgs 502/92)
- Hjärnfonden
- Knut och Alice Wallenbergs Stiftelse
- Stockholms Läns Landsting (562183)
- Norges Forskningsråd
- Regione Piemonte (502/92)
- Haukeland Universitetssjukehus
- Vlaamse regering
- National Institutes of Health (5r01ns019142-03, G0000934, 075491/Z/04, 068545/Z/02, UL1TR000448, NS43559, NS19142, RR024992, CA104021, NS049477)
- U.S. Public Health Service (K23N/S048869)
- Medical Research Council (MC_EX_G0800860, 068545/Z/02, G0000934)
- National Health and Medical Research Council (G0000934)
- Helmholtz Zentrum München
- National Cancer Institute (R01CA104021, CA104021)
- National Institute of Allergy and Infectious Diseases (AI076544, R01AI076544)
- Fogarty International Center (K01TW009996)
- National Institute of Neurological Disorders and Stroke (NS067305, NS26799, NS 43559, NS032830, NS049477, NS19142, R01NS032830, R01NS043559, R01NS026799, R01NS049510, R01NS067305, NS049510, R01NS049477)
- National Center for Research Resources (RR020092, C06RR020092, RR-024992, UL1RR024992)
- National Center for Advancing Translational Sciences
- 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, genetic susceptibility, genome-wide association study, major histocompatibility complex, T helper cell differentiation, cell-mediated immunity, neuroinflammation, neurodegeneration, pathogenesis, genetic susceptibility loci
- MeSH terms
- Alleles, Cell Differentiation, Europe, T-Lymphocytes, Helper-Inducer, HLA-DR Antigens, Humans, Immunity, Cellular, Major Histocompatibility Complex, Multiple Sclerosis, HLA-A Antigens, Genome, Human, Sample Size, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, HLA-DRB1 Chains
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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