Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2

doi:10.1038/nature10251

Cited by 2,697Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyPsoriasis: Treatment and Pathogenesis

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Open access

The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2·2011·Nature

DOI 10.1038/nature10251PMC PMC3182531

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Abstract

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 in MS.
“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]
The paper’s pathway analysis reports MS-associated genes involved in T-cell activation and T-helper-cell differentiation, supporting a role for adaptive immunity and T cells. The cited passages do not identify multiple distinct T-cell subsets implicated in MS, so that part of the sentence is not supported. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The role of B cells, dendritic cells, and natural killer cells has emerged more clearly, broadening the prior narrative of T cell dysregulation from earlier studies.
“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]
The paper’s pathway analysis (section labeled Abstract; page unavailable) reports enrichment of genes involved in T-cell activation and proliferation and implicates T-helper-cell differentiation in multiple sclerosis. That supports the T-cell part of the sentence, but the passages do not identify emerging roles for B cells, dendritic cells, or natural killer cells. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Published efforts to systematically interrogate MS severity have only involved modest numbers of cases and have not identified any convincingly associated genetic variants.
“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]
The paper reports that its analysis found no evidence of genetic associations with MS severity (Abstract; page unavailable), supporting the claim about the absence of convincing variants in this study. It does not establish that published severity studies involved only modest numbers of cases; its reference to modestly powered studies concerns disease susceptibility, not severity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Refinement of 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 and many tens of genes.
“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]
The MHC association analysis (section labelled Abstract; page unavailable) identifies four principal HLA allele signals through stepwise conditioning, supporting the refinement described. It also reports additional independent SNP signals, so it does not establish that just four variants are sufficient to account for all the risk attributed to extended haplotypes. The cited passage does not specify the haplotypes’ length or gene count. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Genome-wide association study enrichment studies all point to multiple sclerosis risk being mediated by gene regulation in CD4+ T cells.
“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]
The paper’s enrichment analysis (section labeled Abstract; no page supplied) finds MS-associated regions enriched for genes involved in T-cell activation and proliferation, and its pathway analysis implicates T-helper-cell differentiation. It does not establish that risk is mediated by gene regulation specifically in CD4+ T cells; it says the functional mechanisms underlying the associations remain to be uncovered. (LLM, conf=0.86)
Experimental — accuracy not yet measured

Several studies have explored the genetic basis of clinical course, age of onset and severity, although no genome-wide significant associations have been discovered.
“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]
The paper’s results passage (indexed under Abstract; page unavailable) reports no genetic associations with clinical course or severity and no other individual SNPs strongly associated with age at onset. But it also says the analysis replicated a previously suggested association between age at onset and DRB1*15:01. The blanket claim that no associations were discovered omits that exception; the passage does not state whether it met a genome-wide significance threshold. (LLM, conf=0.84)
Experimental — accuracy not yet measured
MS susceptibility risk variants do not appear to have any impact on disease severity.
“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]
A 2011 collaborative genome-wide association study of 9772 cases and 17,376 controls of European descent replicated 23 of 26 previously identified associations and identified 29 novel risk loci.
“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]
Multiple sclerosis risk loci are strongly enriched for genes acting in T-cell activation and proliferation pathways.
“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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Authors: The International Multiple Sclerosis Genetics Consortium & The Wellcome Trust Case Control Consortium 2
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-08
Volume: 476
Issue: 7359
Pages: 214-219
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature10251
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)
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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 › 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, 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

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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

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