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Cited by 800Multiple Sclerosis Research StudiesGenetic Associations and EpidemiologyPsoriasis: Treatment and Pathogenesis

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

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International MS Genetics Consortium, De Jager, Philip L, Jia, Xiaoming, Wang, Joanne, de Bakker, Paul I W, Ottoboni, Linda, Aggarwal, Neelum T, Piccio, Laura +26 more·2009·Nature Genetics
DOI 10.1038/ng.401PMC PMC2757648
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Abstract

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

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  • By 2011, common variants in 26 genomic loci had been associated with multiple sclerosis risk and independently replicated.

    “by 2011, common variants in 26 genomic loci had been associated with MS risk and independently replicated”

    From Genome‐wide association studies of multiple sclerosis (2018) · cites this paper as [35]

    The Results (GWAS meta-analysis and replication; page not provided) report MS-risk associations tested in replication samples, and the Discussion lists validated and strongly suggested susceptibility loci. But this 2009 paper does not establish that 26 loci had been independently replicated by 2011; its Discussion also distinguishes strongly suggested loci from validated ones. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 37

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Authors
International MS Genetics Consortium, De Jager, P. L., Jia, X., Wang, J., de Bakker, P. I. W., Ottoboni, L., Aggarwal, N. T., Piccio, L., Raychaudhuri, S., Tran, D., Aubin, C., Briskin, R., Romano, S., Baranzini, S. E., McCauley, J. L., Pericak-Vance, M. A., Haines, J. L., Gibson, R. A., Naeglin, Y., Uitdehaag, B., Matthews, P. M., Kappos, L., Polman, C., McArdle, W. L., Strachan, D. P., Evans, D., Cross, A. H., Daly, M. J., Compston, A., Sawcer, S. J., Weiner, H. L., Hauser, S. L., Hafler, D. A., & Oksenberg, J. R.
Affiliations
  • Brigham and Women's Hospital (US)
  • University of California, San Francisco (US)
  • Broad Institute (US)
  • Rush University (US)
  • Washington University in St. Louis (US)
  • University of Miami (US)
  • Vanderbilt University Medical Center (US)
  • Hammersmith Hospital (GB)
  • University Hospital of Basel (CH)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • University of Bristol (GB)
  • St George's, University of London (GB)
  • University of Cambridge (GB)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2009-06-14
Volume
41
Issue
7
Pages
776-782
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.401
PMC
PMC2757648
OpenAlex
W2042342193
Cited by
800
References
6
Citations by year
2026: 7 · 2025: 13 · 2024: 20 · 2023: 19 · 2022: 31 · 2021: 34 · 2020: 39 · 2019: 38 · 2018: 44 · 2017: 35 · 2016: 48 · 2015: 40 · 2014: 52 · 2013: 79 · 2012: 70
FWCI
11.82
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Bristol Research (University of Bristol) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Explore Bristol Research (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • Wellcome Trust (068545/Z/02), 068545)
  • National Institute for Health and Care Research (NF-SI-0508-10335)
  • Medical Research Council (MC_qA137934)
  • National Institute of Allergy and Infectious Diseases (P01AI039671)
  • National Institute of Neurological Disorders and Stroke (K08NS46341, R01NS046630, K08NS046341, R01NS049477)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR055688)
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 loci, TNFRSF1A, IRF8, CD6, genome-wide association study, replication, rare variants, non-synonymous mutations, type I interferon signaling, interferon response genes, gene expression
MeSH terms
Interferon Regulatory Factor-8, Antigens, Differentiation, T-Lymphocyte, Humans, Multiple Sclerosis, Antigens, CD, Case-Control Studies, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Receptors, Tumor Necrosis Factor, Type I, Interferon Regulatory Factors, Genome-Wide Association Study

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