Genetics of rheumatoid arthritis contributes to biology and drug discovery
Open accessAbstract
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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GWAS, meta-analysis, exome analysis and SNP mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease.
“Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263–269).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [268]
The paper’s Abstract (page unavailable) reports a GWAS meta-analysis of rheumatoid arthritis risk loci and identifies the IL-6R-targeting drug tocilizumab among therapies linked to its RA genetics analysis. It does not establish the claimed genetic associations for IL-6, IL-6R and gp130 across both RA and coronary artery disease, or report exome analysis supporting them. (LLM, conf=0.83)
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Self-citation
- Authors
- the RACI consortium, Okada, Y., the GARNET consortium, Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, K., Suzuki, A., Yoshida, S., Graham, R. R., Manoharan, A., Ortmann, W., Bhangale, T., Denny, J. C., Carroll, R. J., Eyler, A. E., Greenberg, J. D., Kremer, J. M., Pappas, D. A., Jiang, L., Yin, J., Ye, L., Su, D.-F., Yang, J., Xie, G., Keystone, E., Westra, H.-J., Esko, T., Metspalu, A., Zhou, X., Gupta, N., Mirel, D., Stahl, E. A., Diogo, D., Cui, J., Liao, K., Guo, M. H., Myouzen, K., Kawaguchi, T., Coenen, M. J. H., van Riel, P. L. C. M., van de Laar, M. A. F. J., Guchelaar, H.-J., Huizinga, T. W. J., Dieudé, P., Mariette, X., Louis Bridges Jr, S., Zhernakova, A., Toes, R. E. M., Tak, P. P., Miceli-Richard, C., Bang, S.-Y., Lee, H.-S., Martin, J., Gonzalez-Gay, M. A., Rodriguez-Rodriguez, L., Rantapää-Dahlqvist, S., Ärlestig, L., Choi, H. K., Kamatani, Y., Galan, P., Lathrop, M., Eyre, S., Bowes, J., Barton, A., de Vries, N., Moreland, L. W., Criswell, L. A., Karlson, E. W., Taniguchi, A., Yamada, R., Kubo, M., Liu, J. S., Bae, S.-C., Worthington, J., Padyukov, L., Klareskog, L., Gregersen, P. K., Raychaudhuri, S., Stranger, B. E., De Jager, P. L., Franke, L., Visscher, P. M., Brown, M. A., Yamanaka, H., Mimori, T., Takahashi, A., Xu, H., Behrens, T. W., Siminovitch, K. A., Momohara, S., Matsuda, F., Yamamoto, K., & Plenge, R. M.
- Affiliations
- Broad Institute (US)
- Kyoto University (JP)
- Tokyo Women's Medical University (JP)
- RIKEN (JP)
- Genentech (US)
- Vanderbilt University (US)
- New York University Langone Orthopedic Hospital (US)
- Center for Rheumatology (US)
- NewYork–Presbyterian Hospital (US)
- Second Military Medical University (CN)
- Translational Research Institute (AU)
- Mount Sinai Hospital (CA)
- University Medical Center Groningen (NL)
- University of Tartu (EE)
- Beijing Jiaotong University (CN)
- Icahn School of Medicine at Mount Sinai (US)
- Radboud University Medical Center (NL)
- Leiden University Medical Center (NL)
- Inserm (FR)
- University of Cambridge (GB)
- Hanyang University Seoul Hospital (KR)
- Consejo Superior de Investigaciones Científicas (ES)
- Umeå University (SE)
- Boston University (US)
- Fondation Jean Dausset-CEPH (FR)
- McGill University and Génome Québec Innovation Centre (CA)
- National Health Service (GB)
- Manchester Academic Health Science Centre (GB)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Karolinska Institutet (SE)
- Northwell Health (US)
- University of Chicago (US)
- Corresponding author
- Okada, Yukinori
- Plenge, Robert M.
- ORCID
- Okada, Yukinori
- Wu, Di
- Trynka, Gosia
- Raj, Towfique
- Terao, Chikashi
- Ikari, Katsunori
- Kochi, Yuta
- Ohmura, Koichiro
- Suzuki, Akari
- Graham, Robert R.
- Manoharan, Arun
- Ortmann, Ward
- Bhangale, Tushar
- Denny, Joshua C.
- Carroll, Robert J.
- Kremer, Joel M.
- Pappas, Dimitrios A.
- Jiang, Lei
- Yin, Jian
- Ye, Lingying
- Su, Ding-Feng
- Yang, Jian
- Westra, Harm-Jan
- Esko, Tõnu
- Metspalu, Andres
- Zhou, Xuezhong
- Gupta, Namrata
- Stahl, Eli A.
- Diogo, Dorothée
- Cui, Jing
- Liao, Katherine
- Guo, Michael H.
- Kawaguchi, Takahisa
- Coenen, Marieke J. H.
- Guchelaar, Henk-Jan
- Huizinga, Tom W. J.
- Dieudé, Philippe
- Zhernakova, Alexandra
- Tak, Paul P.
- Bang, So-Young
- Lee, Hye-Soon
- Martin, Javier
- Ärlestig, Lisbeth
- Choi, Hyon K.
- Galan, Pilar
- Lathrop, Mark
- Bowes, John
- Barton, Anne
- Moreland, Larry W.
- Criswell, Lindsey A.
- Karlson, Elizabeth W.
- Taniguchi, Atsuo
- Yamada, Ryo
- Kubo, Michiaki
- Liu, Jun S.
- Bae, Sang-Cheol
- Worthington, Jane
- Padyukov, Leonid
- Klareskog, Lars
- Gregersen, Peter K.
- Raychaudhuri, Soumya
- Stranger, Barbara E.
- Franke, Lude
- Visscher, Peter M.
- Brown, Matthew A.
- Yamanaka, Hisashi
- Mimori, Tsuneyo
- Xu, Huji
- Behrens, Timothy W.
- Momohara, Shigeki
- Matsuda, Fumihiko
- Yamamoto, Kazuhiko
- Plenge, Robert M.
- Venue
- Nature
- Published
- 2013-12-25
- Volume
- 506
- Issue
- 7488
- Pages
- 376-381
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3944098
- OpenAlex
- W1989590412
- Cited by
- 2,310
- References
- 4
- Citations by year
- 2026: 84 · 2025: 129 · 2024: 201 · 2023: 186 · 2022: 229 · 2021: 249 · 2020: 193 · 2019: 195 · 2018: 196 · 2017: 185 · 2016: 195 · 2015: 178 · 2014: 83 · 2013: 1 · 2012: 1
- FWCI
- 124.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Twente Research Information (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- University of Twente Research Information (submittedVersion)
- Funders
- GlaxoSmithKline
- Brigham and Women's Hospital
- School of Medicine, Boston University
- University of Pittsburgh
- McGill University
- Génome Québec
- National Institute for Health and Care Research (MANMKBRU-2012-1)
- Institut National de la Santé et de la Recherche Médicale
- Ministry of Education, Culture, Sports, Science and Technology
- Rijksuniversiteit Groningen
- National Natural Science Foundation of China (81273283, 30972339)
- Universiteit van Amsterdam
- Hanyang University
- Science and Technology Commission of Shanghai Municipality
- Umeå Universitet
- ReumaNederland
- Medical Research Council Canada
- Université Paris-Sud
- Université Paris 13
- Assistance publique-Hôpitaux de Paris
- Versus Arthritis (20385)
- National Institutes of Health (5r01ar063759-07, R01‐AR‐063759)
- U.S. Public Health Service (K08-KAR055688A)
- Canadian Institutes of Health Research (79321)
- Medical Research Council
- National Health and Medical Research Council
- Japan Society for the Promotion of Science (24390360, 221S0001, 22133008, 23229007, 24592285, 26460649, 25293225)
- Instituto de Salud Carlos III
- National Key Research and Development Program of China (2011CB946100)
- National Heart, Lung, and Blood Institute (U19HL065962)
- National Institute of General Medical Sciences (U01GM092691)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR060257, R01-AR-063759-01A1, R21AR056042, R01AR059648, R01AR056768, R01AR057108, P60AR047785, K24AR052403, R01AR056291, R01AR065944, R01-AR063759)
- U.S. National Library of Medicine (T15LM007450)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- rheumatoid arthritis, genetic susceptibility loci, drug repurposing, drug discovery, functional annotation, expression quantitative trait loci, pathway analysis, somatic mutations, pathogenesis
- MeSH terms
- Alleles, Animals, Arthritis, Rheumatoid, Female, Humans, Male, Case-Control Studies, Mice, Knockout, Computational Biology, Hematologic Neoplasms, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, White People, Asian People, Mice, Genome-Wide Association Study, Drug Discovery, Drug Repositioning, Molecular Targeted Therapy
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