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Nature DOI:10.1038/nature12873

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

Publication TypeJournal Article
Year of Publication2014
AuthorsOkada, Y, Wu, D, Trynka, G, Raj, T, Terao, C, Ikari, K, Kochi, Y, Ohmura, K, Suzuki, A, Yoshida, S, Graham, RR, Manoharan, A, Ortmann, W, Bhangale, T, Denny, JC, Carroll, RJ, Eyler, AE, Greenberg, JD, Kremer, JM, Pappas, DA, 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, EA, Diogo, D, Cui, J, Liao, K, Guo, MH, Myouzen, K, Kawaguchi, T, Coenen, MJH, van Riel, PLCM, van de Laar, MAFJ, Guchelaar, H-J, Huizinga, TWJ, Dieude, P, Mariette, X, S Bridges, L, Zhernakova, A, Toes, REM, Tak, PP, Miceli-Richard, C, Bang, S-Y, Lee, H-S, Martín, J, Gonzalez-Gay, MA, Rodriguez-Rodriguez, L, Rantapää-Dahlqvist, S, Arlestig, L, Choi, HK, Kamatani, Y, Galan, P, Lathrop, M, Eyre, S, Bowes, J, Barton, A, de Vries, N, Moreland, LW, Criswell, LA, Karlson, EW, Taniguchi, A, Yamada, R, Kubo, M, Liu, JS, Bae, S-C, Worthington, J, Padyukov, L, Klareskog, L, Gregersen, PK, Raychaudhuri, S, Stranger, BE, De Jager, PL, Franke, L, Visscher, PM, Brown, MA, Yamanaka, H, Mimori, T, Takahashi, A, Xu, H, Behrens, TW, Siminovitch, KA, Momohara, S, Matsuda, F, Yamamoto, K, Plenge, RM
Corporate AuthorsRACI consortium, GARNET consortium
JournalNature
Volume506
Issue7488
Pages376-81
Date Published2014 Feb 20
ISSN1476-4687
KeywordsAlleles, Animals, Arthritis, Rheumatoid, Asian Continental Ancestry Group, Case-Control Studies, Computational Biology, Drug Discovery, Drug Repositioning, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematologic Neoplasms, Humans, Male, Mice, Mice, Knockout, Molecular Targeted Therapy, Polymorphism, Single Nucleotide
Abstract

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.

URLhttp://dx.doi.org/10.1038/nature12873
DOI10.1038/nature12873
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24390342?dopt=Abstract

Alternate JournalNature
PubMed ID24390342
PubMed Central IDPMC3944098
Grant ListR01-AR057108 / AR / NIAMS NIH HHS / United States
K08-KAR055688A / / PHS HHS / United States
P60 AR047785 / AR / NIAMS NIH HHS / United States
79321 / / Canadian Institutes of Health Research / Canada
R01 AR059648 / AR / NIAMS NIH HHS / United States
T15 LM007450 / LM / NLM NIH HHS / United States
U19 HL065962 / HL / NHLBI NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
R01-AR065944 / AR / NIAMS NIH HHS / United States
K24 AR052403 / AR / NIAMS NIH HHS / United States
R01-AR059648 / AR / NIAMS NIH HHS / United States
R01 AR057108 / AR / NIAMS NIH HHS / United States
R01-AR056768 / AR / NIAMS NIH HHS / United States
R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
MANMKBRU-2012-1 / / Department of Health / United Kingdom
R21 AR056042 / AR / NIAMS NIH HHS / United States
R01-AR056291 / AR / NIAMS NIH HHS / United States
R01 AR056768 / AR / NIAMS NIH HHS / United States
U01-GM092691 / GM / NIGMS NIH HHS / United States
20385 / / Arthritis Research UK / United Kingdom