Genetics of rheumatoid arthritis contributes to biology and drug discovery

Okada, Yukinori, Wu, Di, Trynka, Gosia, Raj, Towfique, Terao, Chikashi, Ikari, Katsunori, Kochi, Yuta, Ohmura, Koichiro, Suzuki, Akari, Yoshida, Shinji, Graham, Robert R., Manoharan, Arun, Ortmann, Ward, Bhangale, Tushar, Denny, Joshua C., Carroll, Robert J., Eyler, Anne E., Greenberg, Jeffrey D., Kremer, Joel M., Pappas, Dimitrios A., Jiang, Lei, Yin, Jian, Ye, Lingying, Su, Ding-Feng, Yang, Jian, Xie, Gang, Keystone, Ed, Westra, Harm-Jan, Esko, Tõnu, Metspalu, Andres, Zhou, Xuezhong, Gupta, Namrata, Mirel, Daniel, Stahl, Eli A., Diogo, Dorothée, Cui, Jing, Liao, Katherine, Guo, Michael H., Myouzen, Keiko, Kawaguchi, Takahisa, Coenen, Marieke J. H., van Riel, Piet L. C. M., van de Laar, Mart A. F. J., Guchelaar, Henk-Jan, Huizinga, Tom W. J., Dieudé, Philippe, Mariette, Xavier, Louis Bridges Jr, S., Zhernakova, Alexandra, Toes, Rene E. M., Tak, Paul P., Miceli-Richard, Corinne, Bang, So-Young, Lee, Hye-Soon, Martin, Javier, Gonzalez-Gay, Miguel A., Rodriguez-Rodriguez, Luis, Rantapää-Dahlqvist, Solbritt, Ärlestig, Lisbeth, Choi, Hyon K., Kamatani, Yoichiro, Galan, Pilar, Lathrop, Mark, Eyre, Steve, Bowes, John, Barton, Anne, de Vries, Niek, 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., De Jager, Philip L., Franke, Lude, Visscher, Peter M., Brown, Matthew A., Yamanaka, Hisashi, Mimori, Tsuneyo, Takahashi, Atsushi, Xu, Huji, Behrens, Timothy W., Siminovitch, Katherine A., Momohara, Shigeki, Matsuda, Fumihiko, Yamamoto, Kazuhiko, & Plenge, Robert M. (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 506(7488), pp. 376-381.

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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)1. 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, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—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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ID Code: 89155
Item Type: Journal Article
Refereed: Yes
DOI: 10.1038/nature12873
ISSN: 1476-4687
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 15 Oct 2015 02:31
Last Modified: 16 Feb 2016 04:14

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