Genetics of rheumatoid arthritis contributes to biology and drug discovery.
Okada, Yukinori 1, 2, 3; Wu, Di 1, 2, 3, 4, 5; Trynka, Gosia 1, 2, 3; Raj, Towfique 2, 3, 6; Terao, Chikashi 7, 8; Ikari, Katsunori 9; Kochi, Yuta 10; Ohmura, Koichiro 8; Suzuki, Akari 10; Yoshida, Shinji 9; Graham, Robert R. 11; Manoharan, Arun 11; Ortmann, Ward 11; Bhangale, Tushar 11; Denny, Joshua C. 12, 13; Carroll, Robert J. 12; Eyler, Anne E. 13; Greenberg, Jeffrey D. 14; Kremer, Joel M. 15; Pappas, Dimitrios A. 16; Jiang, Lei 17; Yin, Jian 17; Ye, Lingying 17; Su, Ding-Feng 18; Yang, Jian 19, 20; Xie, Gang 21, 22, 23; Keystone, Ed 24; Westra, Harm-Jan 25; Esko, Tonu 3, 26, 27; Metspalu, Andres 26; Zhou, Xuezhong 28; Gupta, Namrata 3; Mirel, Daniel 3; Stahl, Eli A. 29; Diogo, Dorothee 1, 2, 3; Cui, Jing 1, 2, 3; Liao, Katherine 1, 2, 3; Guo, Michael H. 1, 3, 27; Myouzen, Keiko 10; Kawaguchi, Takahisa 7; Coenen, Marieke J. H. 30; van Riel, Piet L. C. M. 31; van de Laar, Mart A. F. J. 32; Guchelaar, Henk-Jan 33; Huizinga, Tom W. J. 34; Dieude, Philippe 35, 36; Mariette, Xavier 37; Bridges, Louis S. Jr 38; Zhernakova, Alexandra 25, 34; Toes, Rene E. M. 34; Tak, Paul P. 39, 40, 41; Miceli-Richard, Corinne 37; Bang, So-Young 42; Lee, Hye-Soon 42; Martin, Javier 43; Gonzalez-Gay, Miguel A. 44; Rodriguez-Rodriguez, Luis 45; Rantapaa-Dahlqvist, Solbritt 46, 47; Arlestig, Lisbeth 46, 47; Choi, Hyon K. 48, 49, 50; Kamatani, Yoichiro 51; Galan, Pilar 52; Lathrop, Mark 53; the RACI consortium +; the GARNET consortium +; Eyre, Steve 54, 55; Bowes, John 54, 55; Barton, Anne 54; de Vries, Niek 56; Moreland, Larry W. 57; Criswell, Lindsey A. 58; Karlson, Elizabeth W. 1; Taniguchi, Atsuo 9; Yamada, Ryo 59; Kubo, Michiaki 60; Liu, Jun S. 4; Bae, Sang-Cheol 42; Worthington, Jane 54, 55; Padyukov, Leonid 61; Klareskog, Lars 61; Gregersen, Peter K. 62; Raychaudhuri, Soumya 1, 2, 3, 63; Stranger, Barbara E. 64, 65; De Jager, Philip L. 2, 3, 6; Franke, Lude 25; Visscher, Peter M. 19, 20; Brown, Matthew A. 19; Yamanaka, Hisashi 9; Mimori, Tsuneyo 8; Takahashi, Atsushi 66; Xu, Huji 17; Behrens, Timothy W. 11; Siminovitch, Katherine A. 21, 22, 23; Momohara, Shigeki 9; Matsuda, Fumihiko 7, 67, 68; Yamamoto, Kazuhiko 10, 69; Plenge, Robert M. 1, 2, 3
[Letter]
Nature.
506(7488):376-381, February 20, 2014.
(Format: HTML, PDF)
: 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 annotation 5, cis-acting expression quantitative trait loci 6 and pathway analyses 7,8,9-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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