Scientific Publications

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

Publication TypeJournal Article
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 DF, Yang J., Xie G., Keystone E., Westra HJ, 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 MJ, van Riel PL, van de Laar MA, Guchelaar HJ, Huizinga TW, Dieudé P., Mariette X., Louis Bridges Jr S., Zhernakova A., Toes RE, Tak PP, Miceli-Richard C., Bang SY, Lee HS, Martin J., Gonzalez-Gay MA, Rodriguez-Rodriguez L., Rantapää-Dahlqvist S., Arlestig L., Choi HK, Kamatani Y., Galan P., Lathrop M., theconsortium RACI, theconsortium GARNET, Eyre S., Bowes J., Barton A., de Vries N., Moreland LW, Criswell LA, Karlson EW, Taniguchi A., Yamada R., Kubo M., Liu JS, Bae SC, 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., and Plenge RM
AbstractA 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, 3, 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.
Year of Publication2013
JournalNature
Date Published (YYYY/MM/DD)2013/12/25
ISSN Number0028-0836
DOI10.1038/nature12873
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24390342?dopt=Abstract