Genetics of rheumatoid arthritis contributes to biology and drug discovery

Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Akari Suzuki, Shinji Yoshida, Robert R. Graham, Arun Manoharan, Ward Ortmann, Tushar Bhangale, Joshua C. Denny, Robert J. Carroll, Anne E. Eyler, Jeffrey D. Greenberg, Joel M. Kremer, Dimitrios A. PappasLei Jiang, Jian Yin, Lingying Ye, Ding-Feng Su, Jian Yang, Gang Xie, Ed Keystone, Harm-Jan Westra, Tonu Esko, Andres Metspalu, Xuezhong Zhou, Namrata Gupta, Daniel Mirel, Eli A. Stahl, Dorothee Diogo, Jing Cui, Katherine Liao, Michael H. Guo, Keiko Myouzen, Takahisa Kawaguchi, Marieke J. H. Coenen, Piet L. C. M. van Riel, Mart A. F. J. van de laar, Henk-Jan Guchelaar, Tom W. J. Huizinga, Philippe Dieude, Xavier Mariette, S. Louis Bridges, Alexandra Zhernakova, Lude Franke, RACI Consortium, GARNET Consortium

Research output: Contribution to journalArticleAcademicpeer-review

1092 Citations (Scopus)

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 similar to 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(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-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.

Original languageEnglish
Pages (from-to)376-381.e15
Number of pages21
JournalNature
Volume506
Issue number7488
DOIs
Publication statusPublished - 20-Feb-2014

Keywords

  • GENOME-WIDE ASSOCIATION
  • RECEPTOR INHIBITION
  • LOCI
  • DISEASE
  • RISK
  • SUSCEPTIBILITY
  • IDENTIFICATION
  • VARIANTS
  • RESOURCE
  • TRAITS

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