Journal Article

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Klareskog, Lars, Worthington, Jane, Carroll, Robert J., Guo, Michael H., Kochi, Yuta, Coenen, Marieke J. H., Terao, Chikashi, Matsuda, Fumihiko, Barton, Anne, Jiang, Lei, Toes, Rene E. M., Su, Ding-Feng, Pappas, Dimitrios A., Greenberg, Jeffrey D., Kamatani, Yoichiro, Yamamoto, Kazuhiko, Trynka, Gosia, Lee, Hye-Soon, Graham, Robert R., Brown, Matthew A., Mirel, Daniel, Kubo, Michiaki, Takahashi, Atsushi, Raychaudhuri, Soumya, Cui, Jing, Moreland, Larry W., Diogo, Dorothée, Bang, So-Young, Gregersen, Peter K., Guchelaar, Henk-Jan, Yoshida, Shinji, Rodriguez-Rodriguez, Luis, Bae, Sang-Cheol, Eyler, Anne E., Xie, Gang, Bowes, John, Raj, Towfique, Siminovitch, Katherine A., Momohara, Shigeki, Esko, Tõnu, de Vries, Niek, Okada, Yukinori, Westra, Harm-Jan, Lathrop, Mark, Liu, Jun S., Yang, Jian, van de Laar, Mart A. F. J., Liao, Katherine, van Riel, Piet L. C. M., Zhernakova, Alexandra, Criswell, Lindsey A., Suzuki, Akari, Gonzalez-Gay, Miguel A., Tak, Paul P., Franke, Lude, Plenge, Robert M., Manoharan, Arun, Eyre, Steve, Padyukov, Leonid, Mimori, Tsuneyo, Stahl, Eli A., Choi, Hyon K., Ikari, Katsunori, Keystone,

2014

Overview

A genome-wide association study meta-analysis of more than 100,000 subjects of European and Asian ancestries reveals 42 new risk loci for rheumatoid arthritis, with follow-up studies identifying 98 biological candidate genes that are either already being targeted by drugs or could be in the future. Rheumatoid arthritis drug targets Virtual screening in a genome-wide association study (GWAS) meta-analysis of more than 100,000 subjects of European and Asian ancestries has revealed 42 previously unknown risk loci for rheumatoid arthritis (RA). As a follow-up, the authors developed a new in silico pipeline to identify 98 biological candidate genes at all known RA risk loci. They show 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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 631/154/1435/2418 / 631/208/205/2138 / Alleles / Animals / Arthritis, Rheumatoid - drug therapy / Arthritis, Rheumatoid - genetics / Arthritis, Rheumatoid - metabolism / Arthritis, Rheumatoid - pathology / Asian people / Asian People - genetics / Autoimmune diseases / Bioinformatics / Cancer / Case-Control Studies / Computational Biology / Confidence intervals / Cytokines / Disease / Drug Discovery / Drug Repositioning / Epigenetics / Female / Gene mapping / Genes / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetic research / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / Genomics / Health risk assessment / Hematologic Neoplasms - genetics / Hematologic Neoplasms - metabolism / Hematology / Human genetics / Humanities and Social Sciences / Humans / Hypotheses / letter / Life Sciences / Male / Meta-analysis / Mice / Mice, Knockout / Molecular Targeted Therapy / multidisciplinary / Polymorphism, Single Nucleotide - genetics / Population / Proteins / Quality control / Quantitative trait loci / Rheumatoid arthritis / Science / Systematic review / Virtual screening / White People - genetics