Genetics and biology of rheumatoid arthritis contribute to drug discovery. Y. Okada1,2,3, D. Wu1,2,3,4, C. Terao5,6, K. Ikari7, Y. Kochi8, K. Ohmura6, A. Suzuki8, H. Yamanaka7, J. Denny9, J. Greenberg10, R. Graham11, M. Brown12, S. Bae13, J. Worthington14,15, L. Padyukov16, L. Klareskog16, P. Gregersen17, P. Visscher12,18, K. Siminovitch19,20, R. Plenge1,2,3, the RACI consortium, the GARNET conrotium 1) Division of Rheumatology, Immunology, and Allergy, BWH, Harvard Medical Schoo, Boston, MA; 2) Division of Genetics, BWH, Harvard Medical School, Boston, MA, USA; 3) Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; 4) Department of Statistics, Harvard University, Cambridge, MA, USA; 5) CGM, Kyoto University Graduate School of Medicine, Kyoto, Japan; 6) Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 7) Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan; 8) Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan; 9) Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA; 10) New York University Hospital for Joint Diseases, NewYork, NY, USA; 11) Immunology Biomarkers Group, Genentech, South San Francisco, CA, USA; 12) The University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia; 13) Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea; 14) Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; 15) National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK; 16) Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; 17) The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA; 18) Queensland Brain Institute, The University of Queensland, St Lucia 4072, Brisbane, Australia; 19) Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada; 20) Department of Medicine, University of Toronto, Toronto, Canada.
A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery. Here, we demonstrate one such strategy for a common autoimmune disease with no known cure, rheumatoid arthritis (RA). We performed a trans-ethnic genome-wide association study (GWAS) in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls). We discovered 42 novel RA risk loci at a genome-wide level of significance (P < 5x10-8), bringing the total to 101.
The common alleles at these RA risk loci reveal: a shared genetic architecture among individuals of European and Asian ancestry; most risk alleles alter gene expression with fewer alleles altering protein structures; two-thirds of loci have pleiotropic effects on other traits, especially disorders of the immune system; an overlap with genes that contribute to human primary immunodeficiency and hematological cancer somatic mutations; and specific cell types (e.g. overlap with H3K4me3 peaks in CD4+ regulatory T cells) and molecular pathways (e.g., T cell, B cell, cytokine signaling) that contribute to RA pathogenesis.
We also demonstrate that RA risk loci are enriched for genes that are the target of approved therapies for RA (e.g., TNF and IL6R), and further suggest that drugs approved for other indications may be repurposed for the treatment of RA (e.g., CDK4/CDK6 inhibitors used in cancers).
Together, this comprehensive genetic study sheds light on fundamental pathways and genes that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery efforts.
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