Letter | Published:

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Nature volume 506, pages 376381 (20 February 2014) | Download Citation

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 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 annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7,8,9—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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Acknowledgements

R.M.P. is supported by National Institutes of Health (NIH) grants R01-AR057108, R01-AR056768, U01-GM092691 and R01-AR059648, and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Y.O. is supported by a grant from the Japan Society of the Promotion of Science. D.W. is supported by a grant from the Australian National Health and Medical Research Council (1036541). G.T. is supported by the Rubicon grant from the Netherlands Organization for Scientific Research. A.Z. is supported by a grant from the Dutch Reumafonds (11-1-101) and from the Rosalind Franklin Fellowship, University of Groningen. S.-C.B., S.-Y.B. and H.-S.L. are supported by the Korea Healthcare technology R&D project, Ministry for Health and Welfare (A121983). J.M., M.A.G.-G. and L.R.-R. are funded by the RETICS program, RIER, RD12/0009 from the Instituto de Salud Carlos III, Health Ministry. S.R.-D. and L.Ä.’s work is supported by the Medical Biobank of Northern Sweden. H.K.C. is supported by NIH (NIAMS) grants R01-AR056291, R01-AR065944, R01-AR056768, P60 AR047785 and R21 AR056042. L.P. and L.K. are supported by a senior investigator grant from the European Research Council. S.R. is supported by NIH grants R01AR063759-01A1 and K08-KAR055688A. P.M.V. is a National Health and Medical Research Council Senior Principal Research Fellow. M.A.B. is funded by the National Health and Medical Research Foundation Senior Principal Research Fellowship, and a Queensland State Government Premier’s Fellowship. H.X. is funded by the China Ministry of Science and Technology (973 program grant 2011CB946100), the National Natural Science Foundation of China (grants 30972339, 81020108029 and 81273283), and the Science and Technology Commission of Shanghai Municipality (grants 08XD1400400, 11410701600 and 10JC1418400). K.A.S. is supported by a Canada Research Chair, The Sherman Family Chair in Genomics Medicine, Canadian Institutes for Health Research grant 79321 and Ontario Research Fund grant 05-075. S.M. is supported by Health and Labour Sciences Research Grants. The BioBank Japan Project is supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government. This study is supported by the BE THE CURE (BTCure) project. We thank K. Akari, K. Tokunaga and N. Nishida for supporting the study.

Author information

Affiliations

  1. Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Yukinori Okada
    • , Di Wu
    • , Gosia Trynka
    • , Dorothée Diogo
    • , Jing Cui
    • , Katherine Liao
    • , Michael H. Guo
    • , Elizabeth W. Karlson
    • , Soumya Raychaudhuri
    •  & Robert M. Plenge
  2. Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Yukinori Okada
    • , Di Wu
    • , Gosia Trynka
    • , Towfique Raj
    • , Dorothée Diogo
    • , Jing Cui
    • , Katherine Liao
    • , Soumya Raychaudhuri
    • , Philip L. De Jager
    •  & Robert M. Plenge
  3. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Yukinori Okada
    • , Di Wu
    • , Gosia Trynka
    • , Towfique Raj
    • , Tõnu Esko
    • , Namrata Gupta
    • , Daniel Mirel
    • , Dorothée Diogo
    • , Jing Cui
    • , Katherine Liao
    • , Michael H. Guo
    • , Soumya Raychaudhuri
    • , Philip L. De Jager
    •  & Robert M. Plenge
  4. Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Di Wu
    •  & Jun S. Liu
  5. Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia.

    • Di Wu
  6. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

    • Towfique Raj
    •  & Philip L. De Jager
  7. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

    • Chikashi Terao
    • , Takahisa Kawaguchi
    •  & Fumihiko Matsuda
  8. Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

    • Chikashi Terao
    • , Koichiro Ohmura
    •  & Tsuneyo Mimori
  9. Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.

    • Katsunori Ikari
    • , Shinji Yoshida
    • , Atsuo Taniguchi
    • , Hisashi Yamanaka
    •  & Shigeki Momohara
  10. Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.

    • Yuta Kochi
    • , Akari Suzuki
    • , Keiko Myouzen
    •  & Kazuhiko Yamamoto
  11. Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA.

    • Robert R. Graham
    • , Arun Manoharan
    • , Ward Ortmann
    • , Tushar Bhangale
    •  & Timothy W. Behrens
  12. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

    • Joshua C. Denny
    •  & Robert J. Carroll
  13. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

    • Joshua C. Denny
    •  & Anne E. Eyler
  14. New York University Hospital for Joint Diseases, New York, New York 10003, USA.

    • Jeffrey D. Greenberg
  15. Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA.

    • Joel M. Kremer
  16. Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.

    • Dimitrios A. Pappas
  17. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.

    • Lei Jiang
    • , Jian Yin
    • , Lingying Ye
    •  & Huji Xu
  18. Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.

    • Ding-Feng Su
  19. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia.

    • Jian Yang
    • , Peter M. Visscher
    •  & Matthew A. Brown
  20. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.

    • Jian Yang
    •  & Peter M. Visscher
  21. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

    • Gang Xie
    •  & Katherine A. Siminovitch
  22. Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada.

    • Gang Xie
    •  & Katherine A. Siminovitch
  23. Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada.

    • Gang Xie
    •  & Katherine A. Siminovitch
  24. Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada.

    • Ed Keystone
  25. Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands.

    • Harm-Jan Westra
    • , Alexandra Zhernakova
    •  & Lude Franke
  26. Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia.

    • Tõnu Esko
    •  & Andres Metspalu
  27. Division of Endocrinology, Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Tõnu Esko
    •  & Michael H. Guo
  28. School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.

    • Xuezhong Zhou
  29. The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA.

    • Eli A. Stahl
  30. Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.

    • Marieke J. H. Coenen
  31. Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.

    • Piet L. C. M. van Riel
  32. Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands.

    • Mart A. F. J. van de Laar
  33. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.

    • Henk-Jan Guchelaar
  34. Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.

    • Tom W. J. Huizinga
    • , Alexandra Zhernakova
    •  & Rene E. M. Toes
  35. Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris 75018, France.

    • Philippe Dieudé
  36. Université Paris 7-Diderot, Paris 75013, France.

    • Philippe Dieudé
  37. Institut National de la Santé et de la Recherche Médicale (INSERM) U1012, Université Paris-Sud, Rhumatologie, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre 94275, France.

    • Xavier Mariette
    •  & Corinne Miceli-Richard
  38. Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • S. Louis Bridges Jr
  39. AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.

    • Paul P. Tak
  40. GlaxoSmithKline, Stevenage SG1 2NY, UK.

    • Paul P. Tak
  41. University of Cambridge, Cambridge CB2 1TN, UK.

    • Paul P. Tak
  42. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea.

    • So-Young Bang
    • , Hye-Soon Lee
    •  & Sang-Cheol Bae
  43. Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain.

    • Javier Martin
  44. Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain.

    • Miguel A. Gonzalez-Gay
  45. Hospital Clinico San Carlos, Madrid 28040, Spain.

    • Luis Rodriguez-Rodriguez
  46. Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.

    • Solbritt Rantapää-Dahlqvist
    •  & Lisbeth Ärlestig
  47. Department of Rheumatology, Umeå University, Umeå SE-901 87, Sweden.

    • Solbritt Rantapää-Dahlqvist
    •  & Lisbeth Ärlestig
  48. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA.

    • Hyon K. Choi
  49. Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

    • Hyon K. Choi
  50. Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

    • Hyon K. Choi
  51. Centre d’Etude du Polymorphisme Humain (CEPH), Paris 75010, France.

    • Yoichiro Kamatani
  52. Université Paris 13 Sorbonne Paris Cité, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France.

    • Pilar Galan
  53. McGill University and Génome Québec Innovation Centre, Montréal, Québec H3A 0G1 Canada.

    • Mark Lathrop
  54. Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.

    • Steve Eyre
    • , John Bowes
    • , Anne Barton
    •  & Jane Worthington
  55. 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 M13 9NT, UK.

    • Steve Eyre
    • , John Bowes
    •  & Jane Worthington
  56. Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.

    • Niek de Vries
  57. Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

    • Larry W. Moreland
  58. Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA.

    • Lindsey A. Criswell
  59. Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan.

    • Ryo Yamada
  60. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.

    • Michiaki Kubo
  61. Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden.

    • Leonid Padyukov
    •  & Lars Klareskog
  62. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York 11030, USA.

    • Peter K. Gregersen
  63. NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.

    • Soumya Raychaudhuri
  64. Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA.

    • Barbara E. Stranger
  65. Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA.

    • Barbara E. Stranger
  66. Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.

    • Atsushi Takahashi
  67. Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.

    • Fumihiko Matsuda
  68. Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

    • Fumihiko Matsuda
  69. Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.

    • Kazuhiko Yamamoto

Consortia

  1. the RACI consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

  2. the GARNET consortium

    Lists of participants and their affiliations appear in the Supplementary Information.

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Contributions

Y.O. carried out the primary data analyses. D.W. managed drug target gene data. G.T. conducted histone mark analysis. T.R., H.-J.W., T.E., A.M., B.E.S., P.L.D. and L.F. conducted eQTL analysis. C.T., K.I., Y.K., K.O., A.S., S.Y., G.X., E.K. and K.A.S. conducted the de novo replication study. R.R.G., A.M., W.O., T.B., T.W.B., L.J., J. Yin, L.Y., D.-F.S., J. Yang, P.M.V., M.A.B. and H.X. conducted the in silico replication study. E.A.S., D.D., J.C., T.K., R.Y. and A.T. managed GWAS data. All other authors, as well as the members of the RACI and GARNET consortia, contributed to additional analyses and genotype and clinical data enrolments. Y.O. and R.M.P. designed the study and wrote the manuscript, with contributions from all authors on the final version of the manuscript.

Competing interests

R.R.G., A.M., W.O., T.B. and T.W.B. are employees of Genentech. P.P.T. is an employee of GlaxoSmithKline. R.M.P. is currently employed by Merck & Company. The other authors declare no competing financial interests.

Corresponding authors

Correspondence to Yukinori Okada or Robert M. Plenge.

Summary statistics from the GWAS meta-analysis, source codes, and data sources used in this study are available at http://plaza.umin.ac.jp/~yokada/datasource/software.htm.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-6 and a Supplementary Note.

Excel files

  1. 1.

    Supplementary Data

    This file contains the source data file for Supplementary Table 2.

  2. 2.

    Supplementary Data

    This file contains the source data file for Supplementary Table 3.

  3. 3.

    Supplementary Data

    This file contains the source data file for Supplementary Table 4.

  4. 4.

    Supplementary Data

    This file contains the source data file for Supplementary Table 5.

  5. 5.

    Supplementary Data

    This file contains the source data file for Supplementary Table 6.

About this article

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DOI

https://doi.org/10.1038/nature12873

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