Nature. 2014 Feb 20;506(7488):376-81. doi: 10.1038/nature12873. Epub 2013 Dec 25.

Genetics of rheumatoid arthritis contributes to biology and drug discovery.

Okada Y¹, Wu D², Trynka G¹, Raj T³, Terao C⁴, Ikari K⁵, Kochi Y⁶, Ohmura K⁷, Suzuki A⁶, Yoshida S⁵, Graham RR⁸, Manoharan A⁸, Ortmann W⁸, Bhangale T⁸, Denny JC⁹, Carroll RJ¹⁰, Eyler AE¹¹, Greenberg JD¹², Kremer JM¹³, Pappas DA¹⁴, Jiang L¹⁵, Yin J¹⁵, Ye L¹⁵, Su DF¹⁶, Yang J¹⁷, Xie G¹⁸, Keystone E¹⁹, Westra HJ²⁰, Esko T²¹, Metspalu A²², Zhou X²³, Gupta N²⁴, Mirel D²⁴, Stahl EA²⁵, Diogo D¹, Cui J¹, Liao K¹, Guo MH²⁶, Myouzen K⁶, Kawaguchi T²⁷, Coenen MJ²⁸, van Riel PL²⁹, van de Laar MA³⁰, Guchelaar HJ³¹, Huizinga TW³², Dieudé P³³, Mariette X³⁴, Bridges SL Jr³⁵, Zhernakova A³⁶, Toes RE³², Tak PP³⁷, Miceli-Richard C³⁴, Bang SY³⁸, Lee HS³⁸, Martin J³⁹, Gonzalez-Gay MA⁴⁰, Rodriguez-Rodriguez L⁴¹, Rantapää-Dahlqvist S⁴², Arlestig L⁴², Choi HK⁴³, Kamatani Y⁴⁴, Galan P⁴⁵, Lathrop M⁴⁶; RACI consortium; GARNET consortium, Eyre S⁴⁷, Bowes J⁴⁷, Barton A⁴⁸, de Vries N⁴⁹, Moreland LW⁵⁰, Criswell LA⁵¹, Karlson EW⁵², Taniguchi A⁵, Yamada R⁵³, Kubo M⁵⁴, Liu JS⁵⁵, Bae SC³⁸, Worthington J⁴⁷, Padyukov L⁵⁶, Klareskog L⁵⁶, Gregersen PK⁵⁷, Raychaudhuri S⁵⁸, Stranger BE⁵⁹, De Jager PL³, Franke L²⁰, Visscher PM¹⁷, Brown MA⁶⁰, Yamanaka H⁵, Mimori T⁷, Takahashi A⁶¹, Xu H¹⁵, Behrens TW⁸, Siminovitch KA¹⁸, Momohara S⁵, Matsuda F⁶², Yamamoto K⁶³, Plenge RM¹.

Collaborators (95)

Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Ärlsetig L, Martin J, Rantapää-Dahlqvist S, Plenge RM, Raychaudhuri S, Klareskog L, Gregersen PK, Worthington J, Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Kawaguchi T, Stahl E, Kurreman F, Nishida N, Ohmiya H, Myouzen K, Takahashi M, Sawada T, Nishioka Y, Yukioka M, Matsubara T, Wakitani S, Teshima R, Tohma S, Takasugi K, Shimada K, Murasawa A, Honjo S, Matsuo K, Tanaka H, Tajima K, Suzuki T, Iwamoto T, Kawamura Y, Tanii H, Okazaki Y, Sasaki T, Gregersen PK, Padyukov L, Worthington J, Siminovitch KA, Lathrop M, Taniguchi A, Takahashi A, Tokunaga K, Kubo M, Nakamura Y, Kamatani N, Mimori T, Plenge RM, Yamanaka H, Momohara S, Yamada R, Matsuda F, Yamamoto K.

Author information

1: 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
2: 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. [5] Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia.
3: 1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
4: 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
5: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
6: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
7: Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
8: Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA.
9: 1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
10: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
11: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
12: New York University Hospital for Joint Diseases, New York, New York 10003, USA.
13: Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA.
14: Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
15: Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
16: Department of Pharmacology, Second Military Medical University, Shanghai 200433, China.
17: 1] University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. [2] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
18: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada.
19: Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada.
20: Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands.
21: 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [2] Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
22: Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia.
23: School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.
24: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
25: The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA.
26: 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
27: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
28: Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.
29: Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.
30: Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands.
31: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
32: Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
33: 1] Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris 75018, France. [2] Université Paris 7-Diderot, Paris 75013, France.
34: 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.
35: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
36: 1] Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
37: 1] AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. [2] GlaxoSmithKline, Stevenage SG1 2NY, UK. [3] University of Cambridge, Cambridge CB2 1TN, UK.
38: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea.
39: Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain.
40: Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain.
41: Hospital Clinico San Carlos, Madrid 28040, Spain.
42: 1] Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden. [2] Department of Rheumatology, Umeå University, Umeå SE-901 87, Sweden.
43: 1] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA. [2] Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [3] Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
44: Centre d'Etude du Polymorphisme Humain (CEPH), Paris 75010, France.
45: Université Paris 13 Sorbonne Paris Cité, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France.
46: McGill University and Génome Québec Innovation Centre, Montréal, Québec H3A 0G1 Canada.
47: 1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. [2] 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.
48: Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
49: Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
50: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
51: Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA.
52: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
53: Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan.
54: Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
55: Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA.
56: Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden.
57: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA.
58: 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.
59: 1] Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA. [2] Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA.
60: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia.
61: Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
62: 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. [3] Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
63: 1] Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. [2] Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.

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). 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 - 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.