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Article Dans Une Revue Nature Année : 2014

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Yukinori Okada (1, 2) , Di Wu (1, 3, 2) , Gosia Trynka (1, 2) , Towfique Raj (2, 4, 1) , Chikashi Terao (5) , Katsunori Ikari (6) , Yuta Kochi (7) , Koichiro Ohmura (5) , Akari Suzuki (7) , Shinji Yoshida (6) , Robert R. Graham (8) , Arun Manoharan (8) , Ward Ortmann (8) , Tushar Bhangale (8) , Joshua C. Denny (9) , Robert J. Carroll (9) , Anne E. Eyler (9) , Jeffrey D. Greenberg (10) , Joel M. Kremer (11) , Dimitrios A. Pappas (12) , Lei Jiang (13) , Jian Yin (13) , Lingying Ye (13) , Ding-Feng Su (13) , Jian Yang (14) , Gang Xie (15, 16) , Ed Keystone (15, 16) , Harm-Jan Westra (17) , Tonu Esko (18, 2, 19) , Andres Metspalu (19) , Xuezhong Zhou (20) , Namrata Gupta (2) , Daniel Mirel (2) , Eli A. Stahl (21) , Dorothée Diogo (1, 2) , Jing Cui (1, 2) , Katherine Liao (1, 2) , Michael H. Guo (1, 18, 2) , Keiko Myouzen (7) , Takahisa Kawaguchi (5) , Marieke J. H. Coenen (22) , Piet L. C. M. van Riel (22) , Mart A. F. J. van de Laar (23, 24) , Henk-Jan Guchelaar (25) , Tom W. J. Huizinga (26) , Philippe Dieudé (27, 28) , Xavier Mariette (29) , S. Louis Bridges (30) , Alexandra Zhernakova (25, 17) , René E. M. Toes (25) , Paul P. Tak (31, 32, 33) , Corinne Miceli-Richard (29) , So-Young Bang (34) , Hye-Soon Lee (34) , Javier Martin (35) , Miguel A. Gonzalez-Gay (36) , Luis Rodríguez-Rodríguez (37) , Solbritt Rantapää-Dahlqvist (38) , Lisbeth Arlestig (38) , Hyon K. Choi (39, 1) , Yoichiro Kamatani (40) , Pilar Galan (41) , Mark Lathrop (42) , Steve Eyre , John Bowes , Anne Barton , Niek de Vries , Larry W. Moreland , Lindsey A. Criswell , Elizabeth W. Karlson (1) , Atsuo Taniguchi (6) , Ryo Yamada , Michiaki Kubo , Jun S. Liu , Sang-Cheol Bae (34) , Jane Worthington , Leonid Padyukov , Lars Klareskog , Peter K. Gregersen , Soumya Raychaudhuri (1, 2) , Barbara E. Stranger , Philip L. de Jager (2, 4, 1) , Lude Franke (17) , Peter M. Visscher (14) , Matthew A. Brown (14) , Hisashi Yamanaka (6) , Tsuneyo Mimori , Atsushi Takahashi , Huji Xu (13) , Timothy W. Behrens (8) , Katherine A. Siminovitch (16) , Shigeki Momohara (6) , Fumihiko Matsuda (5) , Kazuhiko Yamamoto (7) , Robert M. Plenge (1, 2)
1 Harvard University
2 Broad Institute of Harvard and MIT
3 Monash University
4 Brigham and Women's Hospital
5 Kyoto University
6 TWMU - Tokyo Women's Medical University
7 Riken
8 Genetic Engineering Technology
9 Vanderbilt University [Nashville]
10 New York University School of Medicine
11 Albany Medical Center
12 Columbia University [New York]
13 Second Military Medical University
14 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
15 MSH - Mount Sinai Hospital [Toronto, Canada]
16 University of Toronto
17 University of Groningen [Groningen]
18 All Children’s Hospital
19 University of Tartu
20 BJTU - Beijing Jiaotong University
21 MSSM - Icahn School of Medicine at Mount Sinai [New York]
22 Radboud University [Nijmegen]
23 University of Twente
24 Medish Spectrum Twente
25 Universiteit Leiden = Leiden University
26 Leiden Univ, Med Ctr, Dept Rheumatol, NL-2300 RC Leiden, Netherlands
27 UPD7 - Université Paris Diderot - Paris 7
28 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
29 UP11 - Université Paris-Sud - Paris 11
30 UAB - University of Alabama at Birmingham
31 CAM - University of Cambridge [UK]
32 Glaxo Smith Kline
33 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
34 Hanyang University
35 CSIC - Consejo Superior de Investigaciones Cientificas = Spanish National Research Council
36 Hospital Universitario Marqués de Valdecilla [Santander]
37 San Carlos Clinical Hospital
38 Umeå University
39 BU - Boston University [Boston]
40 CEPH - Centre d'Etude du Polymorphisme Humain
41 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
42 McGill University = Université McGill [Montréal, Canada]
Chikashi Terao
  • Fonction : Auteur
Yuta Kochi
  • Fonction : Auteur
Koichiro Ohmura
  • Fonction : Auteur
Akari Suzuki
  • Fonction : Auteur
Jian Yang
Keiko Myouzen
  • Fonction : Auteur
Takahisa Kawaguchi
Xavier Mariette
So-Young Bang
  • Fonction : Auteur
Hye-Soon Lee
  • Fonction : Auteur
Steve Eyre
  • Fonction : Auteur
John Bowes
  • Fonction : Auteur
Anne Barton
  • Fonction : Auteur
Niek de Vries
  • Fonction : Auteur
Larry W. Moreland
  • Fonction : Auteur
Lindsey A. Criswell
  • Fonction : Auteur
Ryo Yamada
  • Fonction : Auteur
Michiaki Kubo
  • Fonction : Auteur
Jun S. Liu
  • Fonction : Auteur
Sang-Cheol Bae
Jane Worthington
  • Fonction : Auteur
Leonid Padyukov
  • Fonction : Auteur
Lars Klareskog
  • Fonction : Auteur
Peter K. Gregersen
  • Fonction : Auteur
Barbara E. Stranger
  • Fonction : Auteur
Tsuneyo Mimori
  • Fonction : Auteur
Atsushi Takahashi
  • Fonction : Auteur
Fumihiko Matsuda
Kazuhiko Yamamoto
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-02639720 , version 1 (28-05-2020)

Identifiants

Citer

Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, et al.. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature, 2014, 506 (7488), pp.376 - 397. ⟨10.1038/nature12873⟩. ⟨hal-02639720⟩
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