Genetics of rheumatoid arthritis contributes to biology and drug discovery

Yukinori Okada; Di Wu; Gosia Trynka; Towfique Raj; Chikashi Terao; Katsunori Ikari; Yuta Kochi; Koichiro Ohmura; Akari Suzuki; Shinji Yoshida; Robert R. Graham; Arun Manoharan; Ward Ortmann; Tushar Bhangale; Joshua C. Denny; Robert J. Carroll; Anne E. Eyler; Jeffrey D. Greenberg; Joel M. Kremer; Dimitrios A. Pappas; Lei Jiang; Jian Yin; Lingying Ye; Ding-Feng Su; Jian Yang; Gang Xie; Ed Keystone; Harm-Jan Westra; Tonu Esko; Andres Metspalu; Xuezhong Zhou; Namrata Gupta; Daniel Mirel; Eli A. Stahl; Dorothée Diogo; Jing Cui; Katherine Liao; Michael H. Guo; Keiko Myouzen; Takahisa Kawaguchi; Marieke J. H. Coenen; Piet L. C. M. van Riel; Mart A. F. J. van de Laar; Henk-Jan Guchelaar; Tom W. J. Huizinga; Philippe Dieudé; Xavier Mariette; S. Louis Bridges; Alexandra Zhernakova; René E. M. Toes; Paul P. Tak; Corinne Miceli-Richard; So-Young Bang; Hye-Soon Lee; Javier Martin; Miguel A. Gonzalez-Gay; Luis Rodríguez-Rodríguez; Solbritt Rantapää-Dahlqvist; Lisbeth Arlestig; Hyon K. Choi; Yoichiro Kamatani; Pilar Galan; Mark Lathrop; Steve Eyre; John Bowes; Anne Barton; Niek de Vries; Larry W. Moreland; Lindsey A. Criswell; Elizabeth W. Karlson; Atsuo Taniguchi; Ryo Yamada; Michiaki Kubo; Jun S. Liu; Sang-Cheol Bae; Jane Worthington; Leonid Padyukov; Lars Klareskog; Peter K. Gregersen; Soumya Raychaudhuri; Barbara E. Stranger; Philip L. de Jager; Lude Franke; Peter M. Visscher; Matthew A. Brown; Hisashi Yamanaka; Tsuneyo Mimori; Atsushi Takahashi; Huji Xu; Timothy W. Behrens; Katherine A. Siminovitch; Shigeki Momohara; Fumihiko Matsuda; Kazuhiko Yamamoto; Robert M. Plenge; RACI Consortium; Panos Deloukas

doi:10.1038/nature12873

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Genetics of rheumatoid arthritis contributes to biology and drug discovery

Journal article

Peer reviewed

Genetics of rheumatoid arthritis contributes to biology and drug discovery

Yukinori Okada, Di Wu, Gosia Trynka, Towfique Raj, Chikashi Terao, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Akari Suzuki, Shinji Yoshida, …

Nature (London), Vol.506(7488), pp.376-397

20/02/2014

DOI: https://doi.org/10.1038/nature12873

PMCID: PMC3944098

PMID: 24390342

Abstract

Life Sciences

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.

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Title: Genetics of rheumatoid arthritis contributes to biology and drug discovery
Creators - without role: Yukinori Okada - Brigham and Women's Hospital
Di Wu - Brigham and Women's Hospital
Gosia Trynka - Brigham and Women's Hospital
Towfique Raj - Brigham and Women's Hospital
Chikashi Terao - Kyoto University
Katsunori Ikari - Tokyo Women's Medical University
Yuta Kochi - RIKEN Center for Integrative Medical Sciences
Koichiro Ohmura - Kyoto University
Akari Suzuki - RIKEN Center for Integrative Medical Sciences
Shinji Yoshida - Tokyo Women's Medical University
Robert R. Graham - GenProMarkers
Arun Manoharan - GenProMarkers
Ward Ortmann - GenProMarkers
Tushar Bhangale - GenProMarkers
Joshua C. Denny - Vanderbilt University
Robert J. Carroll - Vanderbilt University
Anne E. Eyler - Vanderbilt University
Jeffrey D. Greenberg - New York University Langone Orthopedic Hospital
Joel M. Kremer - Albany Medical Center Hospital
Dimitrios A. Pappas - New York Hospital Queens
Lei Jiang - Second Military Medical University
Jian Yin - Second Military Medical University
Lingying Ye - Second Military Medical University
Ding-Feng Su - Second Military Medical University
Jian Yang - Translational Research Institute
Gang Xie - Lunenfeld-Tanenbaum Research Institute
Ed Keystone - Mount Sinai Hospital
Harm-Jan Westra - University Medical Center Groningen
Tonu Esko - University of Tartu
Andres Metspalu - University of Tartu
Xuezhong Zhou - Beijing Jiaotong University
Namrata Gupta - Broad Institute
Daniel Mirel - Broad Institute
Eli A. Stahl - Icahn School of Medicine at Mount Sinai
Dorothée Diogo - Brigham and Women's Hospital
Jing Cui - Brigham and Women's Hospital
Katherine Liao - Brigham and Women's Hospital
Michael H. Guo - Boston University
Keiko Myouzen - RIKEN Center for Integrative Medical Sciences
Takahisa Kawaguchi - Kyoto University
Marieke J. H. Coenen - Radboud University Medical Center
Piet L. C. M. van Riel - Radboud University Medical Center
Mart A. F. J. van de Laar - Medisch Spectrum Twente
Henk-Jan Guchelaar - Leiden University Medical Center
Tom W. J. Huizinga - Leiden University Medical Center
Philippe Dieudé - Hôpital Bichat-Claude-Bernard
Xavier Mariette - Hôpitaux Universitaires Paris-Ouest
S. Louis Bridges - University of Alabama at Birmingham
Alexandra Zhernakova - University of Groningen
René E. M. Toes - Leiden University Medical Center
Paul P. Tak - University of Amsterdam
Corinne Miceli-Richard - Hôpitaux Universitaires Paris-Ouest
So-Young Bang - Hanyang University Seoul Hospital
Hye-Soon Lee - Hanyang University Seoul Hospital
Javier Martin - Instituto de Parasitología y Biomedicina "López - Neyra"
Miguel A. Gonzalez-Gay - Fundación Marques de Valdecilla
Luis Rodríguez-Rodríguez - Hospital Clínico San Carlos
Solbritt Rantapää-Dahlqvist - Umeå University
Lisbeth Arlestig - Umeå University
Hyon K. Choi - Brigham and Women's Hospital
Yoichiro Kamatani - Fondation Jean Dausset-CEPH
Pilar Galan - Nutritional Epidemiology Research Unit
Mark Lathrop - McGill University and Génome Québec Innovation Centre
Steve Eyre
John Bowes - University of Manchester
Anne Barton - University of Manchester
Niek de Vries - Academic Medical Center
Larry W. Moreland - University of Pittsburgh
Lindsey A. Criswell - University of California, San Francisco
Elizabeth W. Karlson - Brigham and Women's Hospital
Atsuo Taniguchi - Tokyo Women's Medical University
Ryo Yamada - Kyoto University
Michiaki Kubo - RIKEN Center for Integrative Medical Sciences
Jun S. Liu - Harvard University
Sang-Cheol Bae - Hanyang University Seoul Hospital
Jane Worthington - University of Manchester
Leonid Padyukov - Karolinska Institutet
Lars Klareskog - Karolinska Institutet
Peter K. Gregersen - Northwell Health
Soumya Raychaudhuri - Brigham and Women's Hospital
Barbara E. Stranger - University of Chicago
Philip L. de Jager - Brigham and Women's Hospital
Lude Franke - University Medical Center Groningen
Peter M. Visscher - University of Queensland
Matthew A. Brown - Translational Research Institute
Hisashi Yamanaka - Tokyo Women's Medical University
Tsuneyo Mimori - Kyoto University
Atsushi Takahashi - RIKEN Center for Integrative Medical Sciences
Huji Xu - Second Military Medical University
Timothy W. Behrens - GenProMarkers
Katherine A. Siminovitch - Lunenfeld-Tanenbaum Research Institute
Shigeki Momohara - Tokyo Women's Medical University
Fumihiko Matsuda - Kyoto University
Kazuhiko Yamamoto - RIKEN Center for Integrative Medical Sciences
Robert M. Plenge - Brigham and Women's Hospital
RACI Consortium
Panos Deloukas - King Abdulaziz University
Publication Details: Nature (London), Vol.506(7488), pp.376-397
Publisher: Nature Publishing Group
Identifiers: 9936923608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article