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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
Genetics of rheumatoid arthritis contributes to biology and drug discovery
Nature, Volume 506, No. 7488, Year 2014
Notification
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Description
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, 3, 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. © 2014 Macmillan Publishers Limited. All rights reserved.
Authors & Co-Authors
Okada, Yukinori
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Trynka, Gosia
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Raj, Towfique
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Terao, Chikashi C.
Japan, Kyoto
Graduate School of Medicine
Japan, Kyoto
Kyoto University
Ikari, Katsunori
Japan, Tokyo
Tokyo Women's Medical University
Kochi, Yuta
Japan, Wako
Riken
Ohmura, Koichiro
Japan, Kyoto
Kyoto University
Suzuki, Akari
Japan, Wako
Riken
Denny, Joshua C.
United States, Nashville
Vanderbilt University School of Medicine
Carroll, Robert J.
United States, Nashville
Vanderbilt University School of Medicine
Kremer, Joel M.
United States, Albany
Albany Medical Center
Jiang, Lei
China, Shanghai
Second Military Medical University
YANG, Jian
Australia, Woolloongabba
Translational Research Institute Australia
Australia, Brisbane
The University of Queensland
Xie, Gang
Canada, Toronto
Mount Sinai Hospital of University of Toronto
Canada, Toronto
Toronto General Hospital Research Institute
Canada, Toronto
University of Toronto
Keystone, Edward Clark
Canada, Toronto
Mount Sinai Hospital of University of Toronto
Westra, Harm Jan
Netherlands, Groningen
Rijksuniversiteit Groningen
Esko, Tönu
United States, Cambridge
Broad Institute
Estonia, Tartu
Tartu Ülikool
United States, Boston
Boston Children's Hospital
Metspalu, Andres H.
Estonia, Tartu
Tartu Ülikool
Gupta, Namrata
United States, Cambridge
Broad Institute
Stahl, Eli Ayumi
United States, New York
Icahn School of Medicine at Mount Sinai
Cui, Jing
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Liao, Katherine P.
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Kawaguchi, Takahisa
Japan, Kyoto
Graduate School of Medicine
Coenen, Marieke J.H.
Netherlands, Nijmegen
Radboud University Medical Center
van Riel, Piet L.C.M.
Netherlands, Nijmegen
Radboud University Medical Center
van de Laar, M. A.F.J.
Netherlands, Enschede
Universiteit Twente
Guchelaar, Henk Jan
Netherlands, Leiden
Leids Universitair Medisch Centrum
Huizinga, Tom W.J.
Netherlands, Leiden
Leids Universitair Medisch Centrum
Dieudé, Philippe
France, Paris
Ap-hp Assistance Publique - Hopitaux de Paris
France, Paris
Université Paris Cité
Mariette, Xavier
France, Gif-sur-yvette
Université Paris-saclay
Bridges, Stanley Louis
United States, Birmingham
The University of Alabama at Birmingham
Zhernakova, Alexandra
Netherlands, Groningen
Rijksuniversiteit Groningen
Netherlands, Leiden
Leids Universitair Medisch Centrum
Toes, René E.M.
Netherlands, Leiden
Leids Universitair Medisch Centrum
Tak, Paul Peter
Netherlands, Amsterdam
Universiteit Van Amsterdam
United Kingdom, Brentford
Glaxosmithkline Plc.
United Kingdom, Cambridge
University of Cambridge
Miceli-Richard, Corinne
France, Gif-sur-yvette
Université Paris-saclay
Bang, So-young
South Korea, Seoul
Hanyang University Hospital for Rheumatic Disease
Lee, Hye-soon
South Korea, Seoul
Hanyang University Hospital for Rheumatic Disease
Martin, Javier
Spain, Madrid
Consejo Superior de Investigaciones Científicas
González-Gay, Miguel Ángel
Spain, Santander
Hospital Universitario Marqués de Valdecilla
Rodríguez-Rodríguez, Luís Pablo
Spain, Madrid
Hospital Clínico San Carlos
Rantapåå-Dahlqvist, Solbritt
Sweden, Umea
Umeå Universitet
Kamatani, Yoichiro
France, Paris
Fondation Jean Dausset - Ceph
Galán, Pilar Redondo
France, Paris
Inrae
Lathrop, Mark G.
Canada, Montreal
Université Mcgill
Eyre, Stephen
United Kingdom, Manchester
The University of Manchester
United Kingdom, Royston
National Institute for Health and Care Research
Bowes, John D.
United Kingdom, Manchester
The University of Manchester
United Kingdom, Royston
National Institute for Health and Care Research
Barton, Anne C.
United Kingdom, Manchester
The University of Manchester
De Vries, Niek
Netherlands, Amsterdam
Amsterdam Umc - University of Amsterdam
Criswell, Lindsey A.
United States, San Francisco
University of California, San Francisco
Yamada, Ryo
Japan, Kyoto
Graduate School of Medicine
Kubo, Michiaki
Japan, Wako
Riken
Liu, Jun S.
United States, Cambridge
Harvard University
Bae, Sang-cheol
South Korea, Seoul
Hanyang University Hospital for Rheumatic Disease
Padyukov, Leonid
Sweden, Stockholm
Karolinska Institutet
Klareskog, Lars G.
Sweden, Stockholm
Karolinska Institutet
Gregersen, Peter K.
United States, New York
Northwell Health System
Raychaudhuri, Soumya
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
United Kingdom, Manchester
Manchester University Nhs Foundation Trust
de Jager, Philip Lawrence
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Franke, Lude L.
Netherlands, Groningen
Rijksuniversiteit Groningen
Visscher, Peter M.
Australia, Woolloongabba
Translational Research Institute Australia
Australia, Brisbane
The University of Queensland
Brown, Matthew A.
Australia, Woolloongabba
Translational Research Institute Australia
Yamanaka, Haisashi
Japan, Tokyo
Tokyo Women's Medical University
Mimori, Tsuneyo
Japan, Kyoto
Kyoto University
Takahashi, Atsushi
Japan, Wako
Riken
Xu, Huji
China, Shanghai
Second Military Medical University
Siminovitch, Katherine Anne
Canada, Toronto
Mount Sinai Hospital of University of Toronto
Canada, Toronto
Toronto General Hospital Research Institute
Canada, Toronto
University of Toronto
Matsuda, Fumihiko
Japan, Kyoto
Graduate School of Medicine
Japan, Kawaguchi
Japan Science and Technology Agency
Yamamoto, Kazuhiko
Japan, Wako
Riken
Japan, Tokyo
Graduate School of Medicine
Plenge, Robert M.
United States, Boston
Brigham and Women's Hospital
United States, Cambridge
Broad Institute
Statistics
Citations: 1,572
Authors: 69
Affiliations: 55
Identifiers
Doi:
10.1038/nature12873
ISSN:
00280836
Research Areas
Cancer
Genetics And Genomics
Study Approach
Quantitative
Systematic review