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Genetics of rheumatoid arthritis contributes to biology and drug discovery

Author

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  • Yukinori Okada

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Di Wu

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Harvard University)

  • Gosia Trynka

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Towfique Raj

    (Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women’s Hospital)

  • Chikashi Terao

    (Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
    Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.)

  • Katsunori Ikari

    (Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.)

  • Yuta Kochi

    (Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.)

  • Koichiro Ohmura

    (Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.)

  • Akari Suzuki

    (Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.)

  • Shinji Yoshida

    (Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.)

  • Robert R. Graham

    (Immunology Biomarkers Group, Genentech)

  • Arun Manoharan

    (Immunology Biomarkers Group, Genentech)

  • Ward Ortmann

    (Immunology Biomarkers Group, Genentech)

  • Tushar Bhangale

    (Immunology Biomarkers Group, Genentech)

  • Joshua C. Denny

    (Vanderbilt University School of Medicine
    Vanderbilt University School of Medicine)

  • Robert J. Carroll

    (Vanderbilt University School of Medicine)

  • Anne E. Eyler

    (Vanderbilt University School of Medicine)

  • Jeffrey D. Greenberg

    (New York University Hospital for Joint Diseases)

  • Joel M. Kremer

    (Albany Medical Center and The Center for Rheumatology)

  • Dimitrios A. Pappas

    (New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University)

  • Lei Jiang

    (Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.)

  • Jian Yin

    (Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.)

  • Lingying Ye

    (Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.)

  • Ding-Feng Su

    (Second Military Medical University, Shanghai 200433, China.)

  • Jian Yang

    (University of Queensland Diamantina Institute, Translational Research Institute
    Queensland Brain Institute, The University of Queensland)

  • Gang Xie

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
    Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada.
    University of Toronto, Toronto, Ontario M5S 2J7, Canada.)

  • Ed Keystone

    (Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada.)

  • Harm-Jan Westra

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands.)

  • Tõnu Esko

    (Program in Medical and Population Genetics, Broad Institute
    Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia.
    Children’s Hospital)

  • Andres Metspalu

    (Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia.)

  • Xuezhong Zhou

    (School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China.)

  • Namrata Gupta

    (Program in Medical and Population Genetics, Broad Institute)

  • Daniel Mirel

    (Program in Medical and Population Genetics, Broad Institute)

  • Eli A. Stahl

    (The Department of Psychiatry at Mount Sinai School of Medicine)

  • Dorothée Diogo

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Jing Cui

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Katherine Liao

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

  • Michael H. Guo

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Children’s Hospital)

  • Keiko Myouzen

    (Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.)

  • Takahisa Kawaguchi

    (Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.)

  • Marieke J. H. Coenen

    (Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.)

  • Piet L. C. M. van Riel

    (Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands.)

  • Mart A. F. J. van de Laar

    (Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands.)

  • Henk-Jan Guchelaar

    (Leiden University Medical Center, Leiden 2300 RC, the Netherlands.)

  • Tom W. J. Huizinga

    (Leiden University Medical Center, Leiden 2300 RC, the Netherlands.)

  • Philippe Dieudé

    (Service de Rhumatologie et INSERM U699 Hôpital Bichat Claude Bernard, Assistance Publique des Hôpitaux de Paris, Paris 75018, France.
    Université Paris 7-Diderot, Paris 75013, France.)

  • Xavier Mariette

    (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.)

  • S. Louis Bridges Jr

    (University of Alabama at Birmingham)

  • Alexandra Zhernakova

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands.
    Leiden University Medical Center, Leiden 2300 RC, the Netherlands.)

  • Rene E. M. Toes

    (Leiden University Medical Center, Leiden 2300 RC, the Netherlands.)

  • Paul P. Tak

    (AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
    GlaxoSmithKline, Stevenage SG1 2NY, UK.
    University of Cambridge, Cambridge CB2 1TN, UK.)

  • Corinne Miceli-Richard

    (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.)

  • So-Young Bang

    (Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea.)

  • Hye-Soon Lee

    (Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea.)

  • Javier Martin

    (Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain.)

  • Miguel A. Gonzalez-Gay

    (Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain.)

  • Luis Rodriguez-Rodriguez

    (Hospital Clinico San Carlos, Madrid 28040, Spain.)

  • Solbritt Rantapää-Dahlqvist

    (Umeå University, Umeå SE-901 87, Sweden.
    Umeå University, Umeå SE-901 87, Sweden.)

  • Lisbeth Ärlestig

    (Umeå University, Umeå SE-901 87, Sweden.
    Umeå University, Umeå SE-901 87, Sweden.)

  • Hyon K. Choi

    (Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School
    Section of Rheumatology, Boston University School of Medicine
    Clinical Epidemiology Research and Training Unit, Boston University School of Medicine)

  • Yoichiro Kamatani

    (Centre d’Etude du Polymorphisme Humain (CEPH), Paris 75010, France.)

  • Pilar Galan

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

  • Mark Lathrop

    (McGill University and Génome Québec Innovation Centre, Montréal, Québec H3A 0G1 Canada.)

  • Steve Eyre

    (Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
    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.)

  • John Bowes

    (Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
    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.)

  • Anne Barton

    (Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.)

  • Niek de Vries

    (Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.)

  • Larry W. Moreland

    (University of Pittsburgh)

  • Lindsey A. Criswell

    (Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco)

  • Elizabeth W. Karlson

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School)

  • Atsuo Taniguchi

    (Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.)

  • Ryo Yamada

    (Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan.)

  • Michiaki Kubo

    (Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.)

  • Jun S. Liu

    (Harvard University)

  • Sang-Cheol Bae

    (Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea.)

  • Jane Worthington

    (Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK.
    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.)

  • Leonid Padyukov

    (Rheumatology Unit, Karolinska Institutet, Stockholm SE-171 76, Sweden.)

  • Lars Klareskog

    (Rheumatology Unit, Karolinska Institutet, Stockholm SE-171 76, Sweden.)

  • Peter K. Gregersen

    (The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System)

  • Soumya Raychaudhuri

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK.)

  • Barbara E. Stranger

    (Section of Genetic Medicine, University of Chicago
    Institute for Genomics and Systems Biology, University of Chicago)

  • Philip L. De Jager

    (Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women’s Hospital)

  • Lude Franke

    (University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands.)

  • Peter M. Visscher

    (University of Queensland Diamantina Institute, Translational Research Institute
    Queensland Brain Institute, The University of Queensland)

  • Matthew A. Brown

    (University of Queensland Diamantina Institute, Translational Research Institute)

  • Hisashi Yamanaka

    (Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.)

  • Tsuneyo Mimori

    (Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.)

  • Atsushi Takahashi

    (Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.)

  • Huji Xu

    (Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.)

  • Timothy W. Behrens

    (Immunology Biomarkers Group, Genentech)

  • Katherine A. Siminovitch

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
    Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada.
    University of Toronto, Toronto, Ontario M5S 2J7, Canada.)

  • Shigeki Momohara

    (Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo 162-0054, Japan.)

  • Fumihiko Matsuda

    (Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
    Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
    Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.)

  • Kazuhiko Yamamoto

    (Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan.
    Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.)

  • Robert M. Plenge

    (Immunology, and Allergy, Brigham and Women’s Hospital, Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School
    Program in Medical and Population Genetics, Broad Institute)

Abstract

A genome-wide association study meta-analysis of more than 100,000 subjects of European and Asian ancestries reveals 42 new risk loci for rheumatoid arthritis, with follow-up studies identifying 98 biological candidate genes that are either already being targeted by drugs or could be in the future.

Suggested Citation

  • 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 Ortman, 2014. "Genetics of rheumatoid arthritis contributes to biology and drug discovery," Nature, Nature, vol. 506(7488), pages 376-381, February.
    • Handle: RePEc:nat:nature:v:506:y:2014:i:7488:d:10.1038_nature12873
    DOI: 10.1038/nature12873
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    1. Thorunn A. Olafsdottir & Gudmar Thorleifsson & Aitzkoa Lopez de Lapuente Portilla & Stefan Jonsson & Lilja Stefansdottir & Abhishek Niroula & Aslaug Jonasdottir & Hannes P. Eggertsson & Gisli H. Halld, 2024. "Sequence variants influencing the regulation of serum IgG subclass levels," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Duc-Hau Le, 2021. "A network-based method for predicting disease-associated enhancers," PLOS ONE, Public Library of Science, vol. 16(12), pages 1-20, December.
    3. Mike Thompson & Mary Grace Gordon & Andrew Lu & Anchit Tandon & Eran Halperin & Alexander Gusev & Chun Jimmie Ye & Brunilda Balliu & Noah Zaitlen, 2022. "Multi-context genetic modeling of transcriptional regulation resolves novel disease loci," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Koen F. Dekkers & Roderick C. Slieker & Andreea Ioan-Facsinay & Maarten Iterson & M. Arfan Ikram & Marleen M. J. Greevenbroek & Jan H. Veldink & Lude Franke & Dorret I. Boomsma & P. Eline Slagboom & J, 2023. "Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    5. Elizabeth C. Goode & Laura Fachal & Nikolaos Panousis & Loukas Moutsianas & Rebecca E. McIntyre & Benjamin Yu Hang Bai & Norihito Kawasaki & Alexandra Wittmann & Tim Raine & Simon M. Rushbrook & Carl , 2024. "Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. Kaitlyn A. Lagattuta & Hannah L. Park & Laurie Rumker & Kazuyoshi Ishigaki & Aparna Nathan & Soumya Raychaudhuri, 2024. "The genetic basis of autoimmunity seen through the lens of T cell functional traits," Nature Communications, Nature, vol. 15(1), pages 1-6, December.
    7. Pietro Demela & Nicola Pirastu & Blagoje Soskic, 2023. "Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Andrew A. Brown & Juan J. Fernandez-Tajes & Mun-gwan Hong & Caroline A. Brorsson & Robert W. Koivula & David Davtian & Théo Dupuis & Ambra Sartori & Theodora-Dafni Michalettou & Ian M. Forgie & Jonath, 2023. "Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Taehyeung Kim & Marta Martínez-Bonet & Qiang Wang & Nicolaj Hackert & Jeffrey A. Sparks & Yuriy Baglaenko & Byunghee Koh & Roxane Darbousset & Raquel Laza-Briviesca & Xiaoting Chen & Vitor R. C. Aguia, 2024. "Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Kenichi Yamamoto & Shinichi Namba & Kyuto Sonehara & Ken Suzuki & Saori Sakaue & Niall P. Cooke & Shinichi Higashiue & Shuzo Kobayashi & Hisaaki Afuso & Kosho Matsuura & Yojiro Mitsumoto & Yasuhiko Fu, 2024. "Genetic legacy of ancient hunter-gatherer Jomon in Japanese populations," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. Maik Pietzner & Eleanor Wheeler & Julia Carrasco-Zanini & Nicola D. Kerrison & Erin Oerton & Mine Koprulu & Jian’an Luan & Aroon D. Hingorani & Steve A. Williams & Nicholas J. Wareham & Claudia Langen, 2021. "Synergistic insights into human health from aptamer- and antibody-based proteomic profiling," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    12. Patrick Wu & QiPing Feng & Vern Eric Kerchberger & Scott D. Nelson & Qingxia Chen & Bingshan Li & Todd L. Edwards & Nancy J. Cox & Elizabeth J. Phillips & C. Michael Stein & Dan M. Roden & Joshua C. D, 2022. "Integrating gene expression and clinical data to identify drug repurposing candidates for hyperlipidemia and hypertension," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    13. Clara Albiñana & Zhihong Zhu & Nis Borbye-Lorenzen & Sanne Grundvad Boelt & Arieh S. Cohen & Kristin Skogstrand & Naomi R. Wray & Joana A. Revez & Florian Privé & Liselotte V. Petersen & Cynthia M. Bu, 2023. "Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Roy Oelen & Dylan H. Vries & Harm Brugge & M. Grace Gordon & Martijn Vochteloo & Chun J. Ye & Harm-Jan Westra & Lude Franke & Monique G. P. Wijst, 2022. "Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Feng Jiang & Shou-Ye Hu & Wen Tian & Nai-Ning Wang & Ning Yang & Shan-Shan Dong & Hui-Miao Song & Da-Jin Zhang & Hui-Wu Gao & Chen Wang & Hao Wu & Chang-Yi He & Dong-Li Zhu & Xiao-Feng Chen & Yan Guo , 2024. "A landscape of gene expression regulation for synovium in arthritis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. James J. Gilchrist & Seiko Makino & Vivek Naranbhai & Piyush K. Sharma & Surya Koturan & Orion Tong & Chelsea A. Taylor & Robert A. Watson & Alba Verge los Aires & Rosalin Cooper & Evelyn Lau & Sara D, 2022. "Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    17. Mary-Ellen Lynall & Blagoje Soskic & James Hayhurst & Jeremy Schwartzentruber & Daniel F. Levey & Gita A. Pathak & Renato Polimanti & Joel Gelernter & Murray B. Stein & Gosia Trynka & Menna R. Clatwor, 2022. "Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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