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Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population

Nature Genetics volume 44, pages 511–516 (2012)Cite this article

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Abstract

Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 × 10−8, including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 × 10−4 and 2.9 × 10−4, respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations.

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Figure 1: Manhattan plots of the GWAS meta-analysis for rheumatoid arthritis in the Japanese population.
Figure 2: Regional plots of the loci newly associated with rheumatoid arthritis at the genome-wide significance threshold of P < 5.0 × 10−8 in the combined study of the meta-analysis and the replication study.
Figure 3: Overlap of the associations with rheumatoid arthritis between Japanese and European populations.

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Acknowledgements

The authors acknowledge the essential role of the GARNET consortium in developing the study. In this study, the following GARNET members are included: CGM of RIKEN, University of Tokyo, the BioBank Japan Project, Kyoto University and IORRA. We would like to thank all the doctors and staff who participated in sample collection for the RIKEN cohort and the BioBank Japan Project. We thank K. Kobayashi and M. Kitazato for their technical assistance. We thank T. Raj for calculation of composite of multiple signals (CMS). We thank M. Kokubo for DNA extraction, GWAS genotyping and secretarial assistance. We would also like to thank H. Yoshifuji, N. Yukawa, D. Kawabata, T. Nojima, T. Usui and T. Fujii for collecting DNA samples. We thank Y. Katagiri for her technical efforts. We also appreciate the contribution of E. Inoue and other members of the Institute of Rheumatology, Tokyo Women's Medical University, for their efforts on the IORRA cohort. This study was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan, the Ministry of Health, Labour and Welfare (MHLW) in Japan, the Japan Society for the Promotion of Science (JSPS), Core Research for Evolutional Science and Technology (CREST), Solution-Oriented Research for Science and Technology (SORST), INSERM and the Okawa Foundation for Information and Telecommunications.

Author information

Author notes

  1. Yukinori Okada, Chikashi Terao, Katsunori Ikari and Yuta Kochi: These authors contributed equally to this work.

  2. Shigeki Momohara, Ryo Yamada, Fumihiko Matsuda and Kazuhiko Yamamoto: These authors jointly directed this work.

Authors and Affiliations

  1. Laboratory for Autoimmune Diseases, Center for Genomic Medicine (CGM), RIKEN, Yokohama, Japan

    Yukinori Okada, Yuta Kochi, Akari Suzuki, Keiko Myouzen & Kazuhiko Yamamoto

  2. Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Yukinori Okada, Yuta Kochi & Kazuhiko Yamamoto

  3. Laboratory for Statistical Analysis, CGM, RIKEN, Yokohama, Japan

    Yukinori Okada, Hiroko Ohmiya & Atsushi Takahashi

  4. Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Chikashi Terao, Takahisa Kawaguchi, Meiko Takahashi & Fumihiko Matsuda

  5. Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Chikashi Terao, Koichiro Ohmura & Tsuneyo Mimori

  6. Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

    Katsunori Ikari, Taku Suzuki, Takuji Iwamoto, Atsuo Taniguchi, Hisashi Yamanaka & Shigeki Momohara

  7. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Eli A Stahl, Fina A S Kurreeman & Robert M Plenge

  8. Broad Institute, Cambridge, Massachusetts, USA

    Eli A Stahl, Fina A S Kurreeman & Robert M Plenge

  9. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    Fina A S Kurreeman

  10. Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Nao Nishida & Katsushi Tokunaga

  11. Department of Rheumatology, Tokyo Medical University Hospital, Tokyo, Japan

    Tetsuji Sawada

  12. Yamanashi Prefectural Central Hospital, Yamanashi, Japan

    Yuichi Nishioka

  13. Department of Orthopaedic Surgery, Yukioka Hospital, Osaka, Japan

    Masao Yukioka

  14. Matsubara Mayflower Hospital, Hyogo, Japan

    Tsukasa Matsubara

  15. Osaka Minami National Hospital, Osaka, Japan

    Shigeyuki Wakitani

  16. Department of Orthopedic Surgery, Tottori University, Tottori, Japan

    Ryota Teshima

  17. Department of Rheumatology, National Hospital Organization, Sagamihara Hospital, Kanagawa, Japan

    Shigeto Tohma & Kota Shimada

  18. Center for Rheumatic Diseases, Dohgo Spa Hospital, Ehime, Japan

    Kiyoshi Takasugi

  19. Department of Rheumatology, Niigata Rheumatic Center, Niigata, Japan

    Akira Murasawa

  20. Saiseikai Takaoka Hospital, Toyama, Japan

    Shigeru Honjo

  21. Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan

    Keitaro Matsuo & Hideo Tanaka

  22. Aichi Cancer Center Hospital and Research Institute, Aichi, Japan

    Kazuo Tajima

  23. Department of Orthopaedic Surgery, Keio University, Tokyo, Japan

    Taku Suzuki & Takuji Iwamoto

  24. Yokohama Clinic, Warakukai Medical Corporation, Yokohama, Japan

    Yoshiya Kawamura

  25. Department of Psychiatry, Mie University School of Medicine, Mie, Japan

    Hisashi Tanii

  26. Metropolitan Matsuzawa Hospital, Tokyo, Japan

    Yuji Okazaki

  27. Graduate School of Education, University of Tokyo, Tokyo, Japan

    Tsukasa Sasaki

  28. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA

    Peter K Gregersen

  29. Department of Medicine in Solna, Rheumatology Unit, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Leonid Padyukov

  30. Arthritis Research Campaign–Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    Jane Worthington

  31. Division of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada

    Katherine A Siminovitch

  32. Commisariat a l'Energie Atomique (CEA), Institut Genomique, Centre National de Genotypage, Evry, France

    Mark Lathrop

  33. Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France

    Mark Lathrop

  34. Laboratory for Genotyping Development, CGM, RIKEN, Yokohama, Japan

    Michiaki Kubo

  35. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yusuke Nakamura

  36. Laboratory for International Alliance, CGM, RIKEN, Yokohama, Japan

    Naoyuki Kamatani

  37. Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto, Japan

    Ryo Yamada

  38. Core Research for Evolutional Science and Technology (CREST) Program, Japan Science and Technology Agency, Kawaguchi, Japan

    Fumihiko Matsuda

  39. Institut National de la Santé et de la Recherche Médicale (INSERM), Unité U852, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Fumihiko Matsuda

Authors
  1. Yukinori Okada
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  2. Chikashi Terao
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Contributions

Y. Okada, C.T., K.I., Y. Kochi and K.O. designed the study and drafted the manuscript. Y. Okada, C.T., K.I., T.K., H.O., N.N., M.T., M.L., K. Tokunaga and M.K. managed genotyping and manipulation of GWAS data. Y. Okada, Y. Kochi, C.T. and K.I. managed genotyping of replication cohorts. Y. Okada, T.K., H.O., E.A.S., A. Takahashi and R.Y. performed statistical analysis. Y. Kochi, A.S., K. Myouzen, T. Sawada, Y. Nishoka, M.Y., T. Matsubara, S.W., R.T. and S.T. collected samples and managed phenotype data for the rheumatoid arthritis cohorts from the BioBank Japan Project and CGM, RIKEN. C.T., K.O., T.K., M.T., K. Takasugi, K.S., A.M., S.H., K. Matsuo, H. Tanaka, K. Tajima and M.L. collected samples and managed phenotype data for the rheumatoid arthritis cohorts from Kyoto University. K.I., T. Suzuki, T.I., Y. Kawamura, H. Tanii, Y. Okazaki and T. Sakaki collected samples and managed phenotype data for the rheumatoid arthritis cohorts from IORRA. Y. Kochi managed the data for the SLE and Graves' disease cohorts. A.S., C.T. and K.I. analyzed the sera of subjects with rheumatoid arthritis. E.A.S., F.A.S.K., P.K.G., J.W., K.A.S., L.P. and R.M.P. managed the data for the rheumatoid arthritis cohorts in European populations. A. Taniguchi, A. Takahashi, K. Tokunaga, M.K., Y. Nakamura, N.K., T. Minori, R.M.P., H.Y., S.M., R.Y., F.M. and K.Y. supervised the overall study.

Corresponding authors

Correspondence to Yuta Kochi or Koichiro Ohmura.

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The authors declare no competing financial interests.

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Okada, Y., Terao, C., Ikari, K. et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet 44, 511–516 (2012). https://doi.org/10.1038/ng.2231

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