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

Journal name:
Nature Genetics
Volume:
44,
Pages:
511–516
Year published:
DOI:
doi:10.1038/ng.2231
Received
Accepted
Published online

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.

At a glance

Figures

  1. Manhattan plots of the GWAS meta-analysis for rheumatoid arthritis in the Japanese population.
    Figure 1: Manhattan plots of the GWAS meta-analysis for rheumatoid arthritis in the Japanese population.

    The genetic loci that satisfied the genome-wide significance threshold of P < 5.0 × 10−8 (gray line) in the meta-analysis or in the combined study of the meta-analysis and the replication study are presented. The y axis shows the −log10 P values of the SNPs in the meta-analysis. The SNPs for which the P values were smaller than 1.0 × 10−15 are indicated at the upper limit of the plot.

  2. Regional plots of the loci newly associated with rheumatoid arthritis at the genome-wide significance threshold of P < 5.0 [times] 10-8 in the combined study of the meta-analysis and the replication study.
    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.

    (ai) Regional plots are shown at B3GNT2 (a), ANXA3 (b), CSF2 (c), CD83 (d), NFKBIE (e), ARID5B (f), PDE2A-ARAP1 (g), PLD4 (h) and PTPN2 (i). Diamonds represent the −log10 P values of the SNPs, and the red diamonds represent the −log10 P values of the SNPs in the meta-analysis. Red color for the smaller circles represents the r2 value with the most significantly associated SNP (larger red circle). The purple circle represents the P value in the combined study. The blue line shows the recombination rates given by the HapMap Phase 2 east Asian populations (release 22). RefSeq genes at the loci are indicated below. Genes nearest to the marker SNPs at the loci are colored blue (Supplementary Note), and genes implicated in eQTL analysis are colored red (Supplementary Table 4). At 11q13, two genes (PDE2A and ARAP1) that are nearest to the SNP selected for the replication study and the most significant SNP in the meta-analysis are highlighted. The plots were drawn using SNP Annotation and Proxy Search (SNAP) version 2.2.

  3. Overlap of the associations with rheumatoid arthritis between Japanese and European populations.
    Figure 3: Overlap of the associations with rheumatoid arthritis between Japanese and European populations.

    (a) Forest plots of SNPs in the rheumatoid arthritis susceptibility loci (Supplementary Table 6). We selected the genetic loci that have been validated to be associated with rheumatoid arthritis susceptibility by showing associations in the reports of multiple cohorts or satisfying the genome-wide significant threshold (P < 5.0 × 10−8) in previous studies, including in the meta-analysis and replication phases1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. For each of the loci, the most significant SNP among those reported in the previous or present study were selected1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. SNPs in the newly identified rheumatoid arthritis susceptibility loci are colored green. Odds ratios and 95% confidence interval (CI) values are based on rheumatoid arthritis risk alleles, and the SNPs are ordered according to the odds ratios in the Japanese study. Several SNPs were monomorphic in the Japanese population. The odds ratios of these SNPs in the European study are presented below. The asterisk indicates that an association of another variant at the IRF5 locus was reported in the Japanese population24. (b) Correlation of the odds ratios of the SNPs in the validated rheumatoid arthritis susceptibility loci between the two populations. SNPs that were polymorphic in both populations were used; odds ratios were based on the minor allele in the Japanese population. (c) Correlation of the odds ratios of the genome-wide SNPs, excluding the rheumatoid arthritis susceptibility loci. Correlations were evaluated for sets of SNPs stratified by the thresholds based on the meta-analysis P values in each population after pruning of the SNPs by LD (r2 < 0.3). Correlation coefficient and 95% CI are indicated on the y axis. Significant correlation of the odds ratios was observed (, P < 0.005), even for the SNPs that showed moderate associations with rheumatoid arthritis (meta-analysis P < 0.4 in each population).

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Author information

  1. These authors contributed equally to this work.

    • Yukinori Okada,
    • Chikashi Terao,
    • Katsunori Ikari &
    • Yuta Kochi
  2. These authors jointly directed this work.

    • Shigeki Momohara,
    • Ryo Yamada,
    • Fumihiko Matsuda &
    • Kazuhiko Yamamoto

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. Rheumatology Unit, Department of Medicine in Solna, 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

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.

Competing financial interests

The authors declare no competing financial interests.

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    Supplementary Tables 1–6, Supplementary Figures 1–3 and Supplementary Note

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