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A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Nature Genetics volume 42, pages 864–868 (2010)Cite this article

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Abstract

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10−9; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10−9). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10−14, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.

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Figure 1: Experimental design of the three-stage Japanese GWAS and extension to different populations.

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Acknowledgements

We thank all participating doctors and staff from collaborating institutes for providing DNA samples. We also thank the technical staff of the Laboratory for Endocrinology and Metabolism at the RIKEN Center for Genomic Medicine for providing technical assistance. We thank the technical staff of the Laboratory for Genotyping Development at the RIKEN Center for Genomic Medicine for SNP genotyping. We also thank all the participants and the staff of the BioBank Japan project. This work was partly supported by a grant from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan.

Funding for the Singapore portion of the study was supported by the National Medical Research Council (NMRC/1115/2007). We thank the staff of the National Healthcare Group Polyclinics and the National University of Singapore for their contributions towards the establishment of the Singapore Diabetes Cohort Study.

The Korean panel was supported by a grant from the Korea Health 21 Research and Development Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (00-PJ3-PG6-GN07-001).

The Danish study was funded by grants from the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LuCAMP), European Union (EUGENE2) grant LSHM-CT-2004-512013, EXGENESIS (Health benefits of exercise: identification of genes and signaling pathways involved in effects of exercise on insulin resistance, obesity and the metabolic syndrome) grant LSHM-CT-2004- 005272 and the Danish Diabetes Association and the Danish Agency for Science, Technology and Innovation, grant no. 271-06-0539. The Inter99 was initiated by T. Jørgensen (primary investigator), K. Borch-Johnsen (co-primary investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises T. Jørgensen, K. Borch-Johnsen and C. Pisinger. The ADDITION (The Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care) study Denmark was initiated by K. Borch-Johnsen (primary investigator), T. Lauritzen (primary investigator) and A. Sandbæk.

Author information

Author notes

  1. Toshimasa Yamauchi, Kazuo Hara and Shiro Maeda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Toshimasa Yamauchi, Kazuo Hara, Momoko Horikoshi, Masahiro Nakamura, Hayato Fujita, Miki Okada-Iwabu, Masato Iwabu, Nobuhiro Shojima & Takashi Kadowaki

  2. Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo, Japan

    Toshimasa Yamauchi, Miki Okada-Iwabu & Masato Iwabu

  3. Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan

    Shiro Maeda

  4. Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Kazuki Yasuda

  5. Laboratory for Statistical Analysis, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan

    Atsushi Takahashi & Naoyuki Kamatani

  6. Hagedorn Research Institute, Gentofte, Denmark

    Niels Grarup, Gitte Andersen, Torben Hansen & Oluf Pedersen

  7. Centre National de la Recherche Scientifique–Unité Mixte de Recherche–8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France

    Stephane Cauchi, Delphine Beury & Philippe Froguel

  8. Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Daniel P K Ng

  9. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong

    Ronald C W Ma, Wing-Yee So & Juliana C N Chan

  10. Laboratory for Medical Informatics, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan

    Tatsuhiko Tsunoda

  11. Laboratory for Genotyping Development, RIKEN Center for Genomic Medicine, Yokohama, Kanagawa, Japan

    Michiaki Kubo

  12. Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Hirotaka Watada & Ryuzo Kawamori

  13. Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

    Hiroshi Maegawa & Atsunori Kashiwagi

  14. Department of Life Science, Laboratory of Genomic Diversity, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, Korea

    Hyoung Doo Shin

  15. Steno Diabetes Center, Gentofte, Denmark

    Daniel R Witte & Torben Hansen

  16. Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

    Daniel R Witte & Oluf Pedersen

  17. Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark

    Torben Jørgensen

  18. Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Torben Jørgensen & Oluf Pedersen

  19. Department of General Practice, University of Aarhus, Aarhus, Denmark

    Torsten Lauritzen & Annelli Sandbæk

  20. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    Torben Hansen

  21. Department of Medicine, Metabolism and Endocrinology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan

    Toshihiko Ohshige, Shintaro Omori & Yasushi Tanaka

  22. Keio University Health Center, Tokyo, Japan

    Ikuo Saito & Hiroshi Hirose

  23. Division of Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan

    Kohei Kaku

  24. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

    Kyong Soo Park

  25. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    E Shyong Tai

  26. Medical Court Life Care Clinic, Hiroshima, Japan

    Chikako Ito

  27. Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Masato Kasuga

  28. Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK

    Philippe Froguel

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

    Yusuke Nakamura

Authors
  1. Toshimasa Yamauchi
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  2. Kazuo Hara
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  46. Takashi Kadowaki
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Contributions

T.K., S.M., T.Y. and K.H. planned and coordinated the study. Y.N. managed BioBank Japan. K.H., S.M., K.Y., M.H., T.Y., M.K., H.W., H.M., H.D.S., D.R.W., T.J., T.L., A.S., T.H., T.O., S.O., I.S., K.K., H.H., W.-Y.S., D.B., E.S.T., C.I., Y.T., A.K., R.K., M.K., O.P. and T.K. recruited and phenotyped or genotyped subject cohorts. A.T., T.T., N.K., S.M., K.H., M.N., H.F., M.O.-I., M.I., N.S., N.G., G.A., S.C., D.P.K.N., R.C.W.M., M.K., T.Y., K.K., J.C.N.C., K.S.P., P.F., T.H., O.P. and T.K. analyzed the genotyping data. T.Y., T.K., S.M. and K.H. wrote the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Shiro Maeda or Takashi Kadowaki.

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The authors declare no competing financial interests.

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Yamauchi, T., Hara, K., Maeda, S. et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet 42, 864–868 (2010). https://doi.org/10.1038/ng.660

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