Letter | Published:

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

Nature Genetics volume 44, pages 6772 (2012) | Download Citation

Abstract

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

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Acknowledgements

We thank all the participants and the staff of the BioBank Japan project. The project was supported by a grant from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan.

The Japan Cardiometabolic Genome Epidemiology (CAGE) Network Studies were supported by grants for the Program for Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); the Core Research for Evolutional Science and Technology (CREST) from the Japan Science Technology Agency; the Grant of National Center for Global Health and Medicine (NCGM).

We thank the Office of Population Studies Foundation research and data collection teams for the Cebu Longitudinal Health and Nutrition Survey. This work was supported by US National Institutes of Health grants DK078150, TW05596, HL085144 and TW008288 and pilot funds from grants RR20649, ES10126, and DK56350.

We acknowledge support from the Hong Kong Government Research Grants Council Central Allocation Scheme (CUHK 1/04C), Research Grants Council Earmarked Research Grant (CUHK4724/07M) and the Innovation and Technology Fund of the Government of the Hong Kong Special Administrative Region (ITS/487/09FP). We acknowledge the Chinese University of Hong Kong Information Technology Services Center for support of computing resources. We would also like to thank the dedicated medical and nursing staff at the Prince of Wales Hospital Diabetes and Endocrine Centre.

This work was supported by grants from Korea Centers for Disease Control and Prevention (4845-301, 4851-302, 4851-307) and an intramural grant from the Korea National Institute of Health (2011-N73005-00), the Republic of Korea.

The work by the National Taiwan University Hospital was supported in part by the grant (NSC99-3112-B-002-019) from the National Science Council of Taiwan. We would also like to acknowledge the National Genotyping Center of National Research Program for Genomic Medicine (NSC98-3112-B-001-037), Taiwan.

The work by the Shanghai Diabetes Genetic Study was supported in part by the US National Institutes of Health grants R01CA124558, R01CA64277, R01CA70867, R01CA90899, R01CA100374, R01CA118229, R01CA92585, UL1 RR024975, DK58845 and HG004399, the Department of Defense Idea Award BC050791, Vanderbilt Ingram professorship funds and the Allen Foundation Fund. We thank the dedicated investigators and staff members from research teams at Vanderbilt University, Shanghai Cancer Institute and the Shanghai Institute of Preventive Medicine, and especially, the study participants for their contributions in the studies.

The work of the Shanghai Diabetes Study was supported by grants from the National 973 Program (2011CB504001), the Project of National Natural Science Foundation of China (30800617) and the Shanghai Rising-Star Program (09QA1404400), China.

The work of the Shanghai Jiao Tong University Diabetes Study was supported by grants from the National 863 Program (2006AA02A409) and the major program of the Shanghai Municipality for Basic Research (08dj1400601), China.

The work of the Seoul National University Hospital was supported by grants from the Korea Health 21 R&D Project, Ministry of Health & Welfare (00-PJ3-PG6-GN07-001) and the World Class University project of the Ministry of Education, Science and Technology (MEST) and National Research Foundation (NRF) (R31-2008-000-10103-0), Korea. The Singapore Prospective Study Program (SP2) was funded through grants from the Biomedical Research Council of Singapore (BMRC05/1/36/19/413 and 03/1/27/18/216) and the National Medical Research Council of Singapore (NMRC/1174/2008). E.S.T. also receives additional support from the National Medical Research Council through a clinicians scientist award (NMRC/CSA/008/2009). The Singapore Malay Eye Study (SiMES) was funded by the National Medical Research Council (NMRC0796/2003 and NMRC/STaR/0003/2008) and Biomedical Research Council (BMRC, 09/1/35/19/616). Y.Y.T. acknowledges support from the Singapore National Research Foundation, NRF-RF-2010-05. The Genome Institute of Singapore carried out all the genotyping for the samples from Singapore also provided funding for the genotyping of the samples from SP2.

Author information

Author notes

    • Yoon Shin Cho
    • , Chien-Hsiun Chen
    • , Cheng Hu
    • , Jirong Long
    • , Rick Twee Hee Ong
    • , Xueling Sim
    • , Fumihiko Takeuchi
    • , Ying Wu
    • , Min Jin Go
    • , Toshimasa Yamauchi
    • , Yi-Cheng Chang
    • , Soo Heon Kwak
    • , Ronald C W Ma
    •  & Ken Yamamoto

    These authors contributed equally to this work.

    • Ryoichi Takayanagi
    • , Kyong Soo Park
    • , Weiping Jia
    • , Lee-Ming Chuang
    • , Juliana C N Chan
    • , Shiro Maeda
    • , Takashi Kadowaki
    • , Jong-Young Lee
    • , Jer-Yuarn Wu
    • , Yik Ying Teo
    • , E Shyong Tai
    • , Xiao Ou Shu
    • , Karen L Mohlke
    • , Norihiro Kato
    • , Bok-Ghee Han
    •  & Mark Seielstad

    These authors jointly directed this work.

Affiliations

  1. Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-do, Cheongwon-gun, Gangoe-myeon, Yeonje-ri, Korea.

    • Yoon Shin Cho
    • , Min Jin Go
    • , Hyung-Lae Kim
    • , Young Jin Kim
    • , Jong-Young Lee
    •  & Bok-Ghee Han
  2. Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan.

    • Chien-Hsiun Chen
    • , Li-Ching Chang
    • , Yuan-Tsong Chen
    •  & Jer-Yuarn Wu
  3. School of Chinese Medicine, China Medical University, Taichung, Taiwan.

    • Chien-Hsiun Chen
    • , Fuu-Jen Tsai
    •  & Jer-Yuarn Wu
  4. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

    • Cheng Hu
    • , Rong Zhang
    • , Congrong Wang
    • , Yuqian Bao
    •  & Weiping Jia
  5. Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Jirong Long
    • , Qiuyin Cai
    • , Wei Zheng
    •  & Xiao Ou Shu
  6. Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore.

    • Rick Twee Hee Ong
    •  & Yik Ying Teo
  7. Centre for Molecular Epidemiology, National University of Singapore, Singapore, Singapore.

    • Xueling Sim
    •  & Yik Ying Teo
  8. Research Institute, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan.

    • Fumihiko Takeuchi
    •  & Norihiro Kato
  9. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Ying Wu
    • , Yun Li
    •  & Karen L Mohlke
  10. Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Toshimasa Yamauchi
    • , Kazuo Hara
    •  & Takashi Kadowaki
  11. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

    • Yi-Cheng Chang
    • , Tien-Jyun Chang
    •  & Lee-Ming Chuang
  12. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

    • Soo Heon Kwak
    • , Young Min Cho
    •  & Kyong Soo Park
  13. Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.

    • Ronald C W Ma
    • , Wing Yee So
    •  & Juliana C N Chan
  14. Division of Genome Analysis, Research Center for Genetic Information, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka, Japan.

    • Ken Yamamoto
  15. Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Linda S Adair
  16. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore.

    • Tin Aung
    • , Wan Ting Tay
    •  & Tien Yin Wong
  17. Department of Ophthalmology, National University of Singapore, Singapore, Singapore.

    • Tin Aung
    •  & Tien Yin Wong
  18. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China.

    • Yutang Gao
  19. Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Frank B Hu
  20. Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Korea.

    • Hyung-Lae Kim
  21. School of Systems Biomedical Science, Soongsil University, Dongjak-gu, Seoul, Korea.

    • Sangsoo Kim
  22. Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore.

    • Jeannette Jen-Mai Lee
    • , Daniel Peng-Keat Ng
    • , Yik Ying Teo
    •  & E Shyong Tai
  23. Office of Population Studies Foundation Inc., University of San Carlos, Cebu City, Philippines.

    • Nanette R Lee
  24. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Yun Li
  25. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.

    • Jian Jun Liu
    • , Yik Ying Teo
    •  & Mark Seielstad
  26. Shanghai Institute of Preventive Medicine, Shanghai, China.

    • Wei Lu
  27. Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

    • Jiro Nakamura
    •  & Eitaro Nakashima
  28. Department of Diabetes and Endocrinology, Chubu Rosai Hospital, Nagoya, Japan.

    • Eitaro Nakashima
  29. Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.

    • Tien Yin Wong
  30. Department of Genome Science, Aichi-Gakuin University, School of Dentistry, Nagoya, Japan.

    • Mitsuhiro Yokota
  31. Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

    • Keizo Ohnaka
  32. Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka-sayama, Osaka, Japan.

    • Hiroshi Ikegami
  33. Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea.

    • Nam H Cho
  34. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Åsa K Hedman
    • , Andrew P Morris
    •  & Mark I McCarthy
  35. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  36. Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

    • Ryoichi Takayanagi
  37. World Class University program, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, Seoul, Korea.

    • Kyong Soo Park
  38. Graduate Institute of Clinical Medicine, National Taiwan University School of Medicine, Taipei, Taiwan.

    • Lee-Ming Chuang
    •  & Shiro Maeda
  39. Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, Yokohama, Japan.

  40. Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.

    • Yik Ying Teo
  41. Department of Medicine, National University of Singapore, Singapore, Singapore.

    • E Shyong Tai
  42. Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.

    • E Shyong Tai
  43. Institute for Human Genetics, University of California, San Francisco, California, USA.

    • Mark Seielstad
  44. Blood Systems Research Institute, San Francisco, California, USA.

    • Mark Seielstad

Consortia

  1. DIAGRAM Consortium

    A list of full members is provided in the Supplementary Note.

  2. MuTHER Consortium

    A list of full members is provided in the Supplementary Note.

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Contributions

The study was supervised by E.S.T., B.-G.H., N.K., Y.S.C., Y.Y.T., W.Z., Q.C., X.O.S., Y.-T.C., J.-Y.W., L.S.A., K.L.M., T.K., C.H., W.J., L.-M.C., Y.M.C., K.S.P., J.-Y.L. and J.C.N.C. The experiments were conceived of and designed by Y.S.C., E.S.T., N.K., D.P.-K.N., J.J.-M.L., M.S., T.Y.W., Y.Y.T., W.Z., F.B.H., X.O.S., C.-H.C., F.-J.T., Y.-T.C., J.-Y.W., L.S.A., K.L.M., S.M., C.H., L.-M.C., K.S.P., M.J.G., M.I.M. and R.C.W.M. The experiments were performed by J.L., M.S., J.J.L., J.-Y.W., S.M., R.Z., K.Y., Y.-C.C., T.-J.C., L.-M.C. and S.H.K. Statistical analyses was performed by M.J.G., X.S., Y.J.K., R.T.H.O., W.T.T., Y.Y.T., F.T., J.L., C.-H.C., L.-C.C., Y.W., Y.L., K.H., C.H., Y.-C.C., S.H.K., A.P.M. and R.C.W.M. The data were analyzed by M.J.G., X.S., Y.J.K., R.T.H.O., W.T.T., Y.Y.T., J.L., C.-H.C., L.-C.C., Y.W., N.R.L., Y.L., L.S.A., K.L.M., T.Y., C.H., Y.-C.C., S.H.K., Y.S.C., S.K., Å.K.H. and R.C.W.M. The reagents, materials and analysis tools were contributed by E.S.T., B.-G.H., N.K., D.P.-K.N., J.J.-M.L., J.L., M.S., T.A., T.Y.W., E.N., M.Y., J.N., J.J.L., W.Z., Q.C., Y.G., W.L., F.B.H., X.O.S., F.-J.T., Y.-T.C., J.-Y.W., N.R.L., Y.L., K.O., H.I., R.T., C.W., Y.B., T.-J.C., L.-M.C., K.S.P., H.-L.K., N.H.C., J.-Y.L., W.Y.S. and J.C.N.C. The manuscript was written by Y.S.C., M.S. and E.S.T. All authors reviewed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yoon Shin Cho or E Shyong Tai or Mark Seielstad.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–10 and Supplementary Figures 1–4.

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DOI

https://doi.org/10.1038/ng.1019

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