Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population

  1. Fumihiko Takeuchi1,2,
  2. Masakuni Serizawa3,
  3. Ken Yamamoto4,
  4. Tomomi Fujisawa5,
  5. Eitaro Nakashima6,7,
  6. Keizo Ohnaka8,
  7. Hiroshi Ikegami9,
  8. Takao Sugiyama10,
  9. Tomohiro Katsuya5,
  10. Makoto Miyagishi3,
  11. Naoki Nakashima11,
  12. Hajime Nawata12,
  13. Jiro Nakamura6,
  14. Suminori Kono13,
  15. Ryoichi Takayanagi14 and
  16. Norihiro Kato3
  1. 1Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan;
  2. 2Wellcome Trust Sanger Institute, Cambridge, U.K;
  3. 3Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, Tokyo, Japan;
  4. 4Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan;
  5. 5Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan;
  6. 6Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan;
  7. 7Department of Metabolism and Endocrine Internal Medicine, Chubu Rosai Hospital, Nagoya, Japan;
  8. 8Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
  9. 9Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine, Osaka, Japan;
  10. 10Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan;
  11. 11Department of Medical Informatics, Kyushu University Hospital, Fukuoka, Japan;
  12. 12Fukuoka Prefectural University, Fukuoka, Tokyo, Japan;
  13. 13Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;
  14. 14Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  1. Corresponding author: Norihiro Kato, nokato{at}ri.imcj.go.jp.

Abstract

OBJECTIVE To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population.

RESEARCH DESIGN AND METHODS In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 × 10–5 for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population.

RESULTS Four loci—1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 × 10–5) and three previously reported—were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10–19). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population.

CONCLUSIONS The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received October 28, 2008.
    • Accepted April 7, 2009.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Published online before print April 28, 2009, doi: 10.2337/db08-1494 Diabetes July 2009 vol. 58 no. 7 1690-1699
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