Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population
- Fumihiko Takeuchi1,2,
- Masakuni Serizawa3,
- Ken Yamamoto4,
- Tomomi Fujisawa5,
- Eitaro Nakashima6,7,
- Keizo Ohnaka8,
- Hiroshi Ikegami9,
- Takao Sugiyama10,
- Tomohiro Katsuya5,
- Makoto Miyagishi3,
- Naoki Nakashima11,
- Hajime Nawata12,
- Jiro Nakamura6,
- Suminori Kono13,
- Ryoichi Takayanagi14 and
- Norihiro Kato (nokato{at}ri.imcj.go.jp)3
- 1 Department of Medical Ecology and Informatics and
- 3 Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan
- 2 Wellcome Trust Sanger Institute
- 4 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University
- 5 Department of Geriatric Medicine, Osaka University Graduate School of Medicine
- 6 Division of Endocrinology and Diabetes, Department of Internal Medicine, Nagoya University Graduate School of Medicine
- 7 Department of Metabolism and Endocrine Internal Medicine, Chubu Rosai Hospital
- 8 Department of Geriatric Medicine
- 13 Department of Preventive Medicine and
- 14 Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University
- 9 Department of Endocrinology, Metabolism and Diabetes, Kinki University School of Medicine
- 10 Institute for Adult Diseases, Asahi Life Foundation
- 11 Department of Medical Informatics, Kyushu University Hospital
- 12 Fukuoka Prefectural University
Abstract
Objective: To identify novel type 2 diabetes gene variants and confirm previously identified ones, a 3-staged genome-wide association (GWA) study was performed in the Japanese.
Research Design and Methods: In the stage-1 scan, we genotyped 519 cases and 503 controls with 482,625 SNP markers; in the stage-2 panel comprising 1,110 cases and 1,014 controls, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy controls 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 cases and 12,569 population-based samples, from which 4,889 non-diabetic controls were pre-selected. 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 3 previously reported—were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10−19). Moreover, significant associations were replicated in 5 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.
Conclusions: The strength of association was more prominent in the Japanese than in Europeans for more than half the confirmed type 2 diabetes loci.
Footnotes
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- Received October 28, 2008.
- Accepted April 7, 2009.
- Copyright © American Diabetes Association
