Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population

Fumihiko Takeuchi, Masakuni Serizawa, Ken Yamamoto, Tomomi Fujisawa, Eitaro Nakashima, Keizo Ohnaka, Hiroshi Ikegami, Takao Sugiyama, Tomohiro Katsuya, Makoto Miyagishi, Naoki Nakashima, Hajime Nawata, Jiro Nakamura, Suminori Kono, Ryoichi Takayanagi, Norihiro Kato

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Abstract

OBJECTIVE-To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genomewide 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.

Original languageEnglish
Pages (from-to)1690-1699
Number of pages10
JournalDiabetes
Volume58
Issue number7
DOIs
Publication statusPublished - Jul 1 2009

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Genetic Loci
Genome-Wide Association Study
Type 2 Diabetes Mellitus
Single Nucleotide Polymorphism
Population
Genome
Computer Simulation
Genes
Healthy Volunteers
Research Design

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. / Takeuchi, Fumihiko; Serizawa, Masakuni; Yamamoto, Ken; Fujisawa, Tomomi; Nakashima, Eitaro; Ohnaka, Keizo; Ikegami, Hiroshi; Sugiyama, Takao; Katsuya, Tomohiro; Miyagishi, Makoto; Nakashima, Naoki; Nawata, Hajime; Nakamura, Jiro; Kono, Suminori; Takayanagi, Ryoichi; Kato, Norihiro.

In: Diabetes, Vol. 58, No. 7, 01.07.2009, p. 1690-1699.

Research output: Contribution to journalArticle

Takeuchi, F, Serizawa, M, Yamamoto, K, Fujisawa, T, Nakashima, E, Ohnaka, K, Ikegami, H, Sugiyama, T, Katsuya, T, Miyagishi, M, Nakashima, N, Nawata, H, Nakamura, J, Kono, S, Takayanagi, R & Kato, N 2009, 'Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population', Diabetes, vol. 58, no. 7, pp. 1690-1699. https://doi.org/10.2337/db08-1494
Takeuchi, Fumihiko ; Serizawa, Masakuni ; Yamamoto, Ken ; Fujisawa, Tomomi ; Nakashima, Eitaro ; Ohnaka, Keizo ; Ikegami, Hiroshi ; Sugiyama, Takao ; Katsuya, Tomohiro ; Miyagishi, Makoto ; Nakashima, Naoki ; Nawata, Hajime ; Nakamura, Jiro ; Kono, Suminori ; Takayanagi, Ryoichi ; Kato, Norihiro. / Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. In: Diabetes. 2009 ; Vol. 58, No. 7. pp. 1690-1699.
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T1 - Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population

AU - Takeuchi, Fumihiko

AU - Serizawa, Masakuni

AU - Yamamoto, Ken

AU - Fujisawa, Tomomi

AU - Nakashima, Eitaro

AU - Ohnaka, Keizo

AU - Ikegami, Hiroshi

AU - Sugiyama, Takao

AU - Katsuya, Tomohiro

AU - Miyagishi, Makoto

AU - Nakashima, Naoki

AU - Nawata, Hajime

AU - Nakamura, Jiro

AU - Kono, Suminori

AU - Takayanagi, Ryoichi

AU - Kato, Norihiro

PY - 2009/7/1

Y1 - 2009/7/1

N2 - OBJECTIVE-To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genomewide 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.

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