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


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 x 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 x 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.
Takeuchi
Fumihiko
F
Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Serizawa
Masakuni
M
Yamamoto
Ken
K
Fujisawa
Tomomi
T
Nakashima
Eitaro
E
Ohnaka
Keizo
K
Ikegami
Hiroshi
H
Sugiyama
Takao
T
Katsuya
Tomohiro
T
Miyagishi
Makoto
M
Nakashima
Naoki
N
Nawata
Hajime
H
Nakamura
Jiro
J
Kono
Suminori
S
Takayanagi
Ryoichi
R
Kato
Norihiro
N
D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007564:Japan; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D015201:Meta-Analysis as Topic; D044469:Racial Groups / Q000235:genetics; D018570:Risk Assessment; D012359:tRNA Methyltransferases
C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human