title: Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.
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.
  
  
  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.
authors.affiliation: Department of Medical Ecology and Informatics, Research Institute, International Medical Center of Japan, Tokyo, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeuchi
authors.forename: Masakuni
authors.initials: M
authors.lastname: Serizawa
authors.forename: Ken
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Eitaro
authors.initials: E
authors.lastname: Nakashima
authors.forename: Keizo
authors.initials: K
authors.lastname: Ohnaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikegami
authors.forename: Takao
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakashima
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
authors.forename: Jiro
authors.initials: J
authors.lastname: Nakamura
authors.forename: Suminori
authors.initials: S
authors.lastname: Kono
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kato
mesh_terms: 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
chemical_list: 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