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

Abstract

OBJECTIVETo 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 METHODSIn 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.RESULTSFour 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.CONCLUSIONSThe strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.

Common variants at the GCK, GCKR, G6PC2–ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations

“…The present study has proven that common variant loci influencing FPG levels are reproducible in two populations of Asian descent, Japanese (East Asians) and Sri Lankan Type 2 diabetes association was tested with the Cochran-Armitage trend test in the case-control analysis a SNPs were genotyped in a Japanese case-control study panel independently of the general Japanese population [27] b In the Sri Lankan population, 515 controls are part of those used for FPG association analysis, whereas 599 cases were independent participants c Results for 18,236 cases and 64,453 controls from a previous study [17] d Results for 4,549 cases and 5,579 controls from the DIAGRAM consortium [37] (South Asians). To our knowledge, this is the first study investigating the genetic associations with FPG and related metabolic traits at four candidate loci, GCK, GCKR, G6PC2-ABCB11 and MTNR1B, in South Asians, who are known to have high prevalence of type 2 diabetes [34].…”

“…In the GWA scans, genotyping was performed with a bead array (Infinium HumanHap550; Illumina, San Diego, CA, USA) as described elsewhere [27] (ESM Fig. 1, ESM SNP genotyping, ESM Quality control of the GWA scan data).…”

“…Then, the association signals were examined in the general populations mentioned above. In addition to quantitative trait analysis, type 2 diabetes associations were tested for index SNPs at G6PC2-ABCB11 in a Japanese case-control study panel comprising 5,629 cases and 6,406 controls as previously reported [27], and in a Sri Lankan case-control study panel (ESM Study samples for type 2 diabetes casecontrol studies). All participants from these different studies provided written informed consent and the local Ethics Committees approved the protocols.…”

Genome-wide association study of coronary artery disease in the Japanese

“…16 The l value for the genomic control was 1.15 in the stage 1a GWA scan samples and the test statistic was adjusted using the genomiccontrol method. 17 To examine the potential influence of population structure on the association results for our GWA study, we further applied the EMMAX model, 18 an efficient implementation of a variance component approach to the stage 1a results.…”

Genetic variants on chromosome 6p21.1 and 6p22.3 are associated with type 2 diabetes risk: a case–control study in Han Chinese

“…[7][8][9][10] Subsequently, four new single nucleotide polymorphisms (SNPs) (rs4712524, rs4712523, rs6931514 and rs10440833) in CDKAL1 were also reported to increase the risk of T2D in GWAS of the Japanese and Caucasian population. [11][12][13][14] Simultaneously, Zeggini et al 7,11 detected another two new T2D susceptible signals at 6p21.1 (the maker SNP: rs9472138 and rs9369425) neighboring to vascular endothelial growth factor A (VEGFA) in a Caucasian T2D GWAS and a meta-analysis of T2D GWAS. However, the two SNPs were failed to replicate in the final validations: further studies will be required to establish the associations with the increased T2D risk.…”