To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS) including 26,488 cases and 83,964 controls of European, East Asian, South Asian, and Mexican and Mexican American ancestry. We observed significant excess in directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven novel T2D susceptibility loci. Furthermore, we observed considerable improvements in fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterisation of complex trait loci, and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D.

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of East Asian ancestry from the AGEN-BP consortium followed by de novo genotypingin 2 stages of replication involving 10,518 and 20,247 East Asian samples. We identified novel genome-wide significant (P < 5 × 10−8) associations between SBP or DBP and variants at four novel loci: ST7L-CAPZA1, FIGN-GRB14, ENPEP, and NPR3, as well as a novel variant near TBX3. Except for NPR3, all novel findings were significantly replicated for SBP or DBP in independent samples. Sevenloci previously reported in populations of European descent were confirmed. On 12q24.13, we observed an ethnic specific association(implicating rs671 at the ALDH2 locus as the causal variant) that affected SBP, DBP and multiple traits related to coronary artery disease. These findings provide novel insights into blood pressure regulation and potential targets for intervention.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

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.