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.

OBJECTIVE-Genetic variants in the fat mass and obesityassociated (FTO) gene have been linked with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO genetic variants in obesity and type 2 diabetes in the Chinese population. RESEARCH DESIGN AND METHODS-We genotyped 19single-nucleotide polymorphisms (SNPs) spanning from the 3Ј end of the neighboring RPGRIP1L gene to the 5Ј flanking region of the FTO gene. We analyzed their associations with obesity (638 case and 1,610 control subjects), type 2 diabetes (759 case and 784 control subjects), and obesity-related traits in nondiabetic subjects.RESULTS-Among the 19 SNPs, the rs9939609 A allele was strongly associated with obesity (P ϭ 7.0 ϫ 10 Ϫ4 ) and BMI (P ϭ 0.0024) in the Chinese population. The odds ratio for obesity was 2.60 (95% CI 1.24 -5.46) (P ϭ 0.011) for the AA genotype and 1.32 (1.05-1.66) (P ϭ 0.018) for the AT genotype compared with the TT genotype. Each additional copy of the rs9936609 A allele was associated with a BMI increase of ϳ0.37 kg/m 2 . The rs9939609 A allele was substantially less common in the Chinese population than in the European population (12.6 vs. 45%). We did not find significant associations of the 19 SNPs with type 2 diabetes or other obesity-related traits.CONCLUSIONS-Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. The risk variant is less common in the Chinese population, but its effect size on BMI is comparable with that in the European population.

OBJECTIVE-Genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene is one of the few validated genetic variants with large effects on the risk of type 2 diabetes in the populations of European ancestry. In this study, we aimed to explore the effect of the TCF7L2 polymorphisms in a Han Chinese population. RESEARCH DESIGN AND METHODS-We genotyped 20single nucleotide polymorphisms (SNPs) across the TCF7L2 gene in 1,520 unrelated subjects from a Han Chinese population in Taiwan. The associations of SNPs and haplotypes with type 2 diabetes and linkage disequilibrium (LD) structure of the TCF7L2 gene were analyzed. RESULTS-The previously reported SNPs rs7903146 T-and rs12255372 T-alleles of the TCF7L2 gene were rare and were not associated with type 2 diabetes in a Chinese population, which may attribute to the low frequencies of these two SNPs. SNP rs290487 located in an LD block close to the 3Ј end of the gene was associated with type 2 diabetes (allele-specific P ϭ 0.0021; permuted P ϭ 0.03). The odds ratio was 1.36 for the CT genotype (95% CI 1.08Ϫ1.71; P ϭ 0.0063) and 1.51 for the CC genotype (1.10 Ϫ2.07; P ϭ 0.0085) compared with the TT genotype, corresponding to a population attributable risk fraction of 18.7%. The haplotypes composed of rs290487 were also significantly associated with type 2 diabetes (global P ϭ 0.012).CONCLUSIONS-We identified a novel risk-conferring genetic variant of TCF7L2 for type 2 diabetes in a Chinese population. Our data suggested that the TCF7L2 genetic polymorphisms are major determinants for risk of type 2 diabetes in the Chinese population. Diabetes 56: [2631][2632][2633][2634][2635][2636][2637] 2007 T ype 2 diabetes is a highly inheritable metabolic disorder of polygenetic nature (1). Although theoretical analyses emphasized the power of genetic association study in common multifactorial diseases, the search for genes that increase the risk of type 2 diabetes has not been very successful so far. The genes implicated in type 2 diabetes confer only modest effects on the disease risk and in many cases have yielded inconsistent results in replication efforts (2). Only few associations, notably the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor (PPARG) gene (3), the Glu23Lys polymorphism in the KCNJ11 gene (4), and the genetic variants of calpain-10 genes (5), have been convincingly replicated.Recently, researchers seeking the cause of a previously identified linkage signal on chromosome 10q found a strong association of a common microsatellite (DG10S478) of the transcription factor 7-like 2 gene (TCF7L2) with type 2 diabetes in an Icelandic sample, and the result was replicated in the samples from the U.S. and Denmark (6). DG10S478 is located within a well-defined linkage disequilibrium (LD) block of 92.1 kb that encompassed exon 4 and parts of two large flanking introns. Five single nucleotide polymorphisms (SNPs) (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) within the LD block also showed similarly robust associations wit...

We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 a-Nacetyl-neuraminide a-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with Pvalues of 4.87 Â 10 À7 (rs2709736) and 6.05 Â 10 À6 (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P = 9.74 Â 10 À6 ) and in CACNB2 (Calcium channel, voltage-dependent, b-2 subunit) gene (rs11013860, P = 5.15 Â 10 À5 ), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P = 6.55 Â 10 À5 and P = 1.48 Â 10 À5 , respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

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