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...

Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of β-catenin into nucleus, leading to down-regulation of c-myc and cyclin D1 via the PI3K pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in breast cancer patients, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and demonstrate that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.

The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelialmesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.HIF1alpha | breast cancer stem cell

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Heritability, the proportion of phenotypic variance explained by genetic factors, can be estimated from pedigree data 1 , but such estimates are uninformative with respect to the underlying genetic architecture. Analyses of data from genome-wide association studies (GWAS) on unrelated individuals have shown that for human traits and disease, approximately one-third to two-thirds of heritability is captured by common SNPs 2-5 . It is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular if the causal variants are rare, or other reasons such as overestimation of heritability from pedigree data. Here we show that pedigree heritability for height and body mass index (BMI) appears to be fully recovered from whole-genome sequence (WGS) data on 21,620 unrelated individuals of European ancestry. We assigned 47.1 million genetic variants to groups based upon their minor allele frequencies (MAF) and linkage disequilibrium (LD) with variants nearby, and estimated and partitioned variation accordingly. The estimated heritability was 0.79 (SE 0.09) for height and 0.40 (SE 0.09) for BMI, consistent with pedigree estimates. Low-MAF variants in low LD with neighbouring variants were enriched for heritability, to a greater extent for protein altering variants, consistent with negative selection thereon. Cumulatively variants in the MAF range of 0.0001 to 0.1 explained 0.54 (SE 0.05) and 0.51 (SE 0.11) of heritability for height and BMI, respectively. Our results imply that the still missing heritability of complex traits and disease is accounted for by rare variants, in particular those in regions of low LD.

No abstract