To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.

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.

AUTHOR CONTRIBUTIONSCGM designed and coordinated the study, designed assays, performed experiments, analyzed data and wrote the manuscript JRC-U generated retroviral vectors and performed Ba/F3 assays LAAP performed JAK sequencing and quantitative PCR assays MLL performed PAR1 deletion genomic PCR WL performed statistical analysis JZ analyzed sequencing data Jing Ma analyzed microarray data EC-S performed flow cytometry and analyzed data RCH and CLW developed FISH assays Julia Meyer performed experiments and analyzed data FMM, AJC and NAH performed FISH assays and analyzed cytogenetic data RTW provided luciferase vectors JC designed subcloning vectors GB and AP provided patient samples SCR performed cytogenetic analysis SPH coordinated studies and sample collection JRD provided patient samples WLC provided patient samples, performed experiments and analyzed data KRR provided samples, performed experiments and analyzed data NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 May 1. Published in final edited form as:Nat Genet. SUMMARYAneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many patients lack a recurring chromosomal alteration. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, non-coding exon of P2RY8 to the coding region of CRLF2 (which encodes cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor). The P2RY8-CRLF2 fusion was identified in 7% of B-progenitor ALL cases, and was identified in over 50% of ALL cases arising in patients with Down syndrome (53% of 75 cases). CRLF2 alteration was associated with the presence of activating JAK mutations, and expression of P2RY8-CRLF2 together with JAK2 mutants resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3-IL7R cells, indicating that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.Chromosomal alterations are a hallmark of acute lymphoblastic leukemia (ALL), the commonest malignancy of childhood, and include aneuploidy (hyperdiploidy and hypodiploidy) and recurring chromosomal translocations, such as t(12;21) [ETV6-RUNX1], t (1;19) [TCF3-PBX1], t(9;22) [BCR-ABL1] and rearrangement of MLL 1 . These alterations are important events in leukemogenesis and influence response to therapy. However, up to onequarter of childhood ALL cases lack a recurring chromosomal alteration, and the genetic basis of these cases is poorly understood.To identify submicroscopic genetic alterations contributing to the pathogenesis of ALL, we previously performed high resolution profiling of DNA copy number alterations and loss of heterozygosity (LOH) using single nucleotide polymorphism (SNP) microarrays, and identified multiple recurring genetic alterations targeting key cellular pathways including lymphoid development, cell cycle regulation and tumor suppression2 , 3. These alterations included a novel deletio...

To characterise type 2 diabetes (T2D) associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D cases and 132,532 controls of European ancestry after imputation using the 1000 Genomes multi-ethnic reference panel. Promising association signals were followed-up in additional data sets (of 14,545 or 7,397 T2D cases and 38,994 or 71,604 controls). We identified 13 novel T2D-associated loci (p<5×10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common SNVs. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion, and in adipocytes, monocytes and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

Introduction Developing in vitro models for studying cell biology and cell physiology is of great importance to the fields of biotechnology, cancer research, drug discovery, toxicity testing, as well as the emerging fields of tissue engineering and regenerative medicine. Traditional two dimensional (2D) methods of mammalian cell culture have several limitations and it is increasingly recognized that cells grown in a three dimensional (3D) environment more closely represent normal cellular function due to the increased cell-to-cell interactions, and by mimicking the in vivo architecture of natural organs and tissues. Areas Covered In this review, we discuss the methods to form 3D multi-cellular spheroids, the advantages and limitations of these methods, and assays used to characterize the function of spheroids. The use of spheroids has led to many advances in basic cell sciences, including understanding cancer cell interactions, creating models for drug discovery and cancer metastasis, and they are being investigated as basic units for engineering tissue constructs. As so, this review will focus on contributions made to each of these fields using spheroid models. Expert Opinion Multi-cellular spheroids are rich in biological content and mimic better the in vivo environment than 2D cell culture. New technologies to form and analyze spheroids are rapidly increasing their adoption and expanding their applications.