Type 2 Diabetes Starr County GWAS and Exome Sequencing
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ABSTRACT:
PROVIDER: PRJNA328292 | ENA |
REPOSITORIES: ENA
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Project description:<p><p><b>The T2D Seq GWAS Starr County Cohort is utilized in the following dbGaP sub-studies.</b> To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" section of this top-level study page <a href="study.cgi?study_id=phs001166">phs001166</a> T2D Seq GWAS Starr County Cohort. <ul> <li><a href="study.cgi?study_id=phs000143">phs000143</a> CIDR T2D Hanis</li> <li><a href="study.cgi?study_id=phs001099">phs001099</a> T2D GENES Starr County</li> </ul> </p></p>
| phs001166 | dbGaP
Project description:<p>An initial observation in the 1970s that Starr County, Texas, had the highest diabetes-specific mortality of any of the 254 Texas counties led to the establishment of a field office in Rio Grande City, Texas (the county seat of Starr County) and the initiation of a series of studies to understand the epidemiology and genetics of type 2 diabetes, its complications and related conditions in this predominantly (97%) Mexican American population. The field office opened in February 1981 and has operated continuously since then. During this time, three systematic surveys of the population have been conducted as well as family and longitudinal studies. Culturally sensitive diabetes education programs have been developed and implemented and also a weight loss intervention. In total, more than 23,000 Mexican American individuals have been examined with more than 200,000 aliquots of biological specimens stored. Collectively, these studies are known as the Starr County Health Studies.</p> <p>The present Genetics of Diabetes Study has the goal of identifying loci/alleles that underlie susceptibility to type 2 diabetes in this high risk population using genome wide markers and association testing. The study makes use of two primary resources that have been developed in order to identify 1,000 type 2 diabetes cases and 1,000 disease free controls. In the first instance we have identified a subset of unrelated cases from the total cases that we have identified. Where multiply affected sibships were available, the youngest onset case with detailed phenotyping (including assessment of diabetic retinopathy) was selected. Controls came from a recent survey to establish a representative sample of the Starr County population. Blocks were randomly selected, households on selected blocks enumerated and one individual randomly selected from each household for a detailed examination. The examination included an oral glucose tolerance test. Those included as controls are those with no prior diagnosis of diabetes and a negative oral glucose tolerance test.</p> <p>This collection of cases and controls provides the opportunity to identify susceptibility loci for type 2 diabetes and its complications, specifically diabetic retinopathy and albuminuria. The data set also allows the examination of impaired fasting glucose and impaired glucose tolerance. The samples are split between those born in the United States and those born in Mexico and this gives a natural contrast for examining genotype and environmental interactions. It is anticipated that the understanding that will come will lead to strategies for delaying and preventing the onset of diabetes and its complications.</p>
| phs000143.v1.p1 | EGA
Project description:Type 2 Diabetes in African Americans, GWAS and Exome Sequencing
| PRJNA328294 | ENA
Project description:Type 2 Diabetes Starr County GWAS and Exome Sequencing
| PRJNA328293 | ENA
Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.
2016-07-12 | GSE76308 | GEO
Project description:GWAS to identify risk genes for type 2 diabetes in Asian Indians
| PRJNA186401 | ENA
Project description:Genomic enhancers are important regulators of gene expression, but their identification is a challenge and methods depend on indirect measures of activity. We developed a method termed STARR-seq to directly and quantitatively assess enhancer activity for millions of candidates from arbitrary sources of DNA, enabling screens across entire genomes. When applied to the Drosophila genome, STARR-seq identifies thousands of cell type-specific enhancers across a broad continuum of strengths, linking differential gene expression to differences in enhancer activity and creating a genome-wide quantitative enhancer map. This map reveals the highly complex regulation of transcription, with several independent enhancers for both developmental regulators and ubiquitously expressed genes. STARR-seq can be used to identify and quantitate enhancer activity in other eukaryotes, including human. STARR-seq was performed in S2 and OSC cells with paired-end sequencing in two replicates and respective inputs. DHS-seq was done with single-end sequencing in two replicates for S2 and OSC cells. RNA-seq was performed with a strand-specific protocol using single-end sequencing in two replicates within S2 and OSC cells. STARR-seq was also performed in HeLa cells with single-end sequencing with a respective input.
2013-01-17 | E-GEOD-40739 | biostudies-arrayexpress
Project description:Custom array designed to tile Linkage Disequilibrium Blocks of T2D GWAS SNPs, monogenic candidates for T2D and Obesity, and all plausible imprinted loci from human and mouse data. Case Control comparison of MeDIP for Type 2 Diabetes. MeDIP versus Input fraction.
2010-12-01 | E-GEOD-20553 | biostudies-arrayexpress
Project description:Recent genome-wide association studies (GWAS) identified Dusp8, a dual-specificity phosphatase targeting MAP kinases, as type 2 diabetes risk gene. Here, we unravel Dusp8 as gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male but not female Dusp8 loss-of-function mice, either with global or CRH neuron-specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic–pituitary–adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of male Dusp8 KO mice, respectively. This sex-specific and rheostatic role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. In summary, our findings suggest GWAS-identified gene Dusp8 as novel hypothalamic factor that plays a functional role in the etiology of type 2 diabetes.
2020-08-17 | PXD019451 | Pride
Project description:We combined Self-Transcribing Active Regulatory Region Sequencing (STARR-seq) with an enrichment step using chromatin immunoprecipitation in a massively parallel reporter assay. We applied this assay, termed ChIP-STARR-seq, to normal (primed) and naive human embryonic stem cells, building up a comprehensive catalogue of functional enhancers. This database record describes the STARR-RNA-seq component.
2017-07-05 | GSE99630 | GEO