An integrated approach to identify environmental modulators of genetic risk factors for complex traits
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ABSTRACT:
PROVIDER: PRJNA743319 | ENA |
REPOSITORIES: ENA
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Project description:Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a novel framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal muscle, fat, and liver relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWAS from 31 distinct polygenic traits, we show that the heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS catalog. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations.
2021-07-09 | GSE179347 | GEO
Project description:Integrated Genomics Approach to Identify Biologically Relevant Alterations in Fewer Samples.
| PRJEB11386 | ENA
Project description:Integrated Genomics Approach to Identify Biologically Relevant Alterations in Fewer Samples.
| PRJEB11800 | ENA
Project description:mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFβ pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival.
2012-03-08 | GSE16476 | GEO
Project description:Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment and Protein-Protein Interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual-difference specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.
2022-02-19 | GSE196849 | GEO
Project description:Interventions: 1)Immune modulators, composed of cyclophosphamide, metformin, celecoxib and cimetidine are administered orally for 1 week 2)Induction phase: 5-peptide cocktail vaccine weekly in combination with immune modulators are administered for 8 weeks 3)Maintenance phase: 5-peptide cocktail vaccine biweekly in combination with immune modulators are administered for 8 weeks 4)Extension phase: maintenance therapy is allowed depending on patient condition
Primary outcome(s): The safety of the immune modulators with/without 5-peptide cocktail vaccine
Study Design: Single arm Non-randomized
| 2641385 | ecrin-mdr-crc
Project description:mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFM-NM-2 pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival. 88 human Neuroblastoma samples were analyzed.
2012-03-08 | E-GEOD-16476 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE23968: Large intergenic non-coding RNAs as novel modulators of reprogramming: ESCs, fibroblast, and fibroblast-derived iPSC (gene expression) GSE23970: Large intergenic non-coding RNAs as novel modulators of reprogramming: human embryonic stem cells, CD34+ cells, and CD34+ derived induced pluripotent stem cells (LincRNA expression) GSE23973: Large intergenic non-coding RNAs as novel modulators of reprogramming: siRNA (gene expression) GSE24181: Large intergenic non-coding RNAs as novel modulators of reprogramming: human embryonic stem cells, fibroblasts, and fibroblast-derived induced pluripotent stem cells (LincRNA expression) Refer to individual Series
2010-11-10 | E-GEOD-24182 | biostudies-arrayexpress
Project description:mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 (http://r2.amc.nl) in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFβ pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival.
2014-05-28 | GSE16481 | GEO
Project description:mRNA profiles of thousands of human tumors are available, but methods to deduce oncogenic signaling networks from these data lag behind. It is especially challenging to identify main-regulatory routes, and to generalize conclusions obtained from experimental models. We designed the bioinformatic platform R2 (http://r2.amc.nl) in parallel with a wet-lab approach of neuroblastoma. Here we demonstrate how R2 facilitates an integrated analysis of our neuroblastoma data. Analysis of the MYCN pathway suggested important regulatory connections to the polyamine synthesis route, the Notch pathway and the BMP/TGFβ pathway. A network of genes emerged connecting major oncogenes in neuroblastoma. Genes in the network carried strong prognostic values and were essential for tumor cell survival.
2015-10-20 | GSE16478 | GEO