From GWAS to PheWAS: Scanning the EMR Phenome for Gene-disease Associations
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PROVIDER: PRJNA428409 | ENA |
REPOSITORIES: ENA
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Project description:From GWAS to PheWAS: Scanning the EMR Phenome for Gene-disease Associations
| PRJNA428408 | ENA
Project description:Genome Wides Association Studies (GWAS) have identified tens of thousands of associations between human genetic variation and common disease. Despite the abundance of GWAS associations, functional identification and characterization of causative variants and effector genes remains a challenging prospect. Human erythropoiesis provides a highly tractable model system for the development of tools for GWAS analysis. Using the Human Umbilical Derived Erythroid Progenitor 2 (HUDEP-2) cell line we have modelled the effects of two variants associated with red blood cell traits using CRISPR/Cas9 facilitated HDR editing.
2023-01-21 | GSE125714 | GEO
Project description:Genome Wides Association Studies (GWAS) have identified tens of thousands of associations between human genetic variation and common disease. Despite the abundance of GWAS associations, functional identification and characterization of causative variants and effector genes remains a challenging prospect. Human erythropoiesis provides a highly tractable model system for the development of tools for GWAS analysis. Using the Human Umbilical Derived Erythroid Progenitor 2 (HUDEP-2) cell line we have modelled the effects of two variants associated with red blood cell traits using CRISPR/Cas9 facilitated HDR editing.
2023-01-21 | GSE125713 | GEO
Project description:Genome Wides Association Studies (GWAS) have identified tens of thousands of associations between human genetic variation and common disease. Despite the abundance of GWAS associations, functional identification and characterization of causative variants and effector genes remains a challenging prospect. Human erythropoiesis provides a highly tractable model system for the development of tools for GWAS analysis. Using the Human Umbilical Derived Erythroid Progenitor 2 (HUDEP-2) cell line we have modelled the effects of two variants associated with red blood cell traits using CRISPR/Cas9 facilitated HDR editing.
2023-01-21 | GSE125712 | GEO
Project description:Phenome analysis of Mycoplasma pneumoniae
| PRJEB10038 | ENA
Project description:Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with disease. To facilitate moving from associations to disease mechanisms, we leveraged the role of pathogens in shaping human evolution with the Hi-HOST Phenome Project (H2P2): a catalog of cellular GWAS comprised of 79 phenotypes in response to 8 pathogens in 528 lymphoblastoid cell lines. Seventeen loci surpass genome-wide significance (p<5x10-8) for phenotypes ranging from pathogen replication to cytokine production. Combining H2P2 with clinical association data on 83,717 patients from the eMERGE Network and experimental validation revealed evidence for mechanisms and connections with diseases. We identified a SNP near CXCL10 as a cis-cytokine-QTL and risk factor for inflammatory bowel disease. A SNP in ZBTB20 demonstrated pleiotropy, likely through suppression of multiple target genes, and was associated with viral hepatitis. Data are in an H2P2 web portal to facilitate interpreting human genome variation through the lens of cell biology.
2018-07-26 | GSE116172 | GEO
Project description:Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies (GWAS). Nevertheless, currently few underlying molecular mechanisms of complex disease are known. Our approach has been to investigate whether variation in binding of a transcription factor, the vitamin D receptor (VDR) whose activating ligand vitamin D has often been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines (LCLs). The VDR-BVs are over-represented in well conserved consensus RXR:VDR binding motifs. However, most fell outside of recognisable RXR:VDR motifs, implying that genetic variation often affects RXR:VDR binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (> 2-fold) enriched in GWAS intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect is modifiable by vitamin D levels.
2017-03-17 | GSE73254 | GEO
Project description:Osteoporosis, characterized by low bone mineral density (BMD), is the most common complex disease affecting bone and constitutes a major societal health problem. Genome-wide association studies (GWASs) have identified over 1100 associations influencing BMD. It has been shown that perturbations to long non-coding RNAs (lncRNAs) influence BMD and the activities of bone cells; however, the extent to which lncRNAs are involved in the genetic regulation of BMD is unknown. Here, we combined the analysis of allelic imbalance (AI) in human acetabular bone fragments with a transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) colocalization analysis using data from the Genotype-Tissue Expression (GTEx) project to identify lncRNAs potentially responsible for GWAS associations. We identified 27 lncRNAs in bone that are located in proximity to a BMD GWAS association and harbor SNPs demonstrating AI. Using GTEx data we identified an additional 31 lncRNAs whose expression was associated (FDR correction<0.05) with BMD through TWAS and had a colocalizing eQTL (regional colocalization probability (RCP)>0.1). The 58 lncRNAs are located in 43 BMD associations. To further support a causal role for the identified lncRNAs, we show that 23 of the 58 lncRNAs are differentially expressed as a function of osteoblast differentiation. Our approach identifies lncRNAs that are potentially responsible for BMD GWAS associations and suggest that lncRNAs play a role in the genetics of osteoporosis.
2021-11-04 | GSE186922 | GEO
Project description:Background: The identification of causal variants responsible for disease associations from genome-wide association studies (GWAS) facilitates functional understanding of the disease mechanisms implicated by GWAS. One of the earliest GWAS associations to COPD spans an intragenic region within FAM13A, but the causal variants at this loci have not yet been identified. Massively parallel reporter assays (MPRA) can be used to prioritize functional regulatory variants in a high-throughput manner. Methods: We used an integrated approach using fine-mapping in over 10,000 subjects from COPD GWAS studies, two MPRA experiments, traditional reporter assays, chromatin conformation capture, and CRISPR-based gene editing to characterize COPD-associated regulatory variants in FAM13A in human bronchial epithelial cell lines. Results: Conditional genetic association and fine mapping analyses identified two independent COPD association signals in FAM13A. MPRA identified 45 common functional regulatory variants, and six COPD-associated putative functional variants were prioritized for further functional investigation. Three variants demonstrated significant activity in traditional reporter assays, and one variant, rs2013701, was selected for further testing in the endogenous genomic context based on a direction of effect consistent with postulated mechanisms of FAM13A-mediated COPD susceptibility. CRISPR-based genome editing for this variant confirmed allele-specific effects on FAM13A expression and altered rates of cellular proliferation, providing multiple levels of functional characterization for this COPD-associated variant. Conclusions: Comprehensive screening for regulatory variants near FAM13A identified the presence of extensive functional regulatory variation within a 250kb window of FAM13A in HBECs. Focused functional evaluation of the COPD-associated functional variants in LD with the two independent association signals in this region prioritized the common variant rs2013701, for which multiple parallel lines of functional evidence confirm allelic effects on FAM13A regulation.
2019-01-19 | GSE109452 | GEO
Project description:Genome Wides Association Studies (GWAS) have identified tens of thousands of associations between human genetic variation and common disease. The majority of causative variants lie in regulatory elements that are located some distance from their target genes. High resolution chromosome conformation capture (3C) has proven useful for identifying enhancer-promoter interaction. We employed targeted Capture-C at loci with GWAS for severe COVID-19, Type-1 Diabetes (T1D), Ankylosing spondylitis (AS) and red blood cell traits (RBC)
2021-08-13 | GSE159867 | GEO