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Project description:Integrated Chromatin Accessibility Mapping and Expression Profiling Enables Functional Annotation of Kidney GWAS Loci
| PRJNA476592 | ENA
Project description:BACKGROUND:Linking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions containing regulatory DNA elements, such as promoters and enhancers. Although researchers have previously published DNA maps of these regulatory regions for kidney tubule cells and glomerular endothelial cells, maps for podocytes and mesangial cells have not been available. METHODS:We generated regulatory DNA maps (DNase-seq) and paired gene expression profiles (RNA-seq) from primary outgrowth cultures of human glomeruli that were composed mainly of podocytes and mesangial cells. We generated similar datasets from renal cortex cultures, to compare with those of the glomerular cultures. Because regulatory DNA elements can act on target genes across large genomic distances, we also generated a chromatin conformation map from freshly isolated human glomeruli. RESULTS:We identified thousands of unique regulatory DNA elements, many located close to transcription factor genes, which the glomerular and cortex samples expressed at different levels. We found that genetic variants associated with kidney diseases (GWAS) and kidney expression quantitative trait loci were enriched in regulatory DNA regions. By combining GWAS, epigenomic, and chromatin conformation data, we functionally annotated 46 kidney disease genes. CONCLUSIONS:We demonstrate a powerful approach to functionally connect kidney disease-/trait-associated loci to their target genes by leveraging unique regulatory DNA maps and integrated epigenomic and genetic analysis. This process can be applied to other kidney cell types and will enhance our understanding of genome regulation and its effects on gene expression in kidney disease.
| S-EPMC6405142 | biostudies-literature
Project description:Genome-wide association study (GWAS) has been a great success in the past decade. However, significant challenges still remain in both identifying new risk loci and interpreting results. Bonferroni-corrected significance level is known to be conservative, leading to insufficient statistical power when the effect size is moderate at risk locus. Complex structure of linkage disequilibrium also makes it challenging to separate causal variants from nonfunctional ones in large haplotype blocks. Under such circumstances, a computational approach that may increase signal replication rate and identify potential functional sites among correlated markers is urgently needed.We describe GenoWAP, a GWAS signal prioritization method that integrates genomic functional annotation and GWAS test statistics. The effectiveness of GenoWAP is demonstrated through its applications to Crohn's disease and schizophrenia using the largest studies available, where highly ranked loci show substantially stronger signals in the whole dataset after prioritization based on a subset of samples. At the single nucleotide polymorphism (SNP) level, top ranked SNPs after prioritization have both higher replication rates and consistently stronger enrichment of eQTLs. Within each risk locus, GenoWAP may be able to distinguish functional sites from groups of correlated SNPs.GenoWAP is freely available on the web at http://genocanyon.med.yale.edu/GenoWAP.
| S-EPMC5963360 | biostudies-literature
Project description:Chromatin accessibility and gene expression in relevant cell contexts can guide identification of regulatory elements and mechanisms at genome-wide association study (GWAS) loci. To identify regulatory elements that display differential activity across adipocyte differentiation, we performed ATAC-seq and RNA-seq in a human cell model of preadipocytes and adipocytes at days 4 and 14 of differentiation. For comparison, we created a consensus map of ATAC-seq peaks in 11 human subcutaneous adipose tissue samples. We identified 58,387 context-dependent chromatin accessibility peaks and 3,090 context-dependent genes between all timepoint comparisons (log2 fold change>1, FDR<5%) with 15,919 adipocyte- and 18,244 preadipocyte-dependent peaks. Adipocyte-dependent peaks showed increased overlap (60.1%) with Roadmap Epigenomics adipocyte nuclei enhancers compared to preadipocyte-dependent peaks (11.5%). We linked context-dependent peaks to genes based on adipocyte promoter capture Hi-C data, overlap with adipose eQTL variants, and context-dependent gene expression. Of 16,167 context-dependent peaks linked to a gene, 5,145 were linked by two or more strategies to 1,670 genes. Among GWAS loci for cardiometabolic traits, adipocyte-dependent peaks, but not preadipocyte-dependent peaks, showed significant enrichment (LD score regression P<0.005) for waist-to-hip ratio and modest enrichment (P < 0.05) for HDL-cholesterol. We identified 659 peaks linked to 503 genes by two or more approaches and overlapping a GWAS signal, suggesting a regulatory mechanism at these loci. To identify variants that may alter chromatin accessibility between timepoints, we identified 582 variants in 454 context-dependent peaks that demonstrated allelic imbalance in accessibility (FDR<5%), of which 55 peaks also overlapped GWAS variants. At one GWAS locus for palmitoleic acid, rs603424 was located in an adipocyte-dependent peak linked to SCD and exhibited allelic differences in transcriptional activity in adipocytes (P = 0.003) but not preadipocytes (P = 0.09). These results demonstrate that context-dependent peaks and genes can guide discovery of regulatory variants at GWAS loci and aid identification of regulatory mechanisms.
| S-EPMC8570510 | biostudies-literature
Project description:[Figure: see text].
| S-EPMC8260472 | biostudies-literature
Project description:Oral ulcers not only influence the physical health of patients, but they also interfere with their quality of life. However, the exact etiology of oral ulcers is not clear. To explore the roles of genetic factors in oral ulcers, a genome-wide association study of the condition in European individuals was re-evaluated by the FUMA v1.3.5e online tool. A total of 380 independent significant single nucleotide polymorphisms (SNPs) and 89 lead SNPs were identified in 34 genomic risk loci. Out of these identified genomic risk loci, 280 possible causal genes were pinpointed by positional mapping and expression quantitative trait locus mapping. Among these genes, 216 novel genes were identified. Furthermore, some genomic loci were mapped to a single gene. Functional annotation of these prioritized genes revealed that the immune response pathway was implicated in the onset of oral ulcers. Overall, our findings revealed novel possible causal genes and demonstrated that the immune response has a crucial role in the occurrence of oral ulcers.
| S-EPMC7376057 | biostudies-literature
Project description:RationaleMitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure, and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP-associated variants and target genes.ObjectiveTo establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci.Methods and resultsWe mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 nonpathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing. Open chromatin peaks were globally similar between pathogenic and nonpathogenic valves. Compared with the heart tissue and cardiac fibroblasts, we found that MV-specific assay for transposase-accessible chromatin with high-throughput sequencing peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motifs in MV-specific open chromatin peaks was for the nuclear factor of activated T cells family of TFs (transcription factors) involved in valve endocardial and interstitial cell formation. We also found that MVP-associated variants were significantly enriched (P<0.05) in mitral valve open chromatin peaks. Integration of the assay for transposase-accessible chromatin with high-throughput sequencing data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. Circular chromatin conformation capture followed by high-throughput sequencing experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on chromosome 2.ConclusionsHere, we describe unprecedented genome-wide open chromatin profiles from human pathogenic and nonpathogenic MVs and report specific gene regulation profiles, compared with the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms. Graphic Abstract: A graphic abstract is available for this article.
| S-EPMC8316483 | biostudies-literature
Project description:The development of epigenetic maps, such as the ENCODE project in humans, provides resources for gene regulation studies and a reference for research of disease-related regulatory elements. However, epigenetic information, such as a bird-specific chromatin accessibility atlas, is currently lacking for the thousands of bird species currently described. The major genomic difference between birds and mammals is their shorter introns and intergenic distances, which seriously hinders the use of humans and mice as a reference for studying the function of important regulatory regions in birds. In this study, using chicken as a model bird species, we systematically compiled a chicken chromatin accessibility atlas using 53 Assay of Transposase Accessible Chromatin sequencing (ATAC-seq) samples across 11 tissues. An average of 50 796 open chromatin regions were identified per sample, cumulatively accounting for 20.36% of the chicken genome. Tissue specificity was largely reflected by differences in intergenic and intronic peaks, with specific functional regulation achieved by two mechanisms: recruitment of several sequence-specific transcription factors and direct regulation of adjacent functional genes. By integrating data from genome-wide association studies, our results suggest that chicken body weight is driven by different regulatory variants active in growth-relevant tissues. We propose CAB39L (active in the duodenum), RCBTB1 (muscle and liver), and novel long non-coding RNA ENSGALG00000053256 (bone) as candidate genes regulating chicken body weight. Overall, this study demonstrates the value of epigenetic data in fine-mapping functional variants and provides a compendium of resources for further research on the epigenetics and evolution of birds and mammals.
| S-EPMC9841184 | biostudies-literature
Project description:BACKGROUND:Genome-wide association studies (GWAS) are an important tool for the mapping of complex traits and diseases. Visual inspection of genomic annotations may be used to generate insights into the biological mechanisms underlying GWAS-identified loci. RESULTS:We developed LocusTrack, a web-based application that annotates and creates plots of regional GWAS results and incorporates user-specified tracks that display annotations such as linkage disequilibrium (LD), phylogenetic conservation, chromatin state, and other genomic and regulatory elements. Currently, LocusTrack can integrate annotation tracks from the UCSC genome-browser as well as from any tracks provided by the user. CONCLUSION:LocusTrack is an easy-to-use application and can be accessed at the following URL: http://gump.qimr.edu.au/general/gabrieC/LocusTrack/. Users can upload and manage GWAS results and select from and/or provide annotation tracks using simple and intuitive menus. LocusTrack scripts and associated data can be downloaded from the website and run locally.
| S-EPMC4351846 | biostudies-literature
Project description:A recent genome-wide association study (GWAS) of central obesity identified 27 loci, from sex-combined analysis, associated with waist-to-hip ratio adjusted for body-mass index (WHRadjBMI) in European-ancestry individuals. Nevertheless, the identified variants may not be the biological causal ones due to the presence of linkage disequilibrium (LD). To better understand the mechanisms underlying the identified loci from the GWAS meta-analysis, we first imputed summary statistics at GWAS loci to increase genetic resolution, and then we applied a Bayesian statistical fine-mapping method through PAINTOR, incorporating LD structure and functional annotations to select and prioritize the most plausible causal variants across WHRadjBMI-associated regions. Using adipose tissue- and cell-specific annotations that showed significant associations with WHRadjBMI, we identified 33 single-nucleotide polymorphisms (SNPs) from 27 sex-combined fine-mapping loci with posterior probability of causality greater than 0.9. Six of the selected 33 SNPs belong to at least one of the top five identified annotations. SNPs rs1440372 (SMAD6) and rs12608504 (JUND) are particularly important since they not only have associated functional annotations but are also GWA hits in the original study. Incorporation of functional annotations helps identify additional plausible causal variants, such as rs2213731 (DNM3-PIGC) and rs4531856 (JUND), that did not reach genome-wide significance in GWAS. Our results provide promising candidates for future functional validation experiments.
| S-EPMC6117358 | biostudies-literature