Ontology highlight
ABSTRACT:
PROVIDER: PRJNA532491 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8886120_1.fastq.gz | Fastqsanger.gz | |||
| SRR8886120_2.fastq.gz | Fastqsanger.gz | |||
| SRR8886121_1.fastq.gz | Fastqsanger.gz | |||
| SRR8886121_2.fastq.gz | Fastqsanger.gz | |||
| SRR8886122_1.fastq.gz | Fastqsanger.gz |
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Project description:Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164. Functional follow-up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type-specific transcriptional regulatory pathways.
2016-10-07 | GSE87711 | GEO
Project description:Genome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164. Functional follow-up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type-specific transcriptional regulatory pathways.
2016-10-07 | GSE87710 | 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.
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Project description:Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organization in 3D space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes.
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Project description:Genome-wide association studies have associated thousands of genetic variants with complex traits and diseases, but pinpointing the causal variant(s) among those in tight linkage disequilibrium with each associated variant remains a major challenge. Here, we used seven experimental assays to characterize all common variants at the multiple disease-associated TNFAIP3 locus in three disease-relevant immune cell types, based on a set of features related to regulatory potential. Trait/disease-associated variants were enriched among SNPs prioritized based on either: (1) residing within CRISPRi-sensitive regulatory regions, or (2) localizing in a chromatin accessible region while displaying allele-specific reporter activity. Of the 15 trait/disease-associated haplotypes at TNFAIP3, 9 had at least one variant meeting one or both of these criteria, with 3 of these haplotypes having a single prioritized variant. 5 of the 9 prioritized variants were further supported by genetic fine-mapping in our and other studies. Our work provides evidence for the efficacy and limitations of strategies for prioritizing disease- and trait-associated genetic variants.
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Project description:Identification of causal variants and mechanisms underlying complex disease traits in humans requires strategies to locate and fine-map functional regulatory variants in disease-relevant cell types. To discover functional regulatory variants in primary aortic endothelial cells (ECs) from humans, we collected genetic, transcriptomic, and four epigenomic phenotypes in a population of up to 150 human donors representing individuals of both sexes and three major ancestries. We found thousands of EC eQTLs that were not present in GTEx at all ranges of effect sizes, indicating novel functional variants not observable from tissue data. We performed several epigenetic assays across 53 donors’ EC to enable molecular QTL mapping, which included chromatin accessibility, histone modification, and transcription factor binding of proteins ERG and NF-kB/p65 in two activation states. We discovered over 3000 regulatory elements where cis-regulatory variants associated to significant differences in epigenetic marks. Co-localization with our eQTLs, TF motif mutations, and 3D confirmation capture data in ECs enabled our discovery of hundreds of high-confidence functional regulatory elements that perturb endothelial molecular phenotypes. Furthermore, this set of variants is enriched at GWAS loci for Coronary Artery disease and other disease traits, with some SNPs demonstrating pleiotropic effects. Together, our dataset and analytical approach provide the genetics and vascular biology communities with specific variants affecting EC biology and serves as a proof-of-principle for how to detect functional regulatory variants in human cells with relevance to complex traits.
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