Dataset Information

Functional genomics and assays of regulatory activity detect mechanisms at loci for lipid traits and coronary artery disease.

ABSTRACT: Many genome-wide association studies (GWAS) have identified signals located in non-coding regions, and an increasing number of functional genomics annotations of regulatory elements and assays of regulatory activity have been used to investigate mechanisms. Genome-wide datasets that characterize chromatin structure help detect potential regulatory elements. Assays to experimentally assess candidate variants include transcriptional reporter assays, and recently, massively parallel reporter assays (MPRAs). Additionally, the effect of candidate regulatory elements and variants on gene expression and function can be evaluated using genomic editing with the CRISPR-Cas9 technology. We highlight some recent studies that employed these strategies to identify variant effects and elucidate molecular and/or biological mechanisms at GWAS loci for lipid traits and coronary artery disease.

SUBMITTER: Roman TS

PROVIDER: S-EPMC6089635 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional genomics and assays of regulatory activity detect mechanisms at loci for lipid traits and coronary artery disease.

Roman Tamara S TS Mohlke Karen L KL

Current opinion in genetics & development 20180220

Many genome-wide association studies (GWAS) have identified signals located in non-coding regions, and an increasing number of functional genomics annotations of regulatory elements and assays of regulatory activity have been used to investigate mechanisms. Genome-wide datasets that characterize chromatin structure help detect potential regulatory elements. Assays to experimentally assess candidate variants include transcriptional reporter assays, and recently, massively parallel reporter assays ...[more]

PMID: 29471259

Similar Datasets

Project description:Coronary artery disease (CAD) is the leading cause of mortality and morbidity driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with CAD and myocardial infarction (MI) susceptibility in multi-ethnic populations. The majority of these variants reside in non-coding regulatory regions and are co-inherited with hundreds of candidate regulatory SNPs. Herein, we use integrative genomic, epigenomic, and transcriptomic fine-mapping in human coronary artery smooth muscle cells (HCASMC) and tissues to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps we prioritize 65 candidate variants and perform allele-specific binding and expression analyses on 7 top candidates. We validate our findings in two independent cohorts of diseased human arterial expression quantitative trait loci (eQTL), which together demonstrate fundamental links between CAD associations and regulatory function in the appropriate disease context. We performed ATAC-seq, ChIP-seq, and RNA-seq on human coronary artery smooth muscle cells grown in SmGM-2 Smooth Muscle Growth Medium-2 including hEGF, insulin, hFGF-B and FBS, but without antibiotics (Lonza, #CC-3182). For ATAC-seq and RNA-seq we performed stimulations with growth factors (TGF-B1, PDGF-BB, PDGF-DD) versus serum-free control. We conducted two biological replicates for each condition using independent donors. For ATAC-seq experiments, sequencing was completed on an Illumina Hiseq 2500, paired-end 50bp reads. For ChIP-seq we performed immunoprecipitations using H3K27ac (Abcam ab4729). We conducted two biological replicates using HCASMC from independent donors, and also did an IgG control for these studies. For RNA-seq we also conducted two replicates using HCASMC from independent donors. For both ChIP-seq and RNA-seq experiments, sequencing was completed on an Illumina HiSeq 2500, paired-end 100bp reads. We also performed ex-vivo ATAC-seq on frozen tissues (isolated media) from normal and atherosclerotic human coronary arteries, using three independent donors for each. Sequencing was also completed on an Illumina HiSeq 2500, paired end 50bp reads.

Dataset Information

Functional genomics and assays of regulatory activity detect mechanisms at loci for lipid traits and coronary artery disease.

Publications

Functional genomics and assays of regulatory activity detect mechanisms at loci for lipid traits and coronary artery disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure