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Series GSE279300 Query DataSets for GSE279300
Status Public on Oct 14, 2024
Title Comprehensive identification of coronary artery disease-associated variants regulating vascular smooth muscle cell gene expression [lentiMPRA]
Organism Homo sapiens
Experiment type Other
Summary Coronary artery disease (CAD) is a complex disorder with genetic and environmental influences. Genome-wide association studies (GWAS) have identified over 300 genomic loci associated with disease risk. However, identifying the functional variants within these loci has been limited in large part due to linkage disequilibrium. This represents a critical step in understanding the molecular mechanisms underlying disease risk. To identify and prioritize candidate causal CAD-associated variants, we performed lentivirus-based massively parallel reporter assays (lentiMPRAs) in primary vascular smooth muscle cells (SMCs), which play significant roles in atherosclerosis, the underlying cause of CAD. We tested 25892 CAD-associated variants for their allele-specific enhancer activity in quiescent and proliferative SMCs, modeling healthy and disease conditions. We identified 122 candidate variants showing significant enhancer activity and differences in reporter gene expression between risk and non-risk alleles. We also identified 23 variants showing condition-biased allelic imbalance and 41 variants showing sex-biased allelic imbalance. We further functionally characterized 25892 variants by performing CUT&RUN assays to identify variants in enhancer and promoter regions of SMCs. By integrating the results of these experiments, we identified a credible set of 49 CAD-associated variants in functionally relevant regions. Furthermore, by comparing these identified variants with our previously obtained expression quantitative trait loci (eQTL) data, 27 of these 49 variants were associated with SMC gene expression levels. Finally, we performed CRISPRi experiments on 8 variants comprising 9 variant-gene pairs, rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF), rs4627080 (NRIP3), to confirm their regulatory potential of nearby gene expression. Taken together, our results comprehensively fine-map the causal variants that confer increased risk of CAD through their effects on vascular smooth muscle cells.
 
Overall design lentiMPRA were performed on 6 vascular smooth muscle cell lines in two different culture conditions, testing 25892 CAD-associated variants for enhancer activity and allelic imbalance.
 
Contributor(s) Barbera N, Wallace A, Perry NR, Lei L, den Ruijter HM, Civelek M
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Submission date Oct 11, 2024
Last update date Nov 15, 2024
Contact name Nicolas Barbera
E-mail(s) unz2ra@virginia.edu
Organization name University of Virginia
Department Department of Genome Sciences
Street address 1335 Lee Street
City Charlottesville
State/province Virginia
ZIP/Postal code 22903
Country USA
 
Platforms (1)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (24)
GSM8566014 SMC Donor1, Quiescent, RNA
GSM8566015 SMC Donor2, Quiescent, RNA
GSM8566016 SMC Donor3, Quiescent, RNA
Relations
BioProject PRJNA1171821

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Supplementary file Size Download File type/resource
GSE279300_5F_ByAllele_dnaAnnot.csv.gz 49.5 Kb (ftp)(http) CSV
GSE279300_5F_ByAllele_dnaCounts.csv.gz 11.1 Mb (ftp)(http) CSV
GSE279300_5F_ByAllele_rnaAnnot.csv.gz 49.5 Kb (ftp)(http) CSV
GSE279300_5F_ByAllele_rnaCounts.csv.gz 14.5 Mb (ftp)(http) CSV
GSE279300_CRS-BC_Assoc_mapq0_CIGAR200_filtered_coords_to_barcodes.pickle.gz 27.2 Mb (ftp)(http) PICKLE
GSE279300_LD04_lentiMPRA_Seq_Labels.tsv.gz 425.5 Kb (ftp)(http) TSV
GSE279300_LD04_lentiMPRA_design.fa.gz 2.1 Mb (ftp)(http) FA
GSE279300_NF_ByAllele_dnaAnnot.csv.gz 51.2 Kb (ftp)(http) CSV
GSE279300_NF_ByAllele_dnaCounts.csv.gz 11.2 Mb (ftp)(http) CSV
GSE279300_NF_ByAllele_rnaAnnot.csv.gz 51.3 Kb (ftp)(http) CSV
GSE279300_NF_ByAllele_rnaCounts.csv.gz 14.3 Mb (ftp)(http) CSV
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