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Regulatory variants of blood pressure genes

ABSTRACT: Genome-wide association studies (GWAS) have identified blood pressure-related loci, but functional insights into causality and related molecular mechanisms lag behind. We functionally characterize 4608 genetic variants in linkage with blood pressure loci in vascular smooth muscle cells (VSMCs) and cardiomyocytes (CMs) by massively parallel reporter assays (MPRAs). Regulatory variants are in non-conserved loci, enriched in repeats, and alter trait-relevant transcription factor binding sites. Higher-order genome organization indicates that loci harboring regulatory variants converge in spatial hubs to control specific signaling pathways required for proper cardiovascular function. Modelling different variant allele frequencies by CRISPR prime editing led to expression changes of KCNK9, SFXN2, and PCGF6. We provide mechanistic insights into how regulatory variants converge their effects on blood pressure genes (i.e. ULK4, MAP4, CFDP1, PDE5A, 10q24.32), and cardiovascular pathways. Our findings support advances in molecular precision medicine to define functionally relevant variants and the genetic architecture of blood pressure genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213558 | GEO | 2023/04/25

REPOSITORIES: GEO

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Project description: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.

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Regulatory variants of blood pressure genes

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