Regulatory variants of blood pressure genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA881331 | ENA |
REPOSITORIES: ENA
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Project description:Regulatory variants of blood pressure genes (Omni-C)
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Project description: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.
2023-04-25 | GSE213558 | GEO
Project description: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.
2023-04-25 | GSE217358 | GEO
Project description:Genome-wide association studies in large population cohorts have now mapped thousands of variants and loci for numerous polygenic traits and diseases. However, with some exceptions, mechanistic understanding of which precise variants affect which genes and in which tissues to modulate trait variation is still lacking. Here, we propose genomic analyses of any complex trait using gene expression and chromatin accessibility across multiple tissues, to identify the TFs and regulatory variants within active enhancers regulating specific genes in individual tissues to explain trait heritability. We apply these methods to blood pressure, a classical polygenic trait, to show that variant heritability contributions of kidney, adrenal, heart and arterial tissues are 3.7%, 5.6%, 6.9%, and 9.8%, respectively, from a total of ~500,000 regulatory variants in the four tissues. We demonstrate that these variants are enriched in enhancers binding specific TFs in each tissue. Our findings suggest that gene regulatory networks perturbed by common regulatory variants in a tissue relevant to a phenotype is the primary source of interindividual variation of BP. These studies provide an approach to scan each human tissue for its physiological contribution to a polygenic trait.
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Project description:High blood pressure (BP) is the major risk factor for cardiovascular disease. Genome-wide association studies have identified genetic variants for BP, but functional insights into causality and related molecular mechanisms lag behind. We functionally characterize 4,608 genetic variants in linkage with 135 BP loci in vascular smooth muscle cells and cardiomyocytes by massively parallel reporter assays. High densities of regulatory variants at BP loci (i.e., ULK4, MAP4, CFDP1, PDE5A) indicate that multiple variants drive genetic association. Regulatory variants are enriched in repeats, alter cardiovascular-related transcription factor motifs, and spatially converge with genes controlling specific cardiovascular pathways. Using heuristic scoring, we define likely causal variants, and CRISPR prime editing finally determines causal variants for KCNK9, SFXN2, and PCGF6, which are candidates for developing high BP. Our systems-level approach provides a catalog of functionally relevant variants and their genomic architecture in two trait-relevant cell lines for a better understanding of BP gene regulation.
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