Regulatory variants of blood pressure genes (Omni-C)
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ABSTRACT:
PROVIDER: PRJNA898604 | ENA |
REPOSITORIES: ENA
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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 | GSE217358 | GEO
Project description:Regulatory variants of blood pressure genes
| PRJNA881331 | ENA
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:We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.
| EGAS00001002991 | EGA
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.
2023-11-01 | GSE200047 | GEO
Project description:Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)
| PRJNA1047941 | ENA
Project description:Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)
| PRJNA1047942 | ENA
Project description:Neferine treatment lower blood pressure in SHR
| PRJNA886633 | ENA
Project description:Systolic Blood Pressure Intervention Trial (SPRINT-Imaging)
| PRJNA1079434 | ENA
Project description:Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4 +CD44hiCD62L lo T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide.
2016-09-12 | GSE85915 | GEO