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Polygenic trait SNPs in noncoding genomic regions: using chromatin maps to elucidate potential regulatory mechanisms in blood pressure [ATAC-seq]

ABSTRACT: Many polygenic traits are associated with hundreds of single nucleotide polymorphisms (SNPs), which predominantly (>95%) reside within noncoding genomic regions, making it difficult to understand how they regulate complex traits, such as blood pressure (BP). Given the central role of the kidney in regulating BP, we hypothesized that chromatin-accessible regions in renal tissue would be enriched for BP-associated SNPs (bpSNPs). We developed chromatin state and transcriptomic maps of the proximal tubules (PT) and medullary thick ascending limbs (mTAL) isolated from humans and rats. These maps revealed shared cis-regulatory elements (CREs) across humans and rats, including upstream transcriptional regulators. Notably, bpSNPs were significantly enriched within open chromatin regions, suggesting they potentially alter the activity of CREs and near genes critical to renal development and function. Collectively, this work lays a foundation for interrogating how intergenic SNPs may regulate polygenic traits such as BP.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE272280 | GEO | 2024/12/09

REPOSITORIES: GEO

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Project description:Although the evidence for a genetic predisposition to human essential hypertension is compelling, the genetic control of blood pressure (BP) is poorly understood. The Dahl salt-sensitive (S) rat is a model for studying the genetic component of BP. Using this model we previously reported the identification of 16 different genomic regions that contain one or more BP quantitative trait loci (QTLs). The proximal region of rat chromosome 1 contains multiple BP QTLs. Of these, we have localized the BP QTL1b region to a 13.5cM (20Mb) region. Interestingly, five additional independent studies in rats and four independent studies in humans have reported genetic linkage for BP control by regions homologous to QTL1b. To view the overall renal transcriptional topography of the positional candidate genes for this QTL, we sought a comparative gene expression profiling between a congenic strain containing QTL1b and control S rats by employing: (1) a saturated QTL1b interval specific oligonucleotide array, and (2) a whole genome cDNA microarray representing 20,465 unique genes that are positioned outside the QTL. Results indicated that 19 out of the 231 positional candidate genes for this QTL are differentially expressed between the two strains tested. Surprisingly, over 1,500 genes outside of QTL1b were differentially expressed between the two rat strains. Integrating the results from the two approaches revealed at least one complex network of transcriptional control initiated by the positional candidate Nr2f2. This network appears to account for the majority of gene expression differences occurring outside of the QTL interval. Further substitution mapping is currently underway to test the validity of each of these differentially expressed positional candidate genes. These results demonstrate the importance of using a saturated oligonucleotide array for identifying and prioritizing differentially expressed positional candidate genes of a BP QTL. Keywords: : rat, hypertension, genetics, polygenic trait, microarray, gene expression

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Polygenic trait SNPs in noncoding genomic regions: using chromatin maps to elucidate potential regulatory mechanisms in blood pressure [ATAC-seq]

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