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Integrative genomic analysis of blood pressure and related phenotypes in rats
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Integrative genomic analysis of blood pressure and related phenotypes in rats
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Journal Article
Integrative genomic analysis of blood pressure and related phenotypes in rats
2021
Overview
Despite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.
Publisher
The Company of Biologists Ltd,The Company of Biologists
Subject
/ Antihypertensive Agents - pharmacology
/ Blood Pressure - drug effects
/ Female
/ gene
/ Gene Expression Regulation - drug effects
/ genome-wide association studies
/ Genomes
/ Genomics
/ locus
/ Male
/ Non-pharmacological intervention
/ Quantitative Trait Loci - genetics
/ Rats
/ Renin-Angiotensin System - genetics
/ Rodents
