Integrative genomic analysis of blood pressure and related phenotypes in rats

• Published in: Disease models & mechanisms 2021-05, Vol.14 (5)
• Main Authors: Takeuchi, Fumihiko, Liang, Yi-Qiang, Isono, Masato, Tajima, Michiko, Cui, Zong Hu, Iizuka, Yoko, Gotoda, Takanari, Nabika, Toru, Kato, Norihiro
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - pharmacology; Blood pressure; Blood Pressure - drug effects; Blood Pressure - genetics; Cardiovascular disease; Cholesterol; Chromosomes; Comparative analysis; Crosses, Genetic; Female; gene; Gene expression; Gene Expression Regulation - drug effects; Gene loci; Genetic diversity; Genetic Linkage; Genetic Variation; genome-wide association studies; Genomes; Genomics; Haplotypes; Haplotypes - genetics; Hypertension; Kallikreins - metabolism; Kinins - metabolism; locus; Male; multifactorial disease; Phenotype; Phylogenetics; Phylogeny; Physical Chromosome Mapping; Quantitative Trait Loci - genetics; Rat as a Disease Model; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Stroke - complications; transcriptome
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.048090

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.