Genomic analyses of hypertensionassociated diseases across ethnic groups and species

To explore genetic architecture of hypertension and end-organ damages, we performed integrative genomic analyses in both humans and inbred hypertensive rat strains. In humans, noting that hypertension is more prevalent and contributes to the increased risk of stroke in people of East Asian ancestry, we performed a multi-stage GWAS for blood pressure (BP) principally in East Asians and meta-analysis in East Asians and Europeans. We reported 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. Some of the ancestry-specific association signals are influenced by a selective sweep. These data provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP. In rats, we also performed genomic analyses of BP and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP). By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n = 1415) and fine congenic mapping (maximum n = 8704) plus comparative analysis with human, 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). We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this analysis, 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. Furthermore, to unravel the mechanisms underlying antihypertensive drug-induced amelioration of end-organ damages, we performed transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred rat strains (SHRSP and WKY). Noticeable changes of mRNA expression were induced particularly by RAS blockade, for example, for genes in the natriuretic peptide system ( Nppb and Corin ) in the heart and for those in the KKS/RAS ( Ren and rat Klk1 paralogs) and those related to calcium ion binding ( Calb1 and Slc8a1 ) in the kidney. Taken together, we provide genetic epidemiological evidence for ethnic differences in hypertension susceptibility and also in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, likely across species.