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Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans

Item Type:Article
Title:Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans
Creators Name:Langley, S.R. and Bottolo, L. and Kunes, J. and Zicha, J. and Zidek, V. and Hubner, N. and Cook, S.A. and Pravenec, M. and Aitman, T.J. and Petretto, E.
Abstract:AIMS: Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large-effect that were replicated across populations. The vast majority of genes detected by GWAS have small-effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. METHODS AND RESULTS: Time-series analysis of radiotelemetric blood pressure (BP) was performed to assess eleven parameters of BP-variation in recombinant inbred strains derived from the Spontaneously Hypertensive Rat. BP-data were integrated with ∼27,000 expression QTLs (eQTLs) mapped across seven tissues, detecting >8,000 significant associations between eQTL genes and BP-variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a sub-set of 2,292 rat-human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP-variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for 'calcium signalling pathway' (P=9.6x10-6) and 'ion channel' genes (P=3.5x10-7), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying 'master regulator' genes and found significant over-representation in the human hypertension gene-set (enrichment P=5x10-4). CONCLUSION: We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways.
Keywords:Integrative Genomics, Expression QTLs, Time Series Analysis, Trans-Acting Regulation, Genome-Wide Association Studies, Animals, Mice, Rats
Source:Cardiovascular Research
Publisher:Oxford University Press
Page Range:653-665
Date:15 March 2013
Official Publication:https://doi.org/10.1093/cvr/cvs329
PubMed:View item in PubMed

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