title: Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans.
abstract: OBJECTIVE
  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 has 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.
  
  
  RESULTS
  Time series analysis of radiotelemetric blood pressure (BP) was performed to assess 11 parameters of BP variation in recombinant inbred strains derived from the spontaneously hypertensive rat. BP data were integrated with ∼27 000 expression quantative trait loci (eQTLs) mapped across seven tissues, detecting >8000 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 subset of 2292 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 = 9.6 × 10(-6)) and 'ion channel' genes (P = 3.5 × 10(-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 = 5 × 10(-4)).
  
  
  CONCLUSIONS
  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.
authors.affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kunes
authors.forename: Josef
authors.initials: J
authors.lastname: Zicha
authors.forename: Vaclav
authors.initials: V
authors.lastname: Zidek
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D040641:Quantitative Trait Loci; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR