Systems biology approaches to exploring molecular mechanism underlying blood pressure

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NHLBI	BIOINFO-8

Authors

• T Huan
• J Zhu
• R Joehanes
• B Zhang
• Z Wang
• A Johnson
• P Munson
• P Courchesne
• C O'Donnell
• J Derry
• S Friend
• X Yang
• D Levy

Abstract

GWAS have identified about 30 loci associated with blood pressure (BP) and hypertension. However, the molecular mechanisms underlying these associations remain unclear. We hypothesize that genetic variations with both strong and subtle effects drive gene subnetworks that in turn affect BP. We surveyed BP-associated molecular interactions in 442 Framingham Heart Study (FHS) subjects by integrating gene expression profiles, eSNPs and BP GWAS with network approaches. We identified 24 BP-correlated expression signatures and 82 co-expression modules, of which 30 were significantly enriched for eSNPs with low p-value associations with BP phenotypes (Fisher’s exact and Kolmogorov-Smirnov tests, p<0.05). The significant BP gene sets were in turn integrated with tissue-specific Bayesian networks and protein interaction networks to identify central network nodes (KDs). We found that the BP gene sets and their KDs are enriched for BP-related biological processes such as ion channel and inflammatory response. The subnetworks derived from KDs were highly enriched for known BP and cardiovascular disease genes. Thirty KDs including FMR1 and ROCK1 were common in multiple tissues. Our analysis not only predicts novel BP risk genes, but it also defined a network structure that entails the molecular interactions among BP and cardiovascular risk genes within, between, and across tissues.

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