Integrative network analysis reveals molecular mechanisms of blood pressure regulation. Issue 4 (16th April 2015)

• Record Type: Journal Article
• Authors: Huan, Tianxiao; Meng, Qingying; Saleh, Mohamed A; Norlander, Allison E; Joehanes, Roby; Zhu, Jun; Chen, Brian H; Zhang, Bin; Johnson, Andrew D; Ying, Saixia; Courchesne, Paul; Raghavachari, Nalini; Wang, Richard; Liu, Poching; The International Consortium for Blood Pressure GWAS (ICBP); O'Donnell, Christopher J; Vasan, Ramachandran; Munson, Peter J; Madhur, Meena S; Harrison, David G; Yang, Xia; Levy, Daniel
• Is Part Of: Molecular systems biology. Volume 11:Issue 4(2015:Apr.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-04-16
• Subjects: Molecular biology -- Periodicals; Systems biology -- Periodicals; 572.8
• DOI: 10.15252/msb.20145399
• Languages: English
• ISSNs: 1744-4292

Abstract

<abstract abstract-type="main" id="msb145399-abs-0001"> <title>Abstract</title> <p>Genome‐wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP‐associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3, 679 individuals, using network approaches. BP transcriptomic signatures at the single‐gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression‐related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP‐related genes were uncovered. As proof‐of‐concept, we validated <italic>SH2B3, </italic> one of the top key drivers, using <italic>Sh2b3</italic>^−/− mice. We found that a significant number of genes predicted to be regulated by <italic>SH2B3</italic> in gene networks are perturbed in <italic>Sh2b3</italic>^−/− mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.</p> </abstract>