Open AccessIntegrative network analysis reveals molecular mechanisms of blood pressure regulation
Author(s) -
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,
O'Donnell Christopher J,
Vasan Ramachandran,
Munson Peter J,
Madhur Meena S,
Harrison David G,
Yang Xia,
Levy Daniel
Publication year - 2015
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20145399
Subject(s) - biology , genome wide association study , gene , computational biology , transcriptome , genetics , gene regulatory network , snp , gene expression , genetic association , single nucleotide polymorphism , genotype
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 SNP s 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 SH 2B3, one of the top key drivers, using Sh2b3 −/− mice. We found that a significant number of genes predicted to be regulated by SH 2B3 in gene networks are perturbed in Sh2b3 −/− 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.