Integrative network analysis reveals molecular mechanisms of blood pressure regulation.

Huan T, Meng Q, Saleh MA, Norlander AE, Joehanes R, Zhu J, Chen BH, Zhang B, Johnson AD, Ying S, Courchesne P, Raghavachari N, Wang R, Liu P, International Consortium for Blood Pressure GWAS (ICBP), O'Donnell CJ, Vasan R, Munson PJ, Madhur MS, Harrison DG, Yang X, Levy D
Mol Syst Biol. 2015 11 (1): 799

PMID: 25882670 · PMCID: PMC4422556 · DOI:10.15252/msb.20145399

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 SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 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.

© 2015 The Authors. Published under the terms of the CC BY 4.0 license.

MeSH Terms (27)

Adult Aged Angiotensin II Animals Blood Pressure Body Mass Index Cohort Studies Disease Models, Animal Female Gene Regulatory Networks Genetic Loci Genome-Wide Association Study Humans Hypertension Intracellular Signaling Peptides and Proteins Linear Models Male Mice Mice, Knockout Middle Aged Polymorphism, Single Nucleotide Protein Interaction Domains and Motifs RNA, Messenger Sequence Analysis, RNA Systems Biology Transcriptome Young Adult

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