期刊
MOLECULAR SYSTEMS BIOLOGY
卷 11, 期 4, 页码 -出版社
WILEY
DOI: 10.15252/msb.20145399
关键词
blood pressure; coexpression network; gene expression; hypertension; systems biology
资金
- National Institutes of Health [N01-HC-25195]
- Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health
- NIH [K08HL121671]
- Division of Intramural Research, National Heart, Lung, and Blood Institute
- Center for Information Technology, National Institutes of Health, Bethesda, MD
- American Heart Association Scientist Development [13SDG17290032]
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.
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