Abstract

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.

Details

Title
Integrative network analysis reveals molecular mechanisms of blood pressure regulation
Author
Tianxiao Huan 1 ; Meng, Qingying 2 ; Saleh, Mohamed A 3 ; Norlander, Allison E 4 ; Joehanes, Roby 5 ; Zhu, Jun 6 ; Chen, Brian H 1 ; Zhang, Bin 6 ; Johnson, Andrew D 7 ; Saixia Ying 8 ; Courchesne, Paul 1 ; Raghavachari, Nalini 9 ; Wang, Richard 10 ; Liu, Poching 10 ; O'Donnell, Christopher J 7 ; Vasan, Ramachandran 11 ; Munson, Peter J 8 ; Madhur, Meena S 4 ; Harrison, David G 4 ; Yang, Xia 2 ; Levy, Daniel 1 

1  The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; The Population Sciences Branch and the Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA 
2  Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA 
3  Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt 
4  Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA 
5  The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; The Population Sciences Branch and the Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA; Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA; Harvard Medical School, Boston, MA, USA; Hebrew SeniorLife, Boston, MA, USA 
6  Institute of Genomics and Multiscale Biology, New York, NY, USA; Graduate School of Biological Sciences, Mount Sinai School of Medicine, New York, NY, USA 
7  The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA; Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA 
8  Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, USA 
9  Division of Geriatrics and Clinical Gerontology, National Institute on Aging, Bethesda, MD, USA 
10  Genomics Core facility Genetics & Developmental Biology Center, The National Heart, Lung and Blood Institute, Bethesda, MD, USA 
11  The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA 
Section
Articles
Publication year
2015
Publication date
Apr 2015
Publisher
EMBO Press
e-ISSN
17444292
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.15252/msb.20145399
ProQuest document ID
2290759827
Copyright
© 2015. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.