title: Integrative network analysis reveals molecular mechanisms of blood pressure regulation.
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.
authors.affiliation: 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.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Huan
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
authors.forename: Qingying
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Allison E
authors.initials: AE
authors.lastname: Norlander
authors.affiliation: 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.
authors.forename: Roby
authors.initials: R
authors.lastname: Joehanes
authors.affiliation: Institute of Genomics and Multiscale Biology, New York, NY, USA Graduate School of Biological Sciences Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Chen
authors.affiliation: Institute of Genomics and Multiscale Biology, New York, NY, USA Graduate School of Biological Sciences Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology National Institutes of Health, Bethesda, MD, USA.
authors.forename: Saixia
authors.initials: S
authors.lastname: Ying
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Courchesne
authors.affiliation: Division of Geriatrics and Clinical Gerontology, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.affiliation: Genomics Core facility Genetics & Developmental Biology Center, The National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wang
authors.affiliation: Genomics Core facility Genetics & Developmental Biology Center, The National Heart, Lung and Blood Institute, Bethesda, MD, USA.
authors.forename: Poching
authors.initials: P
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: The National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Vasan
authors.affiliation: Mathematical and Statistical Computing Laboratory, Center for Information Technology National Institutes of Health, Bethesda, MD, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA xyang123@ucla.edu levyd@nih.gov.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: 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 xyang123@ucla.edu levyd@nih.gov.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D015992:Body Mass Index; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016014:Linear Models; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D049490:Systems Biology; D059467:Transcriptome; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D000804:Angiotensin II
keywords: blood pressure; coexpression network; gene expression; hypertension; systems biology