Integrative network analysis reveals molecular mechanisms of blood pressure regulation

Molecular Systems Biology
Tianxiao HuanDaniel Levy

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...Continue Reading

References

Dec 1, 1975·Preventive Medicine·M FeinleibW P Castelli
Jan 7, 1993·The New England Journal of Medicine·Leif GroopC Saloranta
Jan 17, 2002·Genetic Epidemiology·Gonçalo R AbecasisS S Cherny
Jan 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Keith A ChoateRichard P Lifton
Mar 6, 2003·The Journal of Clinical Investigation·Andrew R Marks
Jul 9, 2003·Nature Medicine·Carlos Bernal-MizrachiClay F Semenkovich
Jul 29, 2003·Proceedings of the National Academy of Sciences of the United States of America·John D Storey, Robert Tibshirani
Jul 9, 2004·Cytogenetic and Genome Research·Jun ZhuEric E Schadt
Jan 18, 2005·Lancet·Patricia M KearneyJiang He
Sep 16, 2005·Human Molecular Genetics·Michael E CusickDavid E Hill
Feb 10, 2006·Journal of Hypertension·Carlene M M LawesAnthony Rodgers
May 2, 2006·Statistical Applications in Genetics and Molecular Biology·Bin Zhang, Steve Horvath
Dec 2, 2006·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Yoshihiro KokuboToshiyuki Miyata
May 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Kwang-Il GohAlbert-László Barabási
Sep 19, 2007·The Journal of Experimental Medicine·Tomasz J GuzikDavid G Harrison
Nov 21, 2007·Bioinformatics·Peter LangfelderSteve Horvath
Mar 18, 2008·Nature·Valur EmilssonKari Stefansson
Mar 18, 2008·Nature·Yanqing ChenEric E Schadt
Nov 8, 2008·Nucleic Acids Research·T S Keshava PrasadAkhilesh Pandey
Dec 31, 2008·BMC Bioinformatics·Peter Langfelder, Steve Horvath
Mar 18, 2009·Bioinformatics·Cole TrapnellSteven L Salzberg
Apr 7, 2009·Biochimica Et Biophysica Acta·Chongren Tang, John F Oram
May 12, 2009·Nature Genetics·Daniel LevyCornelia M van Duijn
Jun 10, 2009·Bioinformatics·Heng Li1000 Genome Project Data Processing Subgroup
Jan 21, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yumiko OishiRyozo Nagai
Feb 20, 2010·Current Opinion in Pharmacology·David G HarrisonMeena S Madhur
Mar 30, 2010·American Journal of Human Genetics·Hua ZhongEric E Schadt
Aug 7, 2010·Circulation Research·Alika K MaunakeaKeji Zhao
Aug 27, 2010·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Yuqing LouShaojun Wen
Sep 14, 2010·Pulmonary Pharmacology & Therapeutics·Michelle J Connolly, Philip I Aaronson
Nov 9, 2010·Genetic Epidemiology·Yun LiGonçalo R Abecasis
Dec 15, 2010·Hypertension·David G HarrisonCornelia M Weyand
Dec 18, 2010·Nature Reviews. Genetics·Albert-László BarabásiJoseph Loscalzo
Jan 26, 2011·Hypertension·Tlili BarhoumiErnesto L Schiffrin
Aug 5, 2011·Journal of Cardiovascular Disease Research·Nan Zhang
Feb 4, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ryousuke SatouHiroyuki Kobori
Apr 13, 2012·Hypertension Research : Official Journal of the Japanese Society of Hypertension·Hyun-Min ChoIn Kyeom Kim
May 16, 2012·Frontiers in Physiology·David G HarrisonJens Titze
Jul 19, 2012·Molecular Systems Biology·I-Ming WangChristopher Roberts
Oct 27, 2012·Trends in Molecular Medicine·Paul R Hiebert, David J Granville
Dec 4, 2012·Nucleic Acids Research·Andrew Chatr-AryamontriMike Tyers
Jan 11, 2013·European Heart Journal·Georg B Ehret, Mark J Caulfield
Mar 30, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Tianxiao HuanDaniel Levy
Mar 30, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Roby JoehanesPeter J Munson
Sep 17, 2013·Nature·Tuuli LappalainenEmmanouil T Dermitzakis
Dec 4, 2013·Nature Reviews. Genetics·Mete Civelek, Aldons J Lusis
Apr 15, 2014·Nature Genetics·Fred A WrightDorret I Boomsma
Jul 18, 2014·PLoS Genetics·Ville-Petteri MäkinenThemistocles L Assimes
Sep 23, 2014·The Journal of Clinical Investigation·Annet KiraboDavid G Harrison
Feb 11, 2015·The Journal of Clinical Investigation·Mohamed A SalehMeena S Madhur

Citations

Feb 26, 2016·American Journal of Epidemiology·M Daniele FallinTerri H Beaty
Dec 26, 2015·International Journal of Epidemiology·Connie W Tsao, Ramachandran S Vasan
Sep 15, 2016·Frontiers in Cardiovascular Medicine·Tina HaaseTanja Zeller
Nov 13, 2016·Translational Research : the Journal of Laboratory and Clinical Medicine·Olivia L Sabik, Charles R Farber
May 13, 2017·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sandosh PadmanabhanAnna F Dominiczak
Jun 24, 2017·ACS Chemical Neuroscience·James J SahnTheodore J Price
Jan 26, 2018·Journal of Hypertension·Alon BotzerRon Unger
Dec 18, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Kala B DixonAnnet Kirabo
Jul 2, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·N BatchuVyacheslav A Korshunov
Nov 30, 2016·Hypertension·Yan-Hui LiNanping Wang
Nov 17, 2016·Hypertension·George A MensahGary H Gibbons
Feb 21, 2019·Circulation. Genomic and Precision Medicine·Örjan ÅkerborgPelin Sahlén
Apr 24, 2018·Briefings in Bioinformatics·Mansoor SaqiCharles Auffray
Aug 29, 2018·Molecular Systems Biology·Daniela MichlmayrEva Harris
Nov 15, 2019·Journal of Atherosclerosis and Thrombosis·Teresa InfanteClaudio Napoli
Dec 24, 2019·Circulation Journal : Official Journal of the Japanese Circulation Society·Giuditta BenincasaClaudio Napoli
Feb 15, 2018·Science Advances·Nicole M FoleyEmma C Teeling
Dec 31, 2015·Current Opinion in Nephrology and Hypertension·Bethany L Dale, Meena S Madhur
Mar 16, 2017·Frontiers in Cardiovascular Medicine·Douglas ArnesonXia Yang
Aug 2, 2018·Frontiers in Cardiovascular Medicine·Baiba Vilne, Heribert Schunkert
Sep 21, 2018·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Lan WangChing-Ti Liu
May 28, 2019·Frontiers in Endocrinology·Robert D Maynard, Cheryl L Ackert-Bicknell
Mar 7, 2020·Scientific Reports·Zixin HuMomiao Xiong
Apr 20, 2018·BMC Systems Biology·Mengxuan LyuShuaicheng Li
Apr 28, 2018·BMC Systems Biology·Frank KramerTanja Zeller
Apr 18, 2019·Nature Reviews. Immunology·Grant R DrummondChristopher G Sobey
Apr 8, 2020·Nature Metabolism·Marcus SeldinAldons J Lusis
Jan 21, 2021·Cell Systems·David G AshbrookRobert W Williams
Jul 6, 2020·IScience·Luis PalomeroMiquel Angel Pujana
Apr 2, 2021·Circulation Research·Meena S MadhurAnnet Kirabo
Apr 2, 2021·Circulation Research·Sandosh PadmanabhanAnna F Dominiczak
Jun 9, 2021·Nature Communications·Basel M Al-BarghouthiCharles R Farber

Datasets Mentioned

BETA
GSE65348

Methods Mentioned

BETA
genotyping

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Spatio-Temporal Regulation of DNA Repair

DNA repair is a complex process regulated by several different classes of enzymes, including ligases, endonucleases, and polymerases. This feed focuses on the spatial and temporal regulation that accompanies DNA damage signaling and repair enzymes and processes.

Glut1 Deficiency

Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.

Separation Anxiety

Separation anxiety is a type of anxiety disorder that involves excessive distress and anxiety with separation. This may include separation from places or people to which they have a strong emotional connection with. It often affects children more than adults. Here is the latest research on separation anxiety.

KIF1A Associated Neurological Disorder

KIF1A associated neurological disorder (KAND) is a rare neurodegenerative condition caused by mutations in the KIF1A gene. KAND may present with a wide range and severity of symptoms including stiff or weak leg muscles, low muscle tone, a lack of muscle coordination and balance, and intellectual disability. Find the latest research on KAND here.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.