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Integrative network analysis reveals molecular mechanisms of blood pressure regulation.
Molecular Systems Biology ( IF 9.9 ) Pub Date : 2015-04-18 , DOI: 10.15252/msb.20145399
Tianxiao Huan 1 , Qingying Meng 2 , Mohamed A Saleh 3 , Allison E Norlander 4 , Roby Joehanes 5 , Jun Zhu 6 , Brian H Chen 1 , Bin Zhang 6 , Andrew D Johnson 7 , Saixia Ying 8 , Paul Courchesne 1 , Nalini Raghavachari 9 , Richard Wang 10 , Poching Liu 10 , , Christopher J O'Donnell 7 , Ramachandran Vasan 11 , Peter J Munson 8 , Meena S Madhur 4 , David G Harrison 4 , Xia Yang 12 , Daniel Levy 13
Affiliation  

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.

中文翻译:

集成网络分析揭示了血压调节的分子机制。

全基因组关联研究(GWAS)已确定许多与血压(BP)相关的基因座。但是,尚不清楚BP调控的分子机制。我们通过使用网络方法,将BP GWAS与全血mRNA表达谱相整合,研究了3679名个体中与BP相关的分子机制。鉴定了单基因和共表达网络模块水平的BP转录组签名。根据遗传推论,四个共表达模块被确定为潜在的因果关系,因为其相应基因的表达相关单核苷酸多态性表明富含BP GWAS信号。来自这四个模块的基因被进一步投影到预定义的分子相互作用网络上,揭示了关键的驱动力。尚未发现需要关键驱动程序与BP相关基因之间发生分子相互作用的基因子网。作为概念验证,我们使用Sh2b3(-/-)小鼠验证了SH2B3,这是最主要的驱动因素之一。我们发现,Sh2b3(-/-)小鼠扰动了基因网络中预计受SH2B3调控的大量基因,这表明对血管紧张素II输注的升压反应过度。我们的发现可能有助于确定预防或治疗高血压的新靶标。
更新日期:2019-11-01
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