Inter-tissue coexpression network analysis reveals DPP4 as an important gene in heart to blood communication

Quan Long, Carmen Argmann, Sander M. Houten, Tao Huang, Siwu Peng, Yong Zhao, Zhidong Tu, The GTEx Consortium, Jun Zhu

Inter-tissue molecular interactions are critical to the function and behavior of biological systems in multicellular organisms, but systematic studies of interactions between tissues are lacking. Also, existing studies of inter-tissue interactions are based on direct gene expression correlations, which can't distinguish correlations due to common genetic architectures versus biochemical or molecular signal exchange between tissues. We developed a novel strategy to study inter-tissue interaction by removing effects of genetic regulation of gene expression (genetic decorrelation). We applied our method to the comprehensive atlas of gene expression across nine human tissues in the Genotype-Tissue Expression (GTEx) project to generate novel genetically decorrelated inter-tissue networks. From this we derived modules of genes important in inter-tissue interactions that are likely driven by biological signal exchange instead of their common genetic basis. Importantly we highlighted communication between tissues and elucidated gene activities in one tissue inducing gene expression changes in others. We reveal global unidirectional inter-tissue coordination of specific biological pathways such as protein synthesis. Using our data, we highlighted a clinically relevant example whereby heart expression of DPP4 was coordinated with a gene expression signature characteristic for whole blood proliferation, potentially impacting peripheral stem cell mobilization. We also showed that expression of the poorly characterized FOCAD in heart correlated with protein biosynthetic processes in the lung. In summary, this is the first resource of human multi-tissue networks enabling the investigation of molecular inter-tissue interactions. With the networks in hand, we may systematically design combination therapies that simultaneously target multiple tissues or pinpoint potential side effects of a drug in other tissues.