title: Causal inference of gene regulation with subnetwork assembly from genetical genomics data.
abstract: Deciphering the causal networks of gene interactions is critical for identifying disease pathways and disease-causing genes. We introduce a method to reconstruct causal networks based on exploring phenotype-specific modules in the human interactome and including the expression quantitative trait loci (eQTLs) that underlie the joint expression variation of each module. Closely associated eQTLs help anchor the orientation of the network. To overcome the inherent computational complexity of causal network reconstruction, we first deduce the local causality of individual subnetworks using the selected eQTLs and module transcripts. These subnetworks are then integrated to infer a global causal network using a random-field ranking method, which was motivated by animal sociology. We demonstrate how effectively the inferred causality restores the regulatory structure of the networks that mediate lymph node metastasis in oral cancer. Network rewiring clearly characterizes the dynamic regulatory systems of distinct disease states. This study is the first to associate an RXRB-causal network with increased risks of nodal metastasis, tumor relapse, distant metastases and poor survival for oral cancer. Thus, identifying crucial upstream drivers of a signal cascade can facilitate the discovery of potential biomarkers and effective therapeutic targets.
authors: Departments of Resource Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, Republic of China, Institute of Statistics, National Tsing Hua University, Hsinchu 30013, Taiwan, Republic of China, Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, Republic of China and Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan, Republic of China.
authors: Chien-Hua
authors: CH
authors: Peng
authors: Yi-Zhi
authors: YZ
authors: Jiang
authors: An-Shun
authors: AS
authors: Tai
authors: Chun-Bin
authors: CB
authors: Liu
authors: Shih-Chi
authors: SC
authors: Peng
authors: Chun-Ta
authors: CT
authors: Liao
authors: Tzu-Chen
authors: TC
authors: Yen
authors: Wen-Ping
authors: WP
authors: Hsieh
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000556:secondary; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D006801:Humans; D008207:Lymphatic Metastasis; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci