Causal inference of gene regulation with subnetwork assembly from genetical genomics data

Chien Hua Peng, Yi Zhi Jiang, An Shun Tai, Chun Bin Liu, Shih Chi Peng, Chun Ta Liao, Tzu Chen Yen, Wen Ping Hsieh

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 randomfield 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.

Original languageEnglish
Pages (from-to)2803-2819
Number of pages17
JournalNucleic acids research
Volume42
Issue number5
DOIs
Publication statusPublished - 2014 Mar 1

All Science Journal Classification (ASJC) codes

  • Genetics

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