Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling

In this study, we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database. These drugs had interactions with 142 targets, whose corresponding genes were defined as drug targeted genes. To explore the complexity between these drugs and their related genes in schizophrenia, we constructed a drug-target gene network. These genes were overrepresented in several pathways including: neuroactive ligand-receptor pathways, glutamate metabolism, and glycine metabolism. Through integrating the pathway information into a drug-gene network, we revealed a few bridge genes connected the sub-networks of the drug-gene network: GRIN2A, GRIN3B, GRIN2C, GRIN2B, DRD1, and DRD2. These genes encode ionotropic glutamate receptors belonging to the NMDA receptor family and dopamine receptors. Haloperidol was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia. This study represents the first systematic investigation of drug-gene interactions in psychosis.