Pathway and network analysis of schizophrenia candidate genes under meta-analysis linkage peaks

Schizophrenia is a major brain-related mental disorder. Many genes are likely associated with schizophrenia; their gene-gene interactions as well as gene-environment interactions may contribute as a major risk to the disorder. Rather than the traditional studies of single gene or marker, in this study we hypothesized that positional candidate genes under linkage peaks may play a major role in causing complex diseases such as schizophrenia through a mechanism of their gene-gene or protein-protein interactions. To test this hypothesis, we identified positional candidate genes under the linkage peaks from recently completed genome scan meta-analysis (GSMA) of the 32 genome-wide linkage studies. For these genes, we examined their enriched Gene Ontology (GO) annotations, identified significantly over-represented KEGG pathways, and, based on the genes in these pathways, extracted subnetworks from whole human protein-protein interaction network. Our results indicated that these schizophrenia candidate genes involve in important functions such as receptor activity, transcriptional regulation, neurobiological and signaling pathways, which support the neurotransmitter and neuroplasticity theories of schizophrenia. This study suggests that gene network and pathway is a powerful approach to uncovering the molecular mechanisms of complex diseases.