| Summary: | 碩士 === 國立陽明大學 === 生物醫學資訊研究所 === 97 === Schizophrenia is a complex disease with multiple factors contributing to pathogenesis. In addition to the environmental factors, genetic factors may also increase the susceptibility of acquiring this disease. In other words, schizophrenia is a highly heritable disease. Some candidate genes were deduced on the basis of their known function and the others were found on the basis of their chromosomal location. Individuals that have multiple candidate genes may increase the risk further. However, it is not clear what kind of gene combinations may productively lead to the disease phenotype. Furthermore, how these genes may work together to increase the risk is yet to be studied
Most pathways except metabolic pathways are rich in protein-protein interactions (PPI). Thus, the PPI network contains pathway information, even though the upstream-downstream relation of PPI is yet to be explored. Here we have constructed a schizophrenia interactome by extracting the nearest neighbour of the 431 reported candidate genes described in the literature. Although these candidate genes were discovered by different approaches, most of the proteins connected to one another and form a big cluster. Seven major protein interaction modules were identified on the basis of the pair-wise distance among the proteins in this sub-network. The most of the clusters might play roles in the synaptic transmission, signal transduction and immune response, based on gene ontology annotation. The protein interactions in the synaptic transmission cluster were used to explain the interaction between NRG1 and CACNG2 genes, which was found by both linkage and association studies. This working hypothesis is supported by the co-expression analysis based on public microarray gene expression.
On the basis of the protein interaction network, the NRG1-triggered NMDAR protein internalization and the CACNG2 mediated AMPA receptor recruiting may act together in glutamatergic signalling process. Since both the NMDA and AMPA receptors are calcium channels, this process may regulate the influx of Ca2+. Reducing the cation influx might be one of the disease mechanisms for schizophrenia. This PPI network analysis approach combined with the support from co-expression analysis may provide an efficient way to propose disease mechanisms for various highly heritable diseases.
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