Schizophrenia as a neuronal synaptic disorder related to multiple rare genetic mutations

Schizophrenia is a highly heritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Synaptic pathology has been reported as a feature of the brain in schizophrenia. Abnormal expression of some synaptic proteins (e.g., SYP, GAP-43, and NRGN) in different brain regions has been linked to this disorder in postmortem brain studies. In our series of genetic studies, we used a resequencing strategy to search for genetic variants in these candidate genes in a sample of patients with schizophrenia and nonpsychotic controls, all of whom were Han Chinese from Taiwan, and conducted further association and functional studies. After resequencing these candidate genes, no common polymorphisms appeared to play a major role in conferring susceptibility to schizophrenia in our population. In contrast, we identified some rare patient-specific variants. The results of the reporter gene assays and software analysis demonstrated the influence of reporter genes on the function of each studied gene, suggesting that they may contribute to the pathogenesis of schizophrenia. These data lend support to the hypothesis that multiple rare mutations are involved in the pathogenesis of schizophrenia, and provide genetic clues that indicate the involvement of synaptic pathology in this disorder.