Abstract
Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia. However, the inheritance of a single major gene does not serve as a vulnerability determinant. Instead, the accumulation of heterogeneous, multiple genetic abnormalities, each with a small effect, contribute to an increased risk of disease in carriers.
Genome- wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Although GWASs have identified promising candidate genes for schizophrenia, they have limited genetic effects and no single proposed gene is sufficient to cause the disease. Therefore, identification of specific pathways will provide the cue to understand the genetic architecture of the disease.
Recently, we performed GWAS of schizophrenia in Japanese population for searching schizophrenia susceptibility genes. In this study, using the data, we focused on a group of genes to examine whether a subset of genes categorized into some signaling pathway are involved in the pathogeneses of disease, beyond single genes. We unveiled the accumulation of association signals from genes of GABAergic pathway in schizophrenia. The GABAergic signaling cascade plays a critical role in the regulation of a diverse array of neuronal functions relevant to the pathogenesis of schizophrenia. These results do provide useful clues to unravel the complicated pathophysiology of schizophrenia.
