Members of the forkhead family of transcription factors might be involved in the pathogenesis of schizophrenia

The mode of inheritance for schizophrenia seems to involve several genes, where each of which might account for only a small part in the susceptibility. Because of this complexity it seems feasible to combine several complementary strategies including genetic association studies as well as animal models. In our aim to identify new candidate genes we used an NMDA receptor antagonist animal model comprising of chronic low dose application of MK801, which mimics several aspects of psychosis on a molecular, cellular, functional and behavioural level. In a functional genomic approach we identified several differentially expressed genes in the rat hippocampus using microarrays. Among them we could identify two members of the forkhead family of transcripiton factors. These are known to be involved in the NGF-induced antiapoptotic signaling in neurons, NGF being linked to schizophrenia by its implication in cognitive deficits. In order to clarify the role of the FOX genes in schizophrenia we genotyped 700 patients with schizophrenia according to DSM-IV and 200 first degree relatives as well as 2000 community-based healthy volunteers using 10 SNPs covering each gene. Interestingly we could identify a significant association of several FOX SNPs with schizophrenia as well as with executive function assessed by WCST. Members of the forkhead family of transcription factors seem to be promising new candidate genes contributing to the risk for schizophrenia.

This study was supported by GSK