Genetic and post-mortem mRNA analysis of the 14-3-3 genes that encode phosphoserine/threonine-binding regulatory proteins in schizophrenia and bipolar disorder

Previous work with animal models of psychosis, human genetic studies, and human post-mortem gene expression studies implicate the 14-3-3 family of genes in schizophrenia. The 14-3-3 genes code for a family of proteins that bind to and regulate other proteins, and they modulate neurodevelopment, cell-division, signal transduction and gene transcription. To explore the role of five 14-3-3 isoforms (β, γ, ɛ, ζ, and η) in schizophrenia by: (1) comparing mRNA levels in post-mortem brain from schizophrenic, bipolar and control subjects and (2) assessing genetic association with schizophrenia in both case-control and nuclear family samples. Quantitative PCR (q-PCR) was used to determine relative mRNA levels in dorsolateral prefrontal cortex (Brodmann's area 46) samples donated by the Stanley Medical Research Institute (SMRI). Selected SNPs were genotyped in all five isoforms for association analysis in both family and case-control samples. No significant differences in 14-3-3 mRNA expression levels between the diagnostic groups were found. A significant genetic association with schizophrenia was found for the 14-3-3ζ isoform in a subset of nuclear families of British ancestry (TDT: χ 2 = 7.2; df = 1; p = 0.0073), in the case-control sample overall ( p = 0.011), and in a subset of the case-control sample. The results, in combination with other published evidence, suggest that further work is necessary to clarify what role the 14-3-3 genes may play in the etiology and pathogenesis of schizophrenia.