Association of GSK-3[beta] Genetic Variation With GSK-3[beta] Expression, Prefrontal Cortical Thickness, Prefrontal Physiology, and Schizophrenia

Objective: Glycogen synthase kinase 3[beta] (GSK-3[beta]) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3[beta] gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. Method: Based on computer predictions, the authors investigated in humans the association of GSK-3[beta] functional variation with 1) GSK-3[beta] mRNA expression from postmortem prefrontal cortex, 2) GSK-3[beta] and [beta] -catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. Results: Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3[beta] (rs12630592) was associated with reduced GSK-3[beta] mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3[beta] protein expression and kinase activity, as well as with downstream effects on [beta]-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. Conclusions: These results suggest that GSK-3[beta] variation is implicated in multiple phenotypes relevant to schizophrenia. [PUBLICATION ABSTRACT]