GSK-3beta genetic variation is associated with GSK-3beta expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia

Objective: Glycogen synthase kinase 3b (GSK-3b) 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-3b 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-3b functional variation with 1) GSK-3b mRNA expression from postmortem prefrontal cortex, 2) GSK-3b and b-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-3b (rs12630592) was associated with reduced GSK-3b mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3b protein expression and kinase activity, as well as with downstream effects on b-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-3b variation is implicated in multiple phenotypes relevant to schizophrenia.