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.
Association of GSK-3 beta Genetic Variation With GSK-3 beta Expression, Prefrontal Cortical Thickness, Prefrontal Physiology, and Schizophrenia
USIELLO, Alessandro;
2013
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
