TY - JOUR
T1 - Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia
AU - Blasi, Giuseppe
AU - Napolitano, Francesco
AU - Ursini, Gianluca
AU - Di Giorgio, Annabella
AU - Caforio, Grazia
AU - Taurisano, Paolo
AU - Fazio, Leonardo
AU - Gelao, Barbara
AU - Attrotto, Maria Teresa
AU - Colagiorgio, Lucia
AU - Todarello, Giovanna
AU - Piva, Francesco
AU - Papazacharias, Apostolos
AU - Masellis, Rita
AU - Mancini, Marina
AU - Porcelli, Annamaria
AU - Romano, Raffaella
AU - Rampino, Antonio
AU - Quarto, Tiziana
AU - Giulietti, Matteo
AU - Lipska, Barbara K.
AU - Kleinman, Joel E.
AU - Popolizio, Teresa
AU - Weinberger, Daniel R.
AU - Usiello, Alessandro
AU - Bertolino, Alessandro
N1 - Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Objective: Glycogen synthase kinase 3β (GSK-3β) 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-3β 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-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-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-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-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-3β variation is implicated in multiple phenotypes relevant to schizophrenia.
AB - Objective: Glycogen synthase kinase 3β (GSK-3β) 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-3β 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-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-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-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-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-3β variation is implicated in multiple phenotypes relevant to schizophrenia.
UR - http://www.scopus.com/inward/record.url?scp=84883367748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883367748&partnerID=8YFLogxK
U2 - 10.1176/appi.ajp.2012.12070908
DO - 10.1176/appi.ajp.2012.12070908
M3 - Article
C2 - 23598903
AN - SCOPUS:84883367748
SN - 0002-953X
VL - 170
SP - 868
EP - 876
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 8
ER -