Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia

Giuseppe Blasi, Francesco Napolitano, Gianluca Ursini, Annabella Di Giorgio, Grazia Caforio, Paolo Taurisano, Leonardo Fazio, Barbara Gelao, Maria Teresa Attrotto, Lucia Colagiorgio, Giovanna Todarello, Francesco Piva, Apostolos Papazacharias, Rita Masellis, Marina Mancini, Annamaria Porcelli, Raffaella Romano, Antonio Rampino, Tiziana Quarto, Matteo Giulietti & 6 others Barbara K. Lipska, Joel Kleinman, Teresa Popolizio, Daniel Weinberger, Alessandro Usiello, Alessandro Bertolino

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)868-876
Number of pages9
JournalAmerican Journal of Psychiatry
Volume170
Issue number8
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Schizophrenia
Catenins
Genotype
Prefrontal Cortex
Phenotype
Blood Cells
Messenger RNA
Protein Kinases
Single Nucleotide Polymorphism
Magnetic Resonance Imaging

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia. / Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Di Giorgio, Annabella; Caforio, Grazia; Taurisano, Paolo; Fazio, Leonardo; Gelao, Barbara; Attrotto, Maria Teresa; Colagiorgio, Lucia; Todarello, Giovanna; Piva, Francesco; Papazacharias, Apostolos; Masellis, Rita; Mancini, Marina; Porcelli, Annamaria; Romano, Raffaella; Rampino, Antonio; Quarto, Tiziana; Giulietti, Matteo; Lipska, Barbara K.; Kleinman, Joel; Popolizio, Teresa; Weinberger, Daniel; Usiello, Alessandro; Bertolino, Alessandro.

In: American Journal of Psychiatry, Vol. 170, No. 8, 01.08.2013, p. 868-876.

Research output: Contribution to journalArticle

Blasi, G, Napolitano, F, Ursini, G, Di Giorgio, A, Caforio, G, Taurisano, P, Fazio, L, Gelao, B, Attrotto, MT, Colagiorgio, L, Todarello, G, Piva, F, Papazacharias, A, Masellis, R, Mancini, M, Porcelli, A, Romano, R, Rampino, A, Quarto, T, Giulietti, M, Lipska, BK, Kleinman, J, Popolizio, T, Weinberger, D, Usiello, A & Bertolino, A 2013, 'Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia', American Journal of Psychiatry, vol. 170, no. 8, pp. 868-876. https://doi.org/10.1176/appi.ajp.2012.12070908
Blasi, Giuseppe ; Napolitano, Francesco ; Ursini, Gianluca ; Di Giorgio, Annabella ; Caforio, Grazia ; Taurisano, Paolo ; Fazio, Leonardo ; Gelao, Barbara ; Attrotto, Maria Teresa ; Colagiorgio, Lucia ; Todarello, Giovanna ; Piva, Francesco ; Papazacharias, Apostolos ; Masellis, Rita ; Mancini, Marina ; Porcelli, Annamaria ; Romano, Raffaella ; Rampino, Antonio ; Quarto, Tiziana ; Giulietti, Matteo ; Lipska, Barbara K. ; Kleinman, Joel ; Popolizio, Teresa ; Weinberger, Daniel ; Usiello, Alessandro ; Bertolino, Alessandro. / Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia. In: American Journal of Psychiatry. 2013 ; Vol. 170, No. 8. pp. 868-876.
@article{d8f164b272e741bf882f4f0a1fc36c23,
title = "Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia",
abstract = "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.",
author = "Giuseppe Blasi and Francesco Napolitano and Gianluca Ursini and {Di Giorgio}, Annabella and Grazia Caforio and Paolo Taurisano and Leonardo Fazio and Barbara Gelao and Attrotto, {Maria Teresa} and Lucia Colagiorgio and Giovanna Todarello and Francesco Piva and Apostolos Papazacharias and Rita Masellis and Marina Mancini and Annamaria Porcelli and Raffaella Romano and Antonio Rampino and Tiziana Quarto and Matteo Giulietti and Lipska, {Barbara K.} and Joel Kleinman and Teresa Popolizio and Daniel Weinberger and Alessandro Usiello and Alessandro Bertolino",
year = "2013",
month = "8",
day = "1",
doi = "10.1176/appi.ajp.2012.12070908",
language = "English (US)",
volume = "170",
pages = "868--876",
journal = "American Journal of Psychiatry",
issn = "0002-953X",
publisher = "American Psychiatric Association",
number = "8",

}

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

AU - Popolizio, Teresa

AU - Weinberger, Daniel

AU - Usiello, Alessandro

AU - Bertolino, Alessandro

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

VL - 170

SP - 868

EP - 876

JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

SN - 0002-953X

IS - 8

ER -