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.
authors.affiliation: Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Attrotto
authors.forename: Lucia
authors.initials: L
authors.lastname: Colagiorgio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Todarello
authors.forename: Francesco
authors.initials: F
authors.lastname: Piva
authors.forename: Apostolos
authors.initials: A
authors.lastname: Papazacharias
authors.forename: Rita
authors.initials: R
authors.lastname: Masellis
authors.forename: Marina
authors.initials: M
authors.lastname: Mancini
authors.forename: Annamaria
authors.initials: A
authors.lastname: Porcelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.forename: Tiziana
authors.initials: T
authors.lastname: Quarto
authors.forename: Matteo
authors.initials: M
authors.lastname: Giulietti
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000328:Adult; D001288:Attention / Q000502:physiology; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D003198:Computer Simulation; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3