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Association of GSK-3β Genetic Variation With GSK-3β Expression, Prefrontal Cortical Thickness, Prefrontal Physiology, and Schizophrenia
Giuseppe Blasi, M.D., Ph.D.; Francesco Napolitano, Ph.D.; Gianluca Ursini, M.D., Ph.D.; Annabella Di Giorgio, M.D., Ph.D.; Grazia Caforio, M.D., Ph.D.; Paolo Taurisano, Ph.D.; Leonardo Fazio, Ph.D.; Barbara Gelao, Ph.D.; Maria Teresa Attrotto, M.D.; Lucia Colagiorgio, M.D.; Giovanna Todarello, M.D.; Francesco Piva, Eng., Ph.D.; Apostolos Papazacharias, M.D.; Rita Masellis, Ph.D.; Marina Mancini, Ph.D.; Annamaria Porcelli, Ph.D.; Raffaella Romano, Ph.D.; Antonio Rampino, M.D., Ph.D.; Tiziana Quarto, Ph.D.; Matteo Giulietti, Ph.D.; Barbara K. Lipska, Ph.D.; Joel E. Kleinman, M.D., Ph.D.; Teresa Popolizio, M.D.; Daniel R. Weinberger, M.D.; Alessandro Usiello, Ph.D.; Alessandro Bertolino, M.D., Ph.D.
Am J Psychiatry 2013;170:868-876. doi:10.1176/appi.ajp.2012.12070908
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The authors report no financial relationships with commercial interests.

Supported by the CARIME Foundation, the “Cassa di Risparmio di Puglia” Foundation, and the Cooperativa “Fratello Sole.”

From the Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy; CEINGE Biotecnologie Avanzate, Naples; IRCCS “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy; Department of Specialized Clinical Sciences and Odontostomatology, Polytechnic University of Marche, Ancona, Italy; Department of Bioscience, Biotechnology, and Pharmacological Sciences, Aldo Moro University, Bari, Italy; Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute of Mental Health, Bethesda, Md.; Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore; Department of Environmental Sciences, Second University of Naples; and European Brain Research Institute, Rome.

Address correspondence to Dr. Bertolino (alessandro.bertolino@uniba.it).

Copyright © 2013 by the American Psychiatric Association

Received July 12, 2012; Revised October 30, 2012; Accepted December 04, 2012.


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.

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FIGURE 1. Association of GSK-3β rs12630592 With GSK-3β mRNA Expression Levels in the Postmortem Prefrontal Cortexa

a Graph depicts normalized log2 ratios (sample/reference). Data from http://braincloud.jhmi.edu/. Error bars indicate standard error.

FIGURE 2. Western Blots and Association of GSK-3β rs12630592 With GSK-3β Protein Expression, Phosphorylation at Ser-9, and β-Catenin Protein Expression in PBMCs of Healthy Individualsa

a PBMCs=peripheral blood mononuclear cells; pGSK-3β=phosphorylated GSK-3β. Error bars indicate standard error.

FIGURE 3. Main Effect of GSK-3β rs12630592 on Prefrontal Activity During fMRI Tasksa

a Data from functional MRI scans and graphs depict main effect on prefrontal activity during the n-back task in panel A and the variable attentional control task in panel B. Error bars indicate standard error.

FIGURE 4. Correlation Analysis Between BOLD Responses and Behavioral Accuracy During Working Memory and Attentional Control as a Function of GSK-3β rs12630592 Genotypea

a BOLD=blood-oxygen-level-dependent; BA=Brodmann’s area. Panel A shows a negative correlation in GG subjects between the difference in prefrontal BOLD responses (three- minus two-back task) and the difference in accuracy (two- minus three-back task) at high cognitive loads during working memory. Panel B shows a similar correlation between deltas of BOLD responses (high minus intermediate) and deltas of accuracy (intermediate minus high) at high cognitive loads during attentional control in GG subjects. In TT subjects, a positive correlation during the n-back task fell short of statistical significance, and no relationship was observed during the variable attentional control task.

FIGURE 5. Association Between GSK-3β rs12630592 and Prefrontal Cortical Thickness (GG > TT) in Healthy Subjects and Values of Cortical Thickness Extracted From a Representative Prefrontal Clustera

a Color bar represents logarithm10 of p values, showing association between GSK-3β rs12630592 and prefrontal cortical thickness (GG > TT) in healthy subjects, and the graph depicts values of cortical thickness extracted from a representative prefrontal cluster (Montreal Neurological Institute coordinates: x=42, y=38, z=26). Error bars indicate standard error.



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