Analysis of differential gene expression mediated by clozapine in human postmortem brains

SCHIZOPHRENIA RESEARCH

卷:185

Article

Lee, Brian J.^1,2  Marchionni, Luigi³  Andrews, Carrie E.¹  Norris, Alexis L.^4,5  Nucifora, Leslie G.¹  Wu, Yeewen Candace¹  Wright, Robert A.⁶  Pevsner, Jonathan^1,4,5  Ross, Christopher A.^1,2,4  Margolis, Russell L.^1,2,4  Sawa, Akira^1,2,4  Nucifora, Frederick C., Jr.¹ 

[1] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Sch Med, 600 N Wolfe St, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Cellular & Mol Med Program, 1830 E Monument St, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 401 N Broadway, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Neurol, Kennedy Krieger Inst, 707 N Broadway, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, William H Welch Med Lib, 1900 E Monument St, Baltimore, MD 21205 USA

关键词: Schizophrenia;    Bipolar affective disorder;    Antipsychotic;    Microarray;   

DOI  :  10.1016/j.schres.2016.12.017

来源: Elsevier

【 摘 要 】

Clozapine is the only medication indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents, but its mechanism of action is poorly understood. To date, no studies of human postmortem brain have characterized the gene expression response to clozapine. Therefore, we addressed this question by analyzing expression data extracted from published microarray studies involving brains of patients on antipsychotic therapy. We first performed a systematic review and identified four microarray studies of postmortem brains from antipsychotic-treated patients, then extracted the expression data. We then performed generalized linear model analysis on each study separately, and identified the genes differentially expressed in response to clozapine compared to other atypical antipsychotic medications, as well as their associated canonical pathways. We also found a number of genes common to all four studies that we analyzed: GCLM, ZNFG52, and GYPC. In addition, pathway analysis highlighted the following processes in all four studies: clathrin-mediated endocytosis, SAPKIINK signaling, 3-phosphoinositide synthesis, and paxillin signaling. Our analysis yielded the first comprehensive compendium of genes and pathways differentially expressed upon clozapine treatment in the human brain, which may provide insight into the mechanism and unique efficacy of clozapine, as well as the pathophysiology of schizophrenia. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

Free