期刊
JOURNAL OF PSYCHIATRIC RESEARCH
卷 46, 期 11, 页码 1464-1474出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jpsychires.2012.08.005
关键词
Schizophrenia; Microarray; Gene expression; Brain; Antipsychotic treatment
类别
资金
- Genomics Core at the UCSD CFAR [AI36214]
- U.S. National Institute of Health (NIH) [P50MH081755, R01MH085521]
- James B. Pendleton Charitable Trust
- Spanish Ministry of Science and Innovation (MICINN) [SAF2009/8460]
- Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM)
- Basque Government [IT199/07]
- Sidney R. Baer, Jr. Foundation
- NARSAD: The Brain and Behavior Research Foundation
Small cohort sizes and modest levels of gene expression changes in brain tissue have plagued the statistical approaches employed in microarray studies investigating the mechanism of schizophrenia. To combat these problems a combined analysis of six prior microarray studies was performed to facilitate the robust statistical analysis of gene expression data from the dorsolateral prefrontal cortex of 107 patients with schizophrenia and 118 healthy subjects. Multivariate permutation tests identified 144 genes that were differentially expressed between schizophrenia and control groups. Seventy of these genes were identified as differentially expressed in at least one component microarray study but none of these individual studies had the power to identify the remaining 74 genes, demonstrating the utility of a combined approach. Gene ontology terms and biological pathways that were significantly enriched for differentially expressed genes were related to neuronal cell-cell signaling, mesenchymal induction, and mitogen-activated protein kinase signaling, which have all previously been associated with the etiopathogenesis of schizophrenia. The differential expression of BAG3, C4B, EGR1, MT1X, NEUROD6, SST and S100A8 was confirmed by real-time quantitative PCR in an independent cohort using postmortem human prefrontal cortex samples. Comparison of gene expression between schizophrenic subjects with and without detectable levels of antipsychotics in their blood suggests that the modulation of MT1X and S100A8 may be the result of drug exposure. In conclusion, this combined analysis has resulted in a statistically robust identification of genes whose dysregulation may contribute to the mechanism of schizophrenia. (C) 2012 Elsevier Ltd. All rights reserved.
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