Schizophrenia-associated MicroRNA–Gene Interactions in the Dorsolateral Prefrontal Cortex

作     者：Danielle M.Santarelli Adam P.Carroll Heath M.Cairns Paul A.Tooney Murray J.Cairns 

作者机构：School of Biomedical Sciences and PharmacyThe University of NewcastleCallaghanNSW 2308Australia Centre for Brain and Mental Health ResearchHunter Medical Research InstituteNewcastleNSW 2305Australia 

出 版 物：《Genomics, Proteomics & Bioinformatics》 (基因组蛋白质组与生物信息学报（英文版）)

年 卷 期：2019年第17卷第6期

页      面：623-634页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学] 

基　　金：supported by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression Hunter Medical Research Institute,and the National Health and Medical Research Council(NHMRC,Grant No.631057) supported by an NHMRC Senior Research Fellowship(Grant No.1121474). 

主　　题：Schizophrenia MicroRNA Dorsolateral prefrontal cortex Network Neuropathology 

摘      要：Schizophrenia-associated anomalies in gene expression in postmortem brain can be attributed to a combination of genetic and environmental influences. Given the small effect size of common variants, it is likely that we may only see the combined impact of some of these at the pathway level in small postmortem studies. At the gene level, however, there may be more impact from common environmental exposures mediated by influential epigenomic modifiers, such as microRNA(miRNA). We hypothesise that dysregulation of miRNAs and their alteration of gene expression have significant implications in the pathophysiology of schizophrenia. In this study, we integrate changes in cortical gene and miRNA expression to identify regulatory interactions and networks associated with the disorder. Gene expression analysis in post-mortem prefrontal dorsolateral cortex(BA 46)(n = 74 matched pairs of schizophrenia, schizoaffective, and control samples)was integrated with miRNA expression in the same cohort to identify gene–miRNA regulatory networks. A significant gene–miRNA interaction network was identified, including miR-92 a, miR-495,and miR-134, which converged with differentially expressed genes in pathways involved in neurodevelopment and oligodendrocyte function. The capacity for miRNA to directly regulate gene expression through respective binding sites in BCL11 A, PLP1, and SYT11 was also confirmed to support the biological relevance of this integrated network model. The observations in this study support the hypothesis that mi RNA dysregulation is an important factor in the complex pathophysiology of schizophrenia.