ABSTRACT

Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics in the etiopathogenesis of SZ still faces many challenges. In this work, we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approach. We identified and replicated two expression and two methylation modules significantly associated with SZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were significantly enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved ageing process with module genes mostly related to oligodendrocyte development and myelination, and specifically expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression at the network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation to SZ and ageing process.

摘要

大量工作证明了遗传学、表观遗传学及其在精神分裂症 (SZ) 病理学中脑转录调控中的相互作用。目前，在分析具有风险的转录组网络的遗传成分方面取得了巨大成功。然而，表观遗传学在SZ发病机制中的调控作用研究仍面临诸多挑战。在这项工作中，我们使用加权相关网络方法研究了精神分裂症患者和健康对照的背外侧前额叶皮层 (DLPFC) 区域的 DNA 甲基化和基因表达。我们鉴定并复制了与 SZ 显着相关的两个表达和两个甲基化模块。他们之中，一对表达和甲基化模块在模块基因中显着重叠，在星形胶质细胞相关功能通路中显着富集，并在星形胶质细胞中特异性表达。另外两个连接的表达-甲基化模块对涉及衰老过程，模块基因主要与少突胶质细胞发育和髓鞘形成有关，并在少突胶质细胞中特异性表达。对潜在数量性状基因座 (QTL) 的进一步检查表明，大多数精神疾病的表达 QTL 的遗传风险显着富集，而甲基化 QTL 则没有。这些结果支持网络水平上甲基化和基因表达之间的一致性，