Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS): {Georgia State University, Georgia Institute of Technology, and Emory University}, Atlanta, USA.
Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, USA.
Epigenetics. 2021 Aug;16(8):876-893. doi: 10.1080/15592294.2020.1827718. Epub 2020 Oct 20.
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.
大量研究表明，遗传学、表观遗传学及其在精神分裂症（SZ）病理中的脑转录调控相互作用具有重要作用。目前，在剖析与风险相关的转录组网络的遗传成分方面已经取得了巨大成功。然而，在 SZ 的发病机制中研究表观遗传学的调节作用仍然面临许多挑战。在这项工作中，我们使用加权相关网络方法研究了 SZ 患者和健康对照者的外侧前额叶皮层（DLPFC）区域的 DNA 甲基化和基因表达。我们鉴定并复制了两个与 SZ 显著相关的表达和甲基化模块。其中，一对表达和甲基化模块在与星形胶质细胞相关的功能途径显著富集的模块基因中显著重叠，并且在星形胶质细胞中特异性表达。另外两个关联的表达-甲基化模块对与年龄相关的过程有影响，其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（QTLs）的进一步检查表明，大多数精神障碍的遗传风险在表达 QTLs 中显著富集，但在甲基化 QTLs 中没有。这些结果支持了在网络水平上甲基化和基因表达之间的一致性，并表明遗传和表观遗传学在调节与 SZ 和衰老过程相关的特定胶质细胞的基因表达网络方面具有组合效应。
