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Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia

机译：精神分裂症的单卵双胞胎之间DNA甲基化差异的起源的见解

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BackgroundDNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. MethodsMethylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). ResultsPathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling ( p =?3.93E-03) and MAPK signaling ( p =?4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons ( p =?1.53E-02), Dopamine- DARPP32 feedback in cAMP signaling ( p =?7.43E-03) and Ephrin receptors ( p =?1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function ( p =?1.71E-03-4.28E-02). ConclusionThe findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients.
机译：先前已报道精神分裂症不一致的单卵双胞胎之间的背景DNA甲基化差异。然而，精神分裂症不一致的单卵双胞胎之间的甲基化差异的起源尚不清楚。此处的发现表明，所有DNA甲基化差异不一定代表疾病的原因。某些原因可能是抗精神病药的作用。方法使用Arraystar Inc.（美国马里兰州罗克维尔）的全基因组DNA甲基化阵列，研究了大鼠脑区以及两对不相关的单精神分裂双胞胎与精神分裂症的甲基化差异。然后使用机巧途径分析（Ingenuity System Inc，CA，USA）进一步鉴定鉴定出的显示出显着改变的DNA甲基化的基因启动子。结果对最重要的基因启动子过度/低甲基化的通路分析表明，在与神经发育和精神疾病直接相关的生物网络和通路中，DNA甲基化变化显着丰富。这些包括与未受影响的双胞胎相比，在精神分裂症患者中涉及高甲基化基因的HIPPO信号通路（p =？3.93E-03）和MAPK信号通路（p = 4.27E-03）。而且，已经鉴定出许多涉及具有低甲基化基因启动子的基因的重要途径和网络。这些包括神经元中的CREB信号传导（p =？1.53E-02），cAMP信号传导的多巴胺-DARPP32反馈（p =？7.43E-03）和Ephrin受体（p =？1.13E-02）。此外，参与神经系统发育和功能的途径显着丰富（p =？1.71E-03-4.28E-02）。结论该发现突出了抗精神病药对精神分裂症患者DNA甲基化的重要性。两对单卵双胞胎中受DNA甲基化影响的独特途径表明，患者特异性途径是该疾病的原因。提示在治疗该疾病中可能需要采用针对患者的治疗策略。该研究反映了开发个性化医学方法的必要性，该方法应考虑患者之间的表观遗传学差异。

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