Gene expression signatures as biomarkers of childhood trauma-related depression

儿童时期暴露在严重或创伤性生活事件中是发展健康问题的一个公认的主要风险因素。童年虐待、忽视和早期丧失一直与成年后精神健康问题的风险增加有关，特别是在长期或反复急性压力暴露的背景下。在之前的一个项目中，研究表明，有童年创伤史的健康成年人在急性应激暴露后表现出不同的基因表达谱。在差异表达的转录本中，显著特征的基因是那些参与促炎反应、受体信号转导和G蛋白偶联受体活性的基因。我们认为，转录应激反应中的这些变化构成了一个关键的脆弱因素，并在机制上参与了将应激与早期创伤暴露的个人的疾病联系起来的过程。这项拟议的项目旨在调查在抑郁症中识别出的转录是否发生了变化，以及这些转录是否能够区分有童年创伤史的抑郁症患者和没有这种病史的抑郁症患者。对基因表达水平的研究可以提供证据，证明在存在或不存在儿童期虐待的情况下，抑郁症患者具有不同的生物学修饰。从长远来看，这项研究可能会对个性化医疗产生影响。已识别的基因表达模式可能用于与童年创伤经历相关的亚型抑郁症，其特征是应激反应信号通路的明显变化，并可能最终指导治疗选择。另一个悬而未决的问题涉及差异基因表达模式的机制。因此，进一步的目的是研究差异DNA甲基化在转录应激反应中的作用。利用现有的数据集(对压力的全基因组mRNA表达谱)，将通过增加全基因组甲基化水平的信息来补充数据。这将允许在胁迫调节的背景下整合甲基组和转录组分析。

Exposure to serious or traumatic life events in childhood is a well-established major risk factor for developing health problems. Childhood abuse, neglect and early loss have been consistently associated with an increased risk for mental health problems in adulthood, especially in the context of chronic or repeated acute stress exposure. In a preceding project, it was shown that healthy adults with a history of childhood trauma displayed distinct gene expression profiles following acute stress exposure. Genes prominently featuring among differentially expressed transcripts are those involved in the pro-inflammatory response, receptor signaling and G-protein coupled receptor activity. We suggest that these alterations in the transcriptional stress response constitute a key vulnerability factor, and are mechanistically involved in the processes linking stress to disease in individuals exposed to early trauma. The proposed project seeks to investigate whether the identified transcripts are altered in depression, and whether these transcripts can distinguish between depressed individuals with a history of childhood trauma vs. depressed patients without such a history. Investigation of gene expression levels can provide evidence of distinct biological modifications in depression in the presence or absence of exposure to childhood abuse. In the long-term, the study may have implications for personalized medicine. Identified gene expression patterns might be utilized to sub-type depression associated with traumatic experience in childhood and characterized by distinct alterations in stress-responsive signaling pathways and might ultimately guide treatment choices.Another open question concerns the mechanism underlying differential gene expression patterns. A further aim is therefore to investigate the role of differential DNA methylation in the transcriptional stress response. Taking advantage of the existing data set (genome-wide mRNA expression profiles in response to stress), data will be complemented by adding information on genome-wide methylation levels. This will allow the integration of methylome and transcriptome analyses in the context of stress regulation.