Epigenetic signatures of war and conflict-related trauma - a study of refugee families in Africa

世界上的难民人数已达到2500多万人。一般估计认为，逃离武装冲突的难民中有50%以上受到创伤后应激障碍（PTSD）等精神健康问题的影响。了解对创伤应激的行为脆弱性和复原力的心理和生物学基础是公共卫生的优先事项，因为它将有助于制定有针对性的预防战略和治疗干预措施。有大量证据表明，暴露于战争和冲突相关的创伤与精神病理风险增加之间存在联系。然而，创伤暴露后PTSD患病率存在显著差异。表观遗传过程被认为是一种中介机制。然而，将创伤暴露和/或创伤相关精神病理与特定表观遗传改变联系起来的令人信服的人类证据仍然很少。这在一定程度上是由于设计上的限制，以及迄今为止大多数研究都集中在跨基因覆盖率低的候选基因上，这可能会错过重要的差异甲基化基因组区域。为数不多的全表观基因组研究规模较小，因此无法检测到影响。因此，到目前为止，还没有清晰的PTSD的表观遗传特征。在拟议的项目中，我们将通过使用最先进的基于阵列的技术来研究在难民营中重新安置的暴露于多重严重创伤的难民家庭的良好动力（n bbb600）和良好特征的样本来解决这些局限性，从而探索整个基因组中PTSD症状相关的改变，然后验证最热门的结果。为此目的，我们已经成功地从位于坦桑尼亚的三个大型难民营中的布隆迪难民家庭三合会（父亲、母亲和一个孩子）的代表性样本中收集了数据。我们的样本特别适合研究创伤经历、创伤相关障碍和潜在的表观遗传机制之间的相互作用，因为样本在创伤经历、种族和遗传背景以及当前生活状况方面都是同质的，并且以战争和冲突相关暴力的形式显示出非常高的创伤暴露水平。在拟议的项目中，我们的目标是确定与创伤后应激障碍相关的DNA甲基化改变，以区分在战争相关创伤暴露后患PTSD的个体和未受相同暴露影响的个体。我们进一步旨在证明创伤负荷与DNA甲基化模式有关。最后，我们的目标是证明DNA甲基化在创伤暴露和PTSD风险之间的关联中的中介作用。此外，我们的目标是使用现有的验证样本来确认我们的发现。

The number of refugees in the world has reached more than 25 million people. General estimates hold that more than 50% of the refugees who have fled armed conflicts are affected by mental health problems, such as posttraumatic stress disorder (PTSD). Understanding the psychological and biological underpinnings of behavioral vulnerability and resilience to traumatic stress is a public health priority, as it would facilitate the development of targeted preventative strategies and therapeutic interventions. There is extensive evidence showing a link between exposure to war- and conflict-related trauma and increased risk for psychopathology. However, there exists significant variability in PTSD prevalence following trauma exposure. Epigenetic processes have been proposed as a mediating mechanism. However, compelling human evidence linking trauma exposure and/or trauma-related psychopathology to specific epigenetic alterations remains sparse. This is partly due to design limitations and the fact that the majority of studies has so far focused on candidate genes with low coverage across genes, which might miss important differentially methylated genomic regions. The few epigenome-wide studies were small and thus underpowered to detect effects. Thus, no clear picture of an epigenetic PTSD signature has emerged so far. In the proposed project, we will address these limitations by investigating a well-powered (n > 600) and well-characterized sample of refugee families exposed to multiple severe trauma who have resettled in refugee camps using state-of-the-art array-based technology to explore PTSD symptom related alterations across the genome, followed by validation of top hits. For this purpose, we have already successfully collected data from a representative sample of Burundian refugee family triads (father, mother, and one child) in three large refugee camps that are located in Tanzania. Our sample is particularly suitable for studying the interplay of traumatic experiences, trauma-related disorders, and potential epigenetic mechanisms because the sample is homogeneous in terms of their traumatic experiences as well as their ethnic and genetic background and current living situation, and shows a very high level of trauma exposure in the form of war- and conflict-related violence. In the proposed project, we aim to identify PTSD-associated alterations of DNA methylation that distinguish between individuals who developed PTSD following war-related trauma exposure and unaffected individuals with the same exposure. We further aim to show that trauma load is related to DNA methylation patterns. Lastly, we aim to demonstrate the mediating role of DNA methylation in the association between trauma exposure and PTSD risk. In addition, we aim to confirm our findings using existing validation samples.