Transgenerational Epigenomics of Trauma and PTSD in Rwanda

项目摘要 拟议工作的目标是描述种族灭绝暴露的跨代基因组影响。 以及卢旺达种族灭绝的女性幸存者及其后代的创伤后应激障碍(PTSD)。 创伤后应激障碍是一种常见的、令人衰弱的精神疾病，对公共健康有深远的影响。4月之间 1994年6月，近100万人死于卢旺达对图西族人的种族灭绝。二十年 后来，卢旺达成年人创伤后应激障碍的患病率为26.1%，说明了这一长期影响。 强有力的证据表明创伤后应激障碍的跨代传播。创伤后应激障碍有已知的病因 组成部分：暴露在涉及生命威胁的极端创伤性应激源中，这会导致生物连锁 这包括对其活动有助于精神病理学发展的基因座进行表观遗传修饰。在……里面 此外，我们在卢旺达的研究表明，创伤后应激障碍传播给种族灭绝的后代 母亲与下丘脑-垂体-肾上腺(HPA)生物改变的传播有关 糖皮质激素受体(NR3C1)基因的轴和表观遗传修饰 糖皮质激素受体调节网络(GRRN)。在这些最近发现的基础上，拟议的工作 寻求表征创伤后应激障碍和创伤暴露的跨代表观遗传效应 卢旺达种族灭绝。我们将使用基因组规模的技术，并将重点放在调节的初步分析 GRRN和相关的HPA轴基因，在最近的全基因组工作中与创伤后应激障碍相关。 具体地说，我们将从我们现有的生物库中测试100个DNA样本，该生物库以前是为了支持我们的 先导研究。我们将通过收集怀孕妇女的新标本来扩展现有的生物库 在卢旺达种族灭绝期间，他们的孩子，以及他们的弟弟妹妹， 在人口统计学上匹配，非种族灭绝暴露的对照组。我们将对一个 在卢旺达和通过H3非洲网络对这些标本进行亚抽样，以测试其他 假设。我们的建议直接针对RFA-RM-16-015支持人类基因组学的关键任务 研究不仅将产生与人类健康相关的重要发现，而且还将作为一种工具 提高非洲实验室和研究机构科学家的研究能力 被执行。它还直接涉及NIMH战略目标1.2：确定基因组和非基因组 与精神疾病相关的因素和2.1：表征大脑的发展轨迹 成熟度和行为维度，以了解不同人群精神疾病的根源。 卢旺达大学、伊利诺伊大学和 H3非洲网络还将通过在卢旺达的科学培训来加强科研能力。

Project Summary The goal of the proposed work is to characterize the transgenerational genomic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the Rwandan genocide and their offspring. PTSD is a common and debilitating mental disorder that has a profound public health impact. Between April and June 1994, almost one million people died in the Rwandan genocide against ethnic Tutsi. Twenty years later the long-term impact is illustrated by the prevalence of PTSD in Rwandan adults at 26.1 % and there is strong evidence pointing towards the transgenerational transmission of PTSD. PTSD has a known etiologic component: exposure to an extreme traumatic stressor involving life threat, which induces a biological cascade that includes epigenetic modification of loci whose activity contributes to psychopathological development. In addition, our study in Rwanda showed that transmission of PTSD to the offspring of genocide-exposed mothers was associated with transmission of biological alterations of the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic modifications of the glucocorticoid receptor (NR3C1) gene, a key player in the glucocorticoid receptor regulatory network (GRRN). Building upon these recent findings, the proposed work seeks to characterize the transgenerational epigenetic effects of PTSD and trauma exposure due to the Rwandan genocide. We will employ genome-scale technologies and focus initial analyses on regulation of GRRN and related HPA axis genes, which have been associated with PTSD in recent genome-wide work. Specifically, we will test 100 DNA samples from our existing biobank, previously established in support of our pilot study. We will extend the existing biobank by collecting new specimens from women who were pregnant during the Rwandan genocide and their resulting children, as well their younger siblings, and a demographically matched, non-genocide exposed control group. We will perform additional analyses on a subsample of these specimens both in Rwanda and through the H3Africa network to test additional hypotheses. Our proposal is directly aimed at a key mission of RFA-RM-16-015, to support human genomics research that will not only generate important findings relevant to human health, but also serve as a vehicle to improve the research capacity of African laboratories and scientists at the institutions where the research is carried out. It also directly addresses NIMH strategic objectives 1.2: Identify the genomic and non-genomic factors associated with mental illnesses and 2.1: Characterize the developmental trajectories of brain maturation and dimensions of behavior to understand the roots of mental illnesses across diverse populations. The unique collaboration between the University of Rwanda, the University of Illinois and members of the H3Africa Network will also strengthen the capacity of scientific research through scientific training in Rwanda.