Epigenetic Links Between the Social Environment and Emotional Brain Function

描述（由申请人提供）：本申请是根据RFA-TW-13-002提交的。此应用程序的主要目标是为R 01应用程序收集试验数据， 鉴定唾液中介导社会环境与行为和临床相关神经表型的个体差异之间的关系的功能相关DNA甲基化（DNAm）特征。这个应用程序将建立在杜克神经遗传学研究（DNS）的独特资源。DNS旨在促进我们对预测与精神病理学风险相关的行为变异性的生物学机制和途径的理解。这一广泛的目标是通过系统测量和整合18-22岁年轻人的基因、大脑、环境和行为来实现的。207名DNS参与者的行为、临床、经验、神经成像和DNA数据已经可用，这些数据可以用于本应用程序中详细介绍的分析。此外，DNS由NIDA资助，将继续收集数据至2月28日。2017年，这将提供约200个额外的样品用于本申请下的甲基化测定。通过神经成像和基因组中常见变异对脑功能连续测量的假设驱动分析，这项研究既认识到NIMH RDoC中描述的维度表型日益重要，并提供了一个基础，从中研究特定的社会环境风险如何影响相对风险和恢复力的神经遗传轨迹，这将为正在进行的促进精神疾病治疗和预防的努力提供信息。病有证据表明DNA是可逆的，因此，这项工作将深入了解为什么以及如何改变社会环境与行为和临床相关结果的快速变化相关，以及相反，我们如何影响不利的社会环境对人类健康的影响。对现有和计划中的DNA样本进行甲基化检测将使我们能够实现以下目标：1）利用唾液DNA，鉴定与功能神经表型相关的候选基因编码区的DNAm特征（例如，与威胁相关的杏仁核反应性）与精神病理学相关; 2）研究社会应激源是否与目标1中确定的DNAm签名相关，以及DNAm签名是否解释了社会环境与功能神经表型之间的关系。我们的工作将直接有助于RFA-TW-13-002的使命，通过揭示可改变的社会暴露如何通过表观遗传过程产生已知与行为和临床相关的脑功能变化的潜在途径。在唾液中识别出与大脑功能相关的可靠DNAm特征，这本身就是该领域的一个巨大进步。这项pilt研究将为纵向工作奠定基础，以测试所观察到的关联的方向性，并为体外工作，旨在确定如何在这里观察到的DNAm签名转化为可观察到的神经表型的差异。

DESCRIPTION (provided by applicant): This application is submitted in response to RFA-TW-13-002. The broad goal of this application is to collect pilot data for an R01 application aimed at identifying functionally relevant DNA methylation (DNAm) signatures in saliva that mediate the relation between the social environment and individual differences in behaviorally and clinically relevant neural phenotypes. This application will build on the unique resource of the Duke Neurogenetics Study (DNS). The DNS seeks to advance our understanding of biological mechanisms and pathways predicting variability in behaviors associated with risk for psychopathology. This broad aim is achieved through the systematic measurement and integration of genes, brain, environment, and behavior in 18-22 year old young adults. Behavioral, clinical, experiential, neuroimaging, and DNA data are already available for 207 DNS participants, and these data are ready for the analyses detailed in this application. Moreover, the DNS is funded by NIDA to continue data collection through February 28. 2017, which will provide approximately 200 additional samples for methylation assays under this application. Through hypothesis-driven analysis of continuous measures of brain function through neuroimaging and common variation in the genome, this research both recognizes the growing importance of dimensional phenotypes as described in the NIMH RDoC, and provides a foundation from which to examine how specific social environmental risks influence neurogenetic trajectories of relative risk and resilience that will inform ongoing efforts to advance treatment and prevention of mental illness. Evidence suggests DNAm is reversible, and therefore, this work will provide insights into why and how changing social environments are associated with rapid changes in behavior and clinically-relevant outcomes and, conversely, how we might influence the impact of adverse social environments on human health. The proposed methylation assays on the existing and planned DNA samples will allow us to address the following aims: 1) Using salivary DNA, to identify DNAm signatures in coding regions of candidate genes associated with functional neural phenotypes (e.g. threat related amygdala reactivity) related to psychopathology; 2) To examine whether social stressors are associated with DNAm signatures identified in Aim 1, and whether DNAm signatures explain the relation between social environment and functional neural phenotypes. Our work will contribute directly to the mission of RFA-TW-13-002, by revealing potential pathways for how modifiable social exposure(s) that act through epigenetic processes produce changes in brain function known to be behaviorally and clinically relevant. The identification of reliable DNAm signatures in saliva that are correlated with brain function would be, in itself, a huge advance for the field. This pilt study will lay the groundwork for longitudinal work to test the directionality of observed associations and for in vitro work aimed at determining how DNAm signatures observed here are translated into observable differences in neural phenotypes.