Epigenetic Links Between the Social Environment and Emotional Brain Function

描述(申请人提供)：本申请是根据RFA-TW-13-002提交的。该应用程序的主要目标是收集R01应用程序的试点数据，该应用程序旨在 确定唾液中功能相关的DNA甲基化(DNaM)签名，这些签名调解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。这一应用程序将建立在杜克大学神经遗传学研究(DNS)的独特资源之上。域名系统试图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。这个广泛的目标是通过对18-22岁的年轻人的基因、大脑、环境和行为的系统测量和整合来实现的。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，这些数据已准备好用于本应用程序中详细的分析。此外，域名系统由NIDA提供资金，以便在2月28日之前继续收集数据。2017年，将为这项申请下的甲基化分析提供大约200个额外样本。通过对通过神经成像和基因组常见变异对大脑功能的连续测量进行假设驱动的分析，这项研究既认识到NIMH RDoC中描述的维度表型日益增长的重要性，又提供了一个基础，从这个基础上考察特定的社会环境风险如何影响相对风险和韧性的神经发生轨迹，这些轨迹将为推进精神疾病的治疗和预防提供信息。有证据表明dNaM是可逆的，因此，这项工作将提供关于为什么以及如何变化的社会环境与行为和临床相关结果的快速变化相关的见解，以及反过来，我们可能如何影响不利的社会环境对人类健康的影响。拟议对现有和计划中的DNA样本进行的甲基化分析将使我们能够达到以下目标：1)使用唾液DNA，在与精神病相关的功能神经表型(例如威胁相关的杏仁核反应性)相关候选基因的编码区确定dNaM签名；2)检查社会应激源是否与目标1中确定的dNaM签名有关，以及dNaM签名是否解释社会环境和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的任务，揭示可改变的社交暴露(S)如何通过表观遗传过程产生已知与行为和临床相关的大脑功能变化的潜在路径。唾液中与大脑功能相关的可靠dNaM信号的识别本身就是该领域的一大进步。这项PILT研究将为测试观察到的联系的方向性的纵向工作和旨在确定这里观察到的dNaM信号如何转化为神经表型中可观察到的差异的体外工作奠定基础。

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.