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.
This application is aimed at revealing potential pathways for how modifiable social exposure(s) that act through DNA methylation processes produce changes in brain function known to be behaviorally and clinically relevant. Given evidence that DNA methylation is reversible, 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.