Characterization of DNA methylation and gene expression profiles in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a debilitating mental disorder precipitated by trauma exposure and characterized by involuntary re-experiencing of the traumatic event, avoidance of trauma-associated stimuli, negative alterations in mood and cognition, and alterations in arousal/reactivity. While most individuals are exposed to a potentially traumatic event at some point in their lives, only a small subset develop PTSD. This suggests that trauma exposure is necessary, but not sufficient, for the pathogenesis of PTSD, and that many other pre-existing factors, including genetic background, play an influential role in determining individual response to trauma. PTSD is a complex syndrome with a great degree of heterogeneity in presentation within and across populations. Similarly, biological correlates associated with PTSD, specifically DNA methylation (DNAm) and gene expression profiles, exhibit tissue specificity and are comprised of two dynamic components: 1) profiles reflecting cellular composition and 2) alterations in DNAm levels at CpG sites and transcriptional activity. In this work, I examine DNA methylation and gene expression profiles that reflect the pathophysiology of PTSD while considering fundamental population contexts and sources of heterogeneity that have not been adequately addressed in the existing PTSD literature – sex, ancestry, and cellular composition. After an overview of relevant literature in Chapter 1, the subsequent two chapters examine sex-specific profiles associated with PTSD. Chapter 2 disentangles the contribution of cellular composition from DNAm alterations in methylomic profiles to discern sex-specific leukocyte composition associated with PTSD using a combined dataset from two independent cohorts. Chapter 3 assesses the relationship between blood and brain transcriptomic profiles in a rat model of PTSD (i.e., individual response to recent trauma exposure) using a publicly available expression dataset. Chapter 4 implements an integrative systems-level approach to investigate the genomic context underlying leukocyte methylomic and transcriptomic profiles in an understudied, at-risk population of African ancestry, and to identify regulatory epigenetic marks that putatively regulate leukocyte gene expression in PTSD. Chapter 5 provides a discussion of the implications of these findings and their contributions to the existing PTSD literature. This work uses genomic approaches to generate mechanistic hypotheses regarding dysregulation observed in PTSD. It contributes novel insights to the current PTSD literature by considering sex-, ancestry-, and cell/tissue-specific contexts, which have historically been overlooked, and by doing so provides input for understanding findings that are often inconsistent across published DNA methylation and gene expression studies of PTSD