Posttraumatic stress disorder (PTSD) develops in approximately one-quarter of trauma-exposed individuals, leading us and others to question the mechanisms underlying this heterogeneous response to trauma. We suggest that the reasons for the heterogeneity relate to a complex interaction between genes and the environment, shaping each individual’s recovery trajectory based on both historical and trauma-specific variables. Epigenetic modifications provide a unique opportunity to elucidate how preexisting risk factors may contribute to PTSD risk through changes in the methylation of DNA. Preexisting risks for PTSD, including depression, stress, and trauma, result in differential DNA methylation of endocrine genes, which may then result in a different biological responses to trauma and subsequently a greater risk for PTSD onset. Although these relationships are complex and currently inadequately described, we provide a critical review of recent studies to examine how differences in genetic and proteomic biomarkers shape an individual’s vulnerability to PTSD development, thereby contributing to a heterogeneous response to trauma. 1. Introduction Up to 90% of individuals experience a traumatic event at some time during their lives, yet most recover and suffer from no long-term ramifications; however, a subset of individuals develop posttraumatic stress disorder (PTSD) and are at high risk for health decline [1–4]. This heterogeneous response suggests that preexisting factors might influence how people respond to traumatic situations. We suggest that a more comprehensive examination of biomarkers that approximate PTSD risk would be of great value. Biomarker discovery in PTSD has been hindered by the lack of prospective studies in traumatized individuals, resulting in an insufficient understanding of the preexisting risk factors for PTSD onset as well as the mechanistic pathways that underlie this risk. Without this knowledge, we are unable to identify traumatized individuals at risk for PTSD development and, therefore, unable to implement effective, preventive interventions. Yet, additional biological analysis methods have become available, and these new strategies will be useful in addressing this critical issue. Specifically, the use of whole-genome gene expression and epigenetic modifications (DNA methylation) provide an opportunity to explore more than candidate biomarkers, to identify novel mechanisms related to PTSD risk, and to pinpoint genetic pathways that may be implicated in both risk and resilience to trauma. A traumatic event places individuals at
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