Epidemiological studies worldwide have documented a high rate of exposure to traumatic events, including life-threatening accidents, rape, combat, physical violence, witnessing the death or injury of others and natural disasters. Such traumatic experiences significantly increase the likelihood of having a mental illness, including posttraumatic stress disorder (PTSD), depression or substance abuse. Although more than 80% of the population will experience a traumatic event, only a fraction of those will develop a mental illness, suggesting a large role for biological risk factors. However, there are currently no biological factors that can be used to prospectively monitor vulnerable individuals. Recent epigenetic studies report extensive DNA methylation differences in those who have experienced trauma that associate with psychopathology. Because changes in DNA methylation accumulate over time, the molecular signature of trauma exposure may be evident substantially before trauma-related symptoms develop. However, the timeline and permanence of epigenetic changes are still unclear. This study will address this question by leveraging infrastructure from an ongoing investigation (R01 MH094757; PI Ressler) that is prospectively characterizing trauma victims from Atlanta's inner-city Level 1 trauma center. To evaluate how DNA methylation changes over time, we will prospectively collect DNA samples for the first 3 months after a traumatic event and characterize the DNA methylation changes that occur acutely (within the first weeks up to 1 month) and stably (through 3 months). We will also evaluate changes in 4 specific stress-response genes (FKBP5, SLC6A4, BDNF and COMT). Finally, we will evaluate whether acute changes in DNA methylation predict psychiatric symptoms and fear-potentiated startle response, a physiological phenotype that has been associated with PTSD, at 3 months after the trauma. This study is highly novel in its focus on acute epigenetic mechanisms; furthermore, it focuses on psychophysiological phenotypes of trauma exposure rather than DSM diagnoses as advocated in the NIMH Research Domains Criteria. The units of analyses will include molecular (DNA methylation), physiological (fear-potentiated startle), and self-report (PTSD Symptom Scale, Beck Depression inventory) measures as dimensional measures of trauma response. This research will provide much needed insight into the pathophysiology of trauma on a molecular level and lay a foundation for early intervention studies. Identification of how the epigenome responds to a traumatic event will provide preliminary data for larger prospective studies that facilitate early detection of trauma-related psychopathology.
Epigenetic modifications, including DNA methylation, induce changes in gene expression through structural alterations of DNA that are maintained through each round of cell division; they respond to changes in the environment, are potentially reversible and can be targeted for disease therapies. Furthermore, these changes appear to be long-lasting as evidenced by studies that have identified epigenetic markers of childhood trauma in adults. Identification of how the epigenome responds to a traumatic event may allow for early detection and effective intervention, particularly in high-risk populations such as low-income, African-Americans.
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