Posttraumatic Stress Disorder in Civilian Women: A Longitudinal Investigation on Cognition, Epigenetics, and Inflammation

Abstract

Post-traumatic stress disorder (PTSD) is a debilitating mental condition that develops in some individuals following exposure to traumatic events such as physical or sexual assault, combat, natural disasters, and accidents. The lifetime prevalence of PTSD is estimated to be 3.9% globally and 6.8% in the United States (US), and it is approximately twice as common in women than men. A growing body of research has associated PTSD with various negative health outcomes, including cognitive impairments. However, much less is known about whether the elevated health risks persist after PTSD symptoms remit. In addition, more work is needed to elucidate the underlying mechanisms of how trauma-related distress becomes biologically embedded and subsequently leads to increased disease risks. One such mechanism is DNA methylation (DNAm), a widely-studied epigenetic modification that has shown great potential in tracing the long-term impact of environmental exposures and life experiences. Despite the increasing DNAm research on PTSD in civilian and female populations, longitudinal investigations of DNAm in PTSD have been limited to predominantly male military samples. Moreover, systematic chronic inflammation is another potential mechanism underlying PTSD that may also mediate the adverse impact of PTSD on subsequent health outcomes. However, population studies have largely relied on assay-based measures of acute inflammatory biomarkers as proxies for chronic inflammation, and the fluctuating nature of these biomarkers may have contributed to inconsistent findings in PTSD-inflammation research. Recent studies indicate that DNAm may offer a more reliable measure of chronic inflammation, but no study has yet examined these DNAm-based proxies of inflammation in relation to PTSD. This dissertation attempted to address these research gaps through a longitudinal investigation using data from trauma-exposed women in the Nurses' Health Study II, a large prospective cohort of nurses in the US. In Chapter 1, we examined PTSD symptom remission in relation to cognitive function and changes over time. We found that unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later, with accelerated cognitive decline observed among women with either unresolved or remitted moderate-severe PTSD symptoms. In Chapter 2, we performed epigenome-wide association analyses of lifetime PTSD diagnosis and symptom severity, utilizing blood samples collected twice over a decade apart. We identified 26 loci and 140 regions where DNAm level or changes were associated with PTSD. In Chapter 3, we examined multiple epigenetic signatures of C-reactive protein (CRP) and interleukin-6 (IL-6) based on published and newly-developed models. Our results showed that PTSD was associated with elevated levels of epigenetic signatures of CRP and a faster increase in these levels over time, as well as a suggestive association between PTSD and increased epigenetic IL-6 levels. These findings highlight the importance of monitoring cognitive function and inflammation in women with PTSD and advance our understanding of the biological pathways underlying PTSD pathophysiology.