The Role of Genes in Defining a Molecular Biology of PTSD

Abstract

Abstract. Because environmental exposure to trauma is the sine qua non for the development of Post Traumatic Stress Disorder (PTSD), the recent focus on genetic studies has been noteworthy. The main catalyst for such studies is the observation from epidemiological studies that not all trauma survivors develop this disorder. Furthermore, neuroendocrine findings suggest preexisting hormonal alterations that confer risk for PTSD. This paper presents the rationale for examining genetic factors in PTSD and trauma exposure, but suggests that studies of genotype may only present a limited picture of the molecular biology of this disorder. We describe the type of information that can be obtained from candidate gene and genomic studies that incorporate environmental factors in the design (i.e., gene -environment interaction and gene-environment correlation studies) and studies that capitalize on the idea that environment modifies gene expression, via epigenetic or other molecular mechanisms. The examination of epigenetic mechanisms in tandem with gene expression will help refine models that explain how PTSD risk, pathophysiology, and recovery is mediated by the environment. Since inherited genetic variation may also influence the extent of epigenetic or gene expression changes resulting from the environment, such studies should optimally be followed up by studies of genotype. If PTSD is a condition precipitated by environmental exposure, why examine genes?For at least two decades after the diagnosis of PTSD was established in 1980, it would have been unheard of to propose that genes might be involved in the etiology or pathogenesis of this condition. PTSD was initially defined as a disorder that resulted from exposure to a traumatic environmental event. The diagnosis was designed to describe universal effects of extreme stress that linger even after the stressor is removed. The theoretical contribution that this made to the biopsychosocial model of mental illness was the realization that the effects of an environmental event are not limited to initial exposure to the event, but can also persist for years and even decades. These long-term effects were conceptualized as being a function of the intensi- * Corresponding author. E-mail: Rachel.Yehuda@va.gov. ty and severity of the event that precipitated the initial symptoms.The implication of the PTSD diagnosis was that the adverse effects of exposure to chronic stressors (e.g., illness, family conflict, or financial pressures) could be alleviated or even eliminated if the challenge to the person was removed (and hence were not precipitants of PTSD). In contrast, the effects of exposure to lifethreatening events like interpersonal violence, combat, and accidents that caused intense fear, helplessness and horror were not only persistent, but were of a specific and universal nature. The basic phenomenology of PTSD asserted that following trauma exposure, the survivor experiences unwanted, uncontrollable memories of the event that generate physical and emotional responses resem...

ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations

“…Taken together, these data are consistent with evidence suggesting that genetic variability contributes to disparities in risk and severity of PTSD (Pitman et al, 2012;Yehuda et al, 2011), and in particular with the identification of APOE as one of these genetic markers (Freeman et al, 2005;Kim et al, 2013). In a group of chronic, combat-related PTSD subjects (n = 44), Freeman et al (2005) demonstrated an association between possession of E2 and more severe re-experiencing symptoms and poorer performance on several memory tests (1).…”

“…It has been estimated that close to 90% of people are exposed to at least one traumatic event, such as rape, assault, disaster, rescue work, or combat, over the course of their lifetime (Kilpatrick et al, 2013). However, PTSD develops only in a subgroup of people exposed to a traumatic event, with the lifetime prevalence of PTSD estimated between 7.8 and 8.7% (Kessler et al, 1995(Kessler et al, , 2005, thus supporting a role for genetic risk factors (Pittman et al, 2012;Yehuda et al, 2011).…”

Animal models for posttraumatic stress disorder: An overview of what is used in research

“…This procedure causes increased anxiety, impaired cognition, cardiovascular reactivity and startle response, as well as an exaggerated response to yohimbine similar to that of human PTSD patients [64] . The idea that epigenetic DNA modification plays a fundamental role in anxiety disorders such as PTSD has been around for a while, and long-term traumatic memory expression is considered to be important in this process [85] . The brain-derived neurotrophic factor gene has been found to be selectively methylated in the hippocampus of rats that underwent the PPS paradigm, which supports the theory that traumatic stress causes (epigenetic) changes in brain regions regulating cognition and stress regulation.…”

Consumer Perspectives on Genetic Testing for Psychiatric Disorders: The Attitudes of Veterans with Posttraumatic Stress Disorder and Their Families

“…In fact, more than 30% of the variance for PTSD risk is attributed to genetic factors, as evidenced by family and twin-heritability studies (Lyons et al, 1993;Sack et al, 1995;Yehuda et al, 2001;Stein et al, 2002;Kremen et al, 2012). More than 30 candidate gene studies have been performed [for reviews see Cornelis et al (2010) and Yehuda et al (2011)]. These studies have produced inconsistent and sometimes contradictory results.…”