PTSD and gene variants: New pathways and new thinking

Abstract

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

“…Genetic studies have documented significant heritability of anxiety and stress vulnerability, implicating several genes as potential risk factors including CRH (Heim and Nemeroff, 2001;Skelton et al, 2012;Smoller et al, 2003). However, the causal role of these candidates and underlying mechanisms are still not clarified.…”

“…Early-life stress may also induce latent alterations in brain development with functional consequences that are only precipitated by additional stress in later life (Hammen et al, 2000). Although multiple factors are likely involved in the mediation of early-life effects on neuropsychiatric risk, major coordinators of the stress response including HPA-axis elements such as glucocorticoid receptor, its binding protein FKBP5, and CRH signaling elements are primary neurobiological candidates in the pathogenesis of PTSD (Skelton et al, 2012).…”

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…There is some suggestion that genes that confer risk for PTSD are also associated either with heightened fear conditioning or with disruption in ability to inhibit conditioned fear in humans [see next section below and see Skelton et al (2012) for review of genetic approaches to fear learning phenotypes]. Examples are genes involved in noradrenergic (ADRA2B), serotonergic (SLC6A4), and catecholamine signaling (COMT), in cellular signaling pathways that support neural plasticity [PRKCA and WWC1; for review see Wilker et al (2014)], and in genes involved in the neuroendocrine stress response [PACAP/PAC1, Ressler et al (2011)] and opioid signaling (Andero et al 2013).…”

Understanding Resilience

“…Heinz and Smolka, 2006;Skelton et al, 2012 Dopaminergic Dopamine transporter gene (DAT1) Contributed to susceptibility to PTSD with a history of trauma. Segman et al, 2002 Dopamine receptor genes (e.g., DRD2, DRD4)…”

“…Catechol-O-Methyltransferase (COMT) is an enzyme that metabolizes catecholamines including norepinephrine, epinephrine and dopamine. The COMT Val 158 Met polymorphism has been linked to deficits in stress response and emotional resilience, and was found to influence the risk for development of PTSD (Heinz and Smolka, 2006;Skelton et al, 2012). In an important study, Kolassa and colleagues showed that, predictably, higher numbers of different lifetime traumatic event types led to a higher prevalence of lifetime PTSD but that this effect was, in a typical gene-environment interaction fashion, modified by gene polymorphism (Kolassa et al, 2010).…”