According to the DSM-IV (APA, 1994
), PTSD is defined as the development of symptoms following exposure to an extreme traumatic event in which an individual experienced an actual or perceived threat of death or serious injury or threat to one's physical integrity; or witnessed an event that involved an actual or perceived threat of death, serious bodily injury or threat to the physical integrity of to another individual. Symptoms are characterized as belonging to one of three independent, but often interconnected, clusters. Re-experiencing
symptoms involve spontaneous, uncontrollable intrusions of the traumatic memory that manifest can themselves as nightmares or memory flashbacks. These intrusions are typically associated with marked physiological responses. Avoidance
symptoms are best described as an individual's efforts to distance themselves from trauma-related stimuli such as television news and fireworks (for combat-related PTSD) or crowds and public transportation vehicles (for civilian trauma-related PTSD). The avoidance cluster can also include emotional and social withdrawal behaviors. Hyperarousal
symptoms include robust physiological reactions such as irritability, hypervigilance, and exaggerated startle. PTSD is unique with respect to acute stress disorder (ASD) or normal recovery from a traumatic experience in that the aforementioned symptoms must persist for at least one month to meet criteria for a diagnosis of PTSD. Exposure to trauma can also result in a posttraumatic “syndrome” characterized by a diagnosis of PTSD and
co-morbidity with major depressive disorder (MDD), generalized anxiety disorder (GAD) as well as somatic symptoms, dissociation, and substance abuse (Pervanidou, 2008
There is currently some debate among psychiatrists as to whether PTSD should remain in the category of anxiety disorders as DSM-V is developed. Arguments in favor of PTSD remaining as an anxiety disorder include its co- morbidity with other anxiety disorders and the efficacy of treatment strategies for PTSD that were previously proven successful with other anxiety-related conditions (Wittchen et al., 2009
). Many of those opposed to the classification of PTSD as an anxiety disorder view it as being more closely related to depression (Watson, 2005
). For the purposes of the present review, we have maintained the classification of PTSD as an anxiety disorder while addressing PTSD co-morbidity with other anxiety disorders as well as major depression.
Previously determined estimates suggest that greater than 75% of the general population will experience a traumatic event during their lifetime (Breslau and Kessler, 2001
), yet as few as 5% of those exposed to a traumatic event will develop PTSD (Kessler et al., 1995
, Adams and Boscarino, 2006
). Recent attempts to characterize individual vulnerability to PTSD from a genetic perspective have been impeded by several factors including, but not limited to, the complex nature of this disorder, the requisite exposure to a traumatic event that precipitates its development, the high degree of psychiatric co-morbidity with PTSD, and the litany of potential confounding factors associated with most genetic analyses.
The genetic background of PTSD has been examined through three primary types of investigation: family studies, twin studies, and candidate gene association studies. Each methodology possesses significant advantages and shortcomings. For example, it stands to reason that if there is a genetic component to PTSD, relatives of PTSD patients (probands) should be at an increased risk to develop the disorder following trauma exposure (Smoller et al., 2008a
). However, a limitation of family studies is that prevalence of PTSD within a family cannot be determined unless relatives themselves experience a traumatic event. Twin studies are beneficial for calculating heritability estimates yet do not allow for identifying the specific genes that are related to PTSD resilience, vulnerability, or chronicity. For the past decade, candidate gene studies have been the primary methodology for detecting genes that may influence development of psychiatric illness. However, the utility of candidate gene association studies for studying the genetic basis of PTSD has been diminished for two reasons. The first reason is inherent to all association studies: there is a low probability of identifying candidate genes that are related to the psychiatric illness of interest (Segman and Shalev, 2003
). The development of whole genome association studies, in which the complete genome of a patient is compared to that of a control subject, may lead to further developments in understanding the genetics of PTSD. The second reason is inherent to PTSD and its complexity: PTSD is a unique psychiatric diagnosis in that it involves an environmental etiologic event and its development and time course are undoubtedly affected by a combination of genetic and environmental factors (Poulton et al., 2008
). provides a schematic illustration of the factors that appear to mediate the development of PTSD following exposure to trauma.
Diagram of genetic factors interacting with developmental stress to impact vulnerability to develop anxiety and other psychopathology.
Nevertheless, several major genotypes have been linked to risk for developing, or resilience to, PTSD following trauma exposure (as reviewed by Broekman et al., 2007
; (Broekman et al., 2007
). Prior candidate gene association studies have identified genes related to the hypothalamic-pituitary-adrenal (HPA) axis, the ascending brainstem locus coeruleus noradrenergic system, and the limbic amygdalar frontal pathway that mediates fear processing (Rasmusson et al., 2003
, Charney, 2004
, Rauch et al., 2006
, Koenen, 2007
). Within the latter anatomical systems, association studies have implicated the serotonin, dopamine, glucocorticoid receptor (GR), gamma-amino-butyric acid (GABA), apolipoprotein (APO), brain-derived neurotrophic factor (BDNF), and neuropeptide Y (NPY) systems in the genetic contribution to the onset of PTSD symptoms following a traumatic event.
As will be discussed throughout this review, the history and progression of genetic studies of PTSD exemplify the course taken by many other explorations into the biological bases of anxiety disorders. For example, early evidence for a genetic contribution to the development of PTSD after trauma exposure came in the form of familial transmission studies (Davidson et al., 1985
, Davidson et al., 1998
) followed by twin studies. Moreover, twin studies suggested a heritability component for susceptibility to experience trauma (Stein et al., 2002
) as well as for the development of PTSD symptoms following a trauma event (Goldberg et al., 1990
, True et al., 1993
). Later twin studies identified potential biomarkers for PTSD such as hippocampal volume (Gilbertson et al., 2002
) and altered acoustic startle responses (Orr et al., 2003
, Pitman et al., 2006