Invited reviewPTSD and gene variants: New pathways and new thinking
Highlights
► Much research on genetic risk factors for PTSD is based on a fear-conditioning model. ► Main effect studies of PTSD have primarily yielded negative results. ► GXE studies have yielded some positive preliminary results. ► Research on epigenetics may help clarify genetic factors underlying risk for PTSD. ► GWAS and Whole genome studies of PTSD may yield new candidate genes.
Introduction
Posttraumatic Stress Disorder (PTSD) is classified as an Anxiety Disorder within DSM-IV. It is defined as the development of symptoms following exposure to an extreme traumatic event (criterion A). These symptoms are characterized as belonging to three separate but interrelated symptom clusters: re-experiencing, avoidance and numbing, and hyperarousal (DSM 1994). Individuals diagnosed with PTSD experience significant functional impairment, including increased risk for unemployment, disrupted relationships, and diminished physical health (Kessler, 2000, Kubzansky et al., 2007). While the lifetime prevalence of PTSD in adult Americans is estimated to be 6.8% (Kessler et al., 2005), the conditional risk for PTSD following trauma exposure ranges from 5 to 31% (Kulka et al., 1990, Kessler et al., 1995, Breslau et al., 1998, Adams and Boscarino, 2006) with interpersonal and combat trauma associated with relatively greater risk. While an estimated 75% of the population has experienced a criterion A traumatic event (Breslau and Kessler, 2001), only a minority of those individuals subsequently develop PTSD. This finding suggests that certain individuals have an underlying vulnerability to developing this disorder in the aftermath of trauma. Identifying those vulnerable individuals may allow for early and targeted intervention to prevent or reduce the symptoms and functional impairment associated with PTSD.
Section snippets
Family studies of heritability
If the risk for PTSD following traumatic exposure is associated with an underlying genetic vulnerability, it would be expected that biological relatives (family) of an individual with PTSD (proband) would have a higher risk of developing the disorder following trauma exposure than similarly traumatized non-relatives. Family studies of PTSD have demonstrated this finding. Specifically, PTSD diagnosis was more frequent in adult children of Holocaust survivors with PTSD as compared to children of
Twin studies of heritability
Studies of twins (who share identical genetic inheritance) allow researchers to differentiate genetic from environmental influence on the development of a disorder. Twin studies have demonstrated that genetic factors influence the risk of exposure to traumatic events (Lyons et al., 1993, Stein et al., 2002). This finding, known as gene–environment correlation, may be related to the effect of genetics on temperament, anger and irritability. However, even after accounting for genetic impact on
Candidate genes and neurobiological pathways
While twin studies can indicate a heritable genetic risk for the development of PTSD, they cannot provide information on which specific genes confer that risk. Molecular genetic studies can be used to determine if specific genes influence risk or resilience for a specific disorder, such as PTSD. However, in the absence of large GWAS or similar hypothesis-neutral gene-discovery studies, knowledge of the underlying neurobiology of the disorder is needed in order to effectively identify
HPA axis
The HPA axis coordinates the neuroendocrine response to stress. Neurons within the paraventricular nucleus (PVN) of the hypothalamus project to the median eminence where they release corticotrophin-releasing hormone (CRH) which subsequently binds to CRH1 receptors in the anterior pituitary gland promoting the secretion to adrenocorticotrophic hormone (ACTH). ACTH is released into the systemic circulation where it stimulates the production and release of cortisol from the adrenal cortex, which
LC–noradrenergic system
The LC is the primary noradrenergic nucleus within the mammalian brain. It receives neuronal input from and provides output to the hypothalamus, the amygdala, and the prefrontal cortex amongst other regions (Benarroch, 2009). Activation of the LC can stimulate release of CRH from the hypothalamus and noradrenergic hyperactivity within the basolateral amygdala has been hypothesized to mediate the overconsolidation of fear memory in PTSD (Southwick et al., 1999). Because cortisol can reduce
Limbic–frontal system
The amygdala is composed of several nuclei located within the temporal lobe of the brain and is generally roughly divided into the basolateral nucleus (BLA) which receives the majority of the neuronal input and the central nucleus (CeA) which provides the majority of the output. The CeA projects to and activates both the HPA axis at the level of the hypothalamus and the LC–noradrenergic system. The BLA appears to be the locus for the comparison and development of associations between the
Epigenetics
While an improvement over studying the main effects of genes alone, studies of G × E interaction do not explain the importance of developmental timing of stressor exposure to producing phenotypic changes associated with PTSD. However, investigation of the epigenetic modification of DNA can provide insight into this issue. Epigenetic modification describes an environmentally induced change in DNA which alters the function rather than the structure of a gene. These changes can be specific to
Endophenotypes
PTSD is a complex diagnostic construct requiring exposure to a traumatic event and comprising a series of up to 17 symptoms organized into three symptom clusters. It is therefore difficult to tease out the multiple interacting genes likely to play a role in the heritability of this complex psychiatric disorder. Rather than examining the global diagnostic entity of PTSD, studying endophenotypes of the disorder may be more directly revealing. An endophenotype refers to a heritable, measurable
Future directions
While there are no agreed upon validated animals models of PTSD, there are established animal models of conditioned fear and fear inhibition amongst other biomarkers associated with PTSD as noted above. Human genetic investigations can be hampered by limitations such as sample size, statistical power and the inherent drawbacks of association studies. “Top down” translational studies, in which human genetic findings are validated by subsequent work in rodents, can address some of these
Summary and implications
PTSD is a prevalent anxiety disorder that can develop in the aftermath of exposure to a traumatic event. It is associated with significant adverse impact on occupational and social function, as well as physical and mental health and can become chronically disabling. The etiology and maintenance of PTSD is the result of multiple, complex interactions between genes and environmental influences. Understanding the nature of these influences, as well as their interaction, will be important to
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