Combat exposure severity as a moderator of genetic and environmental liability to post-traumatic stress disorder.

The diagnosis of posttraumatic stress disorder (PTSD) requires exposure to a traumatic experience by definition (APA, 1994), with the implication being that trauma exposure exerts a direct causal effect on the development of the disorder. However, there is also evidence that individual differences in heritable factors affect risk for PTSD. Specifically, several twin studies focused on veteran and adult samples have suggested that approximately 30–46% of the variance in PTSD is attributable to genetic factors (True et al. 1993; Xian et al. 2000; Stein et al. 2002; Scherrer et al. 2008; Sartor et al. 2012), while one study of young adult women found that 72% of the variance in PTSD was attributable to genetic factors (Sartor et al. 2011). Twin studies also suggest that aspects of the environment that are not shared across members of a twin pair (e.g., severity and type of trauma exposure) tend to contribute the majority of the variance in risk for PTSD (True et al. 1993; Stein et al. 2002; Sartor et al. 2012). The effects of combat exposure have been extensively studied among veteran populations. Twin studies suggest that traumatic events that occur in the context of combat exposure partially explain the prevalence and chronicity of PTSD (Goldberg et al. 1990; Roy-Byrne et al. 2004; Gilbertson et al. 2010) and also contribute to the development of other conditions such as depression and substance-dependence (Koenen et al. 2003). As not all individuals exposed to the same traumatic combat events will develop PTSD, it is likely that combat experiences interact with other individual-difference characteristics to affect risk for PTSD and other psychological disorders. One possibility is that combat exposure interacts with an individual’s genetic vulnerability for PTSD to increase risk for the disorder. Gene by environment interaction (G X E), sometimes referred to as G X E interplay, exists when the effects of a person’s genotype on risk for psychopathology is at least partially dependent on the environment. G X E implies that individuals with genetic risk variants are more sensitive to the negative or positive effects of specific environments than are individuals without the genetic risk (Moffitt et al. 2005). The diathesis-stress model of disease reflects a form of G X E in which a harmful environment interacts with a genetic predisposition towards pathology and increases the risk for the pathology. Thus, the basic concept underlying G X E is that risk for a given trait or disorder is not static, but rather is dependent on the synergy between basic biological and environmental risk factors. The aim of this study was to evaluate the extent to which combat exposure interacts with genetic factors and affects risk for PTSD. We examined this in a sample of U.S. military monozygotic (MZ) and dizygotic (DZ) twins who served in South East Asia during the Vietnam War era. There are two competing hypotheses to consider regarding the potential effects of combat exposure on the heritability of PTSD. First, exposure to combat may increase the heritability of PTSD if it causes underlying differences in genetic risk variants to exert their pathological effects. This is the classic example of diathesis-stress wherein the genetic vulnerability is manifested only under certain environmental conditions. For example, G X E research suggests that the effect of single nucleotide polymorphisms (SNPs) in the gene FK506 binding protein 5 (FKBP5) on PTSD is dependent on severity of childhood abuse (Binder et al. 2008; Xie et al. 2010), such that the effect is only evident under conditions of abuse. Similar genotype by trauma effects have been obtained for a number of other genes in predicting PTSD, including the serotonin transporter (SLC6A4; Xie et al. 2009), catechol-O-methyltransferase (COMT; Kolassa, et al. 2010) and gammaaminobutyric acid receptor, alpha-2 (GABRA2; Nelson et al. 2009). In these examples, the association between the genotype and PTSD is dependent on exposure to trauma such that the effect is stronger among those exposed to higher levels of trauma. Alternatively, exposure to combat may decrease the heritability of PTSD. This might occur if the combat experience is so severely traumatic that it overrides the effects of genes (and perhaps other individual difference factors, see below) such that virtually everyone so exposed would develop the disorder (Jang et al. 2007). As proof-of-principle, consider the heritability of height: although adult height is highly heritable (e.g., Dubois et al. 2012), its heritability is decreased significantly under conditions of malnourishment such that lack of adequate nutrition (an environmental variable) becomes a primary contributor to height (Silventoinen, 2003). Similarly, the heritability of intelligence has been shown to be moderated by socioeconomic status among children such that genes contribute negligibly to intelligence under conditions of poverty but contribute the majority of the variance under conditions of affluence (Turkheimer et al. 2003). In theory, a similar relationship could exist between combat exposure, genes, and risk for PTSD. Just as individual-level genetic vulnerabilities may interact with the effects of combat exposure to increase or decrease the risk of PTSD, it is also possible that the effect of the environment on risk for PTSD may vary as a function of combat exposure (i.e., E X E). G X E twin studies provide the opportunity to evaluate if the effects of unmeasured environmental factors (reflected as the common environment and non-shared environment) are dependent on an observed environmental variable. The effects of combat exposure could increase the importance of other environmental variables that have previously been shown to affect risk for PTSD. For example, exposure to combat may amplify the risk for PTSD that is associated with exposure to early childhood trauma (i.e., a childhood trauma by combat exposure interaction). This could manifest in greater severity of childhood trauma-related PTSD symptoms in those exposed to subsequent combat trauma. Alternatively, it is conceivable that combat exposure could decrease the importance of other environmental factors because combat exposure trumps other environmental variables in importance for determining risk for PTSD (e.g., in the same way that extreme exposure might override any genetic effects). In sum, there are reasons to hypothesize that combat exposure may either increase or decrease the strength of the genetic and/or environmental pathways that predict PTSD. This study allowed us to test these competing hypotheses about the effects of measured combat exposure on the genetic and environmental etiology of PTSD.