Variant in RGS2 Moderates Posttraumatic Stress Symptoms following Potentially Traumatic Event Exposure

Potentially traumatic events (PTE), such as disasters, physical and sexual abuse or assault, motor vehicle accident, or unexpected/sudden death of a loved one, occur frequently and embody a distinctive set of stressors that have effects on many levels such as basic needs, functional impairment, physical health, and mental health (Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Kilpatrick et al., 2003; Norris et al., 2002; Resnick, Kilpatrick, Dansky, Saunders, & Best, 1993). A growing literature has investigated the psychiatric correlates of PTEs (Galea, Nandi, & Vlahov, 2005; Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Kilpatrick et al., 2003; Norris et al., 2002; Resnick, Kilpatrick, Dansky, Saunders, & Best, 1993), generally concluding that PTE exposure increases the risk for a variety of psychiatric phenotypes including posttraumatic stress disorder [PTSD] and that risk is affected by a number of factors, such as severity of exposure (Acierno et al., in press), interpersonal victimization (Resnick, Kilpatrick, Dansky, Saunders, & Best, 1993), and lack of social support (Brewin, Andrews, & Valentine, 2000) (for review see Brewin, Andrews, & Valentine, 2000). Further, most individuals who experience traumatic stressors never develop PTSD (Bonanno, 2004), and it is therefore also important to elucidate mechanisms of risk and resilience. Although considerable effort has been given to identify variables (e.g., individual difference variables, aspects of the environment) that are related to risk, a high percentage of variance remains unexplained (Bonanno, 2004). Following, there has been a growing interest in examining genetic determinates of PTSD (Lee et al., 2005; Zhang et al., 2006); however, modern studies of genetic risk factors for PTSD remain few in number. Most extant genetic research is guided by a “main effects” model that examines direct effects of either genotype or environment upon manifestation of mental disorders; in fact, out of the 11 case-control candidate gene studies conducted to date on PTSD, 9 have used this model, with mixed success (Koenen, 2008). As noted by Moffitt and colleagues “ … it seems reasonable to suggest that whenever there is variation among human’s psychological reactions to a major environmental pathogen for mental disorder, [gene-environment interactions] must be expected to some degree” (p.473; Moffitt, Caspi, & Rutter, 2005). The gene by environment (GxE) interaction model posits that the effects of environmental stressors on mental disorder phenotypes are moderated by genotype. In contrast to the “main effect” model, the interaction model proposed by Moffitt and colleagues (Moffitt, Caspi, & Rutter, 2005) provides a new paradigm for the study of phenotypic expression that is highly suited for PTSD research, given that a criteria of the disorder is exposure to an environmental stressor. Two GxE studies of PTSD have been published. Binder and colleagues found that childhood sexual abuse interacted with FKPB5 to predict PTSD in adults (Binder et al., 2008). Kilpatrick and colleagues’ (Kilpatrick et al., 2007) analyses of the 5-HTTLPR polymorphism replicated, and extended to PTSD, Caspi and colleagues’ (Caspi et al., 2003) model of a GxE effect, specifically the interaction between environmental variables (severity of disaster exposure, level of social support) and genotype afforded more power in the prediction of major depression and PTSD than did the main effect analyses. The present study examines an additional gene, regulator of G-protein signaling 2 (RGS2), utilizing the same sample. G-protein coupled receptors comprise one of the largest groups of signaling proteins (Hollmann, Strumper, Serroeder, & Durieux, 2005). G-protein-coupled receptors are extracellular ligand proteins that alert the cell to certain changes in the intercellular environment through changes in their conformation (Hollinger & Helper, 2002). First, the binding induces an alteration in the conformation of the receptor. Second, coupling and activation of one (or more) G-proteins occurs. Third, these G-proteins then regulate events in the intercellular environment. G-proteins get their name because their primary action is with interactions of the guanine nucleotide (Hollmann, Strumper, Serroeder, & Durieux, 2005). G-protein activation signals a cascade in vascular smooth muscle cell receptors that causes in increase in Ca2+ which then leads to vasoconstriction (Hollinger & Helper, 2002). Regulators of G-protein signaling bind to Gα subunits and increase their GTPase activity which then attenuates downstream signaling (Hollinger & Helper, 2002). RGS2, a potent regulator that reduces G-protein activity, selectively inhibits Gqα (Heximer, 2004), thereby increasing GTPase activity and decreasing vasoconstriction (and lowering blood pressure). The RGS2 gene has been associated with anxiety in animal models and in human correlational studies. RGS2 knockout mice, both hetero- and homozygous, have increased hypertension (Heximer et al., 2003), increased excitability in CA1 neurons in the hippocampus (Oliviera-dos-Santos et al., 2000), and anxiety (Yalcin et al., 2004). A targeted genome screen found modest evidence for linkage between markers including RGS2 and anxiety disorder proneness (Smoller et al., 2001). Recently, Legraf, and colleagues (Leygraf et al., 2006) found that polymorphisms in RGS2 were associated with panic disorder in humans, with the strongest association being observed for a haplotype containing SNPs rs4606 (C as risk allele) and rs3767488. Smoller and colleagues (2008) also found significant associations between rs4606 and anxiety-related temperament, personality, and brain function (Smoller et al., 2008), but this paper found G to be the risk allele. Cui and colleagues found a significant difference in the distribution of rs4606 genotypes in suicide victims versus controls (Cui et al., 2007). Variation in rs4606 is of particular interest because it is associated with variation in RGS2 mRNA expression (Semplicini et al., 2006). The present study examined the association between rs4606, a polymorphism in RGS2, and PTSD in an epidemiologic sample of adults exposed to the 2004 Florida hurricanes. Following previous research (Leygraf et al., 2006), we hypothesized that the C allele, in comparison to the G allele, of RGS2 would increase risk for PTSD symptoms under conditions of high environmental stress (high disaster/PTE exposure and low social support).