Interactive Effect of Stressful Life Events and the Serotonin Transporter 5-HTTLPR Genotype on Posttraumatic Stress Disorder Diagnosis in 2 Independent Populations

Abstract

Context: The 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) has been found to moderate several categories of emotional response after stressful life events. Previous studies generally focused on its effect on depressive symptoms; little is known about its moderation of the development of post-traumatic stress disorder (PTSD). Objective: To examine the effects of childhood adversity, adult traumatic events, 5-HTTLPR genotypes, and gene×environment interactions on the etiology of PTSD. Design: A cross-sectional study in which participants in several studies investigating the genetics of substance dependence were also screened for lifetime PTSD. The triallelic system of 5-HTTLPR was genotyped. Logistic regression modeling was used in the analyses. Setting: General community. Participants: Five hundred eighty-two European American and 670 African American individuals who reported experiences of childhood adversity, adult traumatic events, or both. Main Outcome Measure: Diagnosis of PTSD, defined by DSM-IV diagnostic criteria and assessed through the Semi-Structured Assessment for Drug Dependence and Alcoholism interview. Results: Childhood adversity and adult traumatic events both predicted PTSD. Although the 5-HTTLPR genotype alone did not predict the onset of PTSD, it interacted with adult traumatic events and childhood adversity to increase the risk for PTSD, especially for those with high rates of both types of trauma exposure (European American: odds ratio [OR], 2.86; 95% confidence interval [CI], 1.50-5.45; P=.002; African American: OR, 1.88; 95% CI, 1.04-3.40; P=.04; pooled: OR, 2.31; 95% CI, 1.50-3.56; P<.001). Conclusions: Participants who had both childhood adversity and adult traumatic events were more likely to develop lifetime PTSD compared with those who experienced either type of adverse event. The risk was increased in individuals with 1 or 2 copies of the S′ (S) allele compared with the L′ (L) homozygotes. Our study provides additional direct evidence that PTSD is influenced by the interactive effect of environmental and genetic factors.

Intergenerational Transmission of Stress in Humans

“…In addition, studies have begun to investigate the offspring methylation status and gene variants of SLC6A4, the serotonin transporter gene, and an association with intergenerational stress, as SLC6A4 has been shown to moderate risk for psychopathology in the face of environmental stressors (Taylor et al, 2006;Kilpatrick et al, 2007;Grabe et al, 2009;Xie et al, 2009). Offspring born to mothers with at least one major stressful/traumatic life event during pregnancy have lower serotonin transporter mRNA levels compared with those without maternal prenatal stress.…”

Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene

“…Most research has focused on: (1) the hypothalamic-pituitary-adrenal (HPA) axis, (2) the ascending brainstem locus coeruleus noradrenergic system, and (3) the limbic amygdalar frontal pathway mediating fear processing. Among the over 25 PTSD candidate genes currently reported (Amstadter et al, 2009(Amstadter et al, , 2011Binder et al, 2008;Boscarino et al, 2011;Cao et al, 2013;Comings et al, 1996;Dragan and Oniszczenko, 2009;Gillespie et al, 2013;Goenjian et al, 2012;Grabe et al, 2009;Guffanti et al, 2013;Hauer et al, 2011;Kolassa et al, 2010;Logue et al, 2013a,b;Lyons et al, 2013;Mellman et al, 2009;Nelson et al, 2009;Ressler et al, 2011;Segman et al, 2002;Solovieff et al, 2014;Voisey et al, 2010;Wilker et al, 2013;Xie et al, 2013), promising findings include associations of PTSD symptoms with the serotonin transporter gene (SERT, SLC6A4) (Xie et al, 2009), which is linked to depression and anxiety disorders, as well as differential acquisition of conditioned fear and increased amygdala excitability in humans. In addition, FKBP5, a co-chaperone of the glucocorticoid receptor involved in the HPA axis, has a significant interaction with severity of child abuse in the prediction of adult PTSD symptoms, indicating a gene by environment (GxE) interaction (Binder et al, 2008).…”

Understanding Resilience

“…A particularly strong association between the s-allele and risk of developing depression was found in the group with a history of childhood maltreatment (Karg et al, 2011;Southwick and Charney, 2012). The s-allele of the 5-HTTLPR gene was also found, in two independent populations, to interact with childhood and adult traumatic experiences to increase the risk for PTSD (Xie et al, 2009). Polymorphisms in several serotonin receptor genes, such as HTR1A, HTR3A, and HTR2C, have been shown to interact with stressful life environment as well as polymorphisms from other genes (e.g., Val 66 Met in the BDNF gene) to predict susceptibility to depression (Kim et al, 2007(Kim et al, , 2011aGatt et al, 2010), and to mediate HPA-axis activation and emotional response to stress (Brummett et al, 2012).…”