Molecular Variation at the SLC6A3 Locus Predicts Lifetime Risk of PTSD in the Detroit Neighborhood Health Study

Abstract

Recent work suggests that the 9-repeat (9R) allele located in the 3′UTR VNTR of the SLC6A3 gene increases risk of posttraumatic stress disorder (PTSD). However, no study reporting this association to date has been based on population-based samples. Furthermore, no study of which we are aware has assessed the joint action of genetic and DNA methylation variation at SLC6A3 on risk of PTSD. In this study, we assessed whether molecular variation at SLC6A3 locus influences risk of PTSD. Participants (n = 320; 62 cases/258 controls) were drawn from an urban, community-based sample of predominantly African American Detroit adult residents, and included those who had completed a baseline telephone survey, had provided blood specimens, and had a homozygous genotype for either the 9R or 10R allele or a heterozygous 9R/10R genotype. The influence of DNA methylation variation in the SLC6A3 promoter locus was also assessed in a subset of participants with available methylation data (n = 83; 16 cases/67 controls). In the full analytic sample, 9R allele carriers had almost double the risk of lifetime PTSD compared to 10R/10R genotype carriers (OR = 1.98, 95% CI = 1.02–3.86), controlling for age, sex, race, socioeconomic status, number of traumas, smoking, and lifetime depression. In the subsample of participants with available methylation data, a significant ( p = 0.008) interaction was observed whereby 9R allele carriers showed an increased risk of lifetime PTSD only in conjunction with high methylation in the SLC6A3 promoter locus, controlling for the same covariates. Our results confirm previous reports supporting a role for the 9R allele in increasing susceptibility to PTSD. They further extend these findings by providing preliminary evidence that a “double hit” model, including both a putatively reduced-function allele and high methylation in the promoter region, may more accurately capture molecular risk of PTSD at the SLC6A3 locus.

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression

“…The role of dopamine in the pathogenesis of PTSD has been supported by outcomes of elevated urinary and plasma levels in dopamine-related disorders (Chang et al, 2012). Additionally, there is a significant link between dopamine concentration and symptom severity (Chang et al, 2012). Our findings showed that maternal PTSD reduced the dopamine levels in the offspring, in accordance with previous reports.…”

“…A previous report showed that 5-HT levels were lower in the rat hippocampus and prefrontal cortex (PFC) in a predator exposure/psychosocial stress model of PTSD (Wilson et al, 2014). The role of dopamine in the pathogenesis of PTSD has been supported by outcomes of elevated urinary and plasma levels in dopamine-related disorders (Chang et al, 2012). Additionally, there is a significant link between dopamine concentration and symptom severity (Chang et al, 2012).…”

“…Geracioti et al (2013) found that the acute decline in central nervous system homovanillic acid (HVA) concentrations is associated with laboratory-induced symptoms in patients with chronic PTSD. Another study showed that the nine-repeat allele in the 3' untranslated region variable number of tandem repeat (VNTR) of the SLC6A3 gene increases the risk of PTSD (Chang et al, 2012).…”

Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors

“…The analysis covered eight CpGs, with the NGFI-A consensus binding sequence encompassing CpG positions 3 and 4. Because glucocorticoid-related changes in memory formation were repeatedly found to be more pronounced in men (Andreano and Cahill, 2006;Preuss and Wolf, 2009), we also considered possible gender differences in the present study. We first compared DNA methylation between genders and found significant differences between men and women at several CpG positions ( p Ͻ 0.05, e.g., methylation levels at NR3C1_CpG3 were significantly higher in women than in men, p ϭ 0.01).…”

“…Human studies have shown that the memory-enhancing effects of stress-induced elevations of glucocorticoids are usually more pronounced in men (Andreano and Cahill, 2006;Preuss and Wolf, 2009;Cornelisse et al, 2011). Furthermore, there is evidence that glucocorticoids impair the retrieval of memory processes (de Quervain et al, 2009).…”