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

Shun-Chiao Chang,Karestan C Koenen,Richelo Soliven,Monica Uddin,Allison E Aiello,Derek E Wildman,Sandro Galea

doi:10.1371/journal.pone.0039184

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.

Highlights

Posttraumatic stress disorder (PTSD) is a complex disorder characterized by three symptom clusters including re-experiencing, avoidance, and hyperarousal [1]
After adjusting for age, sex, socio-economic status, race, smoking, number of traumatic events and lifetime depression, 9R allele carriers showed almost twice the risk of PTSD compared to 10R/10R carriers (OR = 1.98, 95% CI = 1.02–3.86) (Table 2)
We have explored how genetic and epigenetic molecular variation at the SLC6A3 locus shapes risk of PTSD

Summary

Introduction

Posttraumatic stress disorder (PTSD) is a complex disorder characterized by three symptom clusters including re-experiencing, avoidance, and hyperarousal [1]. Twin studies have shown that genetic influences account for a substantial proportion (35– 70%) of variance in PTSD risk [2,3,4]. The SLC6A3 (solute carrier family 6 (neurotransmitter transporter, dopamine), member 3; known as DAT1 or DAT) locus is a biologically plausible candidate gene for PTSD. SLC6A3 encodes a dopamine transporter, a member of the sodium- and chloride-dependent neurotransmitter transporter family, which plays a key role in the regulation of dopaminergic neurotransmission by removing dopamine from the synaptic cleft via reuptake through the transporter [5]. Studies investigating the association between genetic variation at the SLC6A3 locus and PTSD have produced conflicting results

Methods

Results

Conclusion