Association between the dopamine transporter gene and posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) is a chronic anxiety disorder that follows exposure to extreme events. A large twin study of Vietnam veterans had demonstrated a significant genetic contribution to chronic PTSD upon exposure to combat.1,2 The underlying genes, however, have not been described. Given previous findings of abnormal dopamine (DA) function in PTSD, and given the putative effect of dopamine neurotransmission in shaping the responses to stress in animals, this study examined the association of the dopamine transporter (DAT) SLC6A3 3Ј variable number tandem repeat (VNTR) polymorphism with PTSD. The study evaluated 102 chronic PTSD patients and 104 carefully-documented trauma survivors (TS) who did not develop PTSD. Significant excess of 9 repeat allele was observed among PTSD patients (43% vs 30.5% in TS controls; 2 = 6.3, df = 1, P = 0.012). An excess of 9 repeat homozygous genotype was also observed in PTSD (20.43% in PTSD vs 9.47% in TS controls; 2 = 6.11, df = 2, P Ͻ 0.047). These findings suggest that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors. Molecular Psychiatry (2002) 7, 903-907. doi:10.1038/ sj.mp.4001085 Post-traumatic stress disorder (PTSD) is an extreme and sustained maladaptive response to stressful events. The disorder consists of symptoms of intrusive recall, avoidance of cues reminding of the traumatic event and hyper-arousal. These symptoms may persist for years, and are often associated with significant disability and distress. The etiology of PTSD is complex and multifactorial.3 Importantly, exposure to a traumatic event does not fully explain the occurrence of the disorder. 4 Exposure, in fact, triggers a cascade of biological events that ultimately lead to the occurrence of chronic PTSD.5 Individuals with prior vulnerability are at higher risk for developing PTSD upon exposure to a traumatic event. Inherited vulnerability is among the better researched vulnerability factors, as follows:True et al, 1 studied 4042 twin pairs from the Vietnam Twin Registry and found that inherited factors accounted for up to 32% of the variance of PTSD symptoms, above and beyond the contribution of trauma intensity. Xiang et al, 2 examined 3304 twin pairs of the Vietnam Twin Registry and similarly found 35.3%, inherited liability to develop PTSD upon combat exposure, 20% of which pertained specifically to PTSD and an additional 15.3% were common to both PTSD and substance dependence. Other studies 6 have shown an aggregation of anxiety disorders in families of PTSD patients.The molecular basis of the above-mentioned vulnerability is hardly known at this point. Two association studies evaluated the Taq-I RFLP site near the D2 dopamine receptor (DRD2) gene in PTSD. The first study 7 compared 37 drug and alcohol addicts with PTSD with 19 addicts without PTSD and found higher frequency of the A1 allele among the former. The second study 8 failed to replicate this finding in a sample of 52 PTSD patients and 82 normal con...

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

“…We also compiled a list of genes that have been reported in the literature to be significantly associated with PTSD, either showing a main effect for the genetic marker, and/or a significant GxE interaction (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). Since most studies were performed in subjects of either European or African descent, we used these specific ancestry groups for comparison with MRS. We found that most of the 25 candidate genes showed nominally significant associations in MRS for at least one of the SNPs tested.…”

“…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).…”

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

“…These include polymorphisms or expression of BDNF (Krishnan et al, 2007), GABRA2 (Nelson et al, 2009), 5-HT1A receptors, dopamine or serotonin transporters (Segman et al, 2002;Kilpatrick et al, 2007;Stein et al, 2009;Wald et al, 2013), catechol-O-methyl transferase (COMT; Jabbi et al, 2007;Kolassa et al, 2010), glucocorticoid receptors and factors that modulate them such as FK506-binding protein (FKBP5;Binder et al, 2008;Derijk and de Kloet, 2008;McGowan et al, 2009;Sarapas et al, 2011), and methylation of corticotrophin-releasing factor (CRF) receptor DNA (Elliott et al, 2010). Several genetically distinct rodent lines are differentially resistant/vulnerable to the effects of stress (Razzoli et al, 2011;Savignac et al, 2011;Camp et al, 2012;Fuchsl et al, 2014).…”

Interaction between BDNF Val66Met and Dopamine Transporter Gene Variation Influences Anxiety-Related Traits

“…Furthermore, serotonin transporter function was demonstrated as being influenced by BDNF in a 5-HTTLPR genotype-dependent fashion (Mössner et al, 2000). The DAT VNTR has been less intensively investigated, although it had been reported previously as being associated with post-traumatic stress disorder (PTSD) (Segman et al, 2002). It seems, therefore, reasonable to examine potential interactive influences of these polymorphisms and BDNF on individual differences in Neuroticism and related personality traits.…”