One study of Army soldiers screened up to four months after returning from deployment to Iraq showed that 27% met criteria for alcohol abuse and were at increased risk for related harmful behaviors (e.g., drinking and driving, using illicit drugs) [3
]. In another study based on DRD2 allelic association, 35 PTSD patients with the A1(+) (A1A1, A1A2) allele consumed more than twice the daily amount of alcohol than the 56 patients with the A1(−) (A2A2) allele, and this difference was highly significant [4
]. When the hourly rate of alcohol consumed was compared, A1(+) allelic patients consumed twice the rate of the A1(−) allelic patients [4
Serotonin is an important neurotransmitter involved in brain reward circuitry, and serotonergic system dysfunction has been implicated in PTSD. Genetic polymorphisms associated with serotonin signaling may predict differences in brain circuitry involved in emotion processing and deficits associated with PTSD. In healthy individuals, common functional polymorphisms in the serotonin transporter gene (SLC6A4) have been shown to modulate amygdala and prefrontal cortex activity in response to salient emotional stimuli. Similar patterns of differential neural responses to emotional stimuli have been demonstrated in PTSD, but genetic factors influencing these activations have yet to be examined. Morey et al. [5
] found that the SLC6A4 SNPs rs16965628 and 5-HTTLPR are associated with a bias in neural responses to traumatic reminders and cognitive control of emotions in patients with PTSD.
The opioid receptor mu-1 (OPRM1) gene may play a role in both PTSD and alcohol use. Nugent et al. [6
] examined the association between PTSD and drinking motives as well as variation in the OPRM1 as a predictor of both PTSD and drinking motives in a sample of 201 persons living with HIV (PLH) reporting recent binge drinking. Self-reported PTSD symptom severity was significantly associated with drinking motives for coping, enhancement, and socialization. OPRM1 variation was associated with decreased PTSD symptom severity as well as enhancement motives for drinking.
GABAergic systems have been implicated in the pathogenesis of anxiety, depression, and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in PTSD. Feusner et al. [7
] concluded in a population of PTSD patients, heterozygosity of the GABRB3 major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity.
Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer’s disease and PTSD. In one particular study, Voisey et al. [8
] reported that the 957C>T polymorphism in the D2 dopamine receptor (DRD2) gene is one of the genetic factors for susceptibility to PTSD. Lawford et al. [9
] identified clusters of patients with PTSD according to symptom profile and examined the association of the A1 allele of the DRD2 gene with these clusters. They found that veterans with the DRD2 A1 allele — compared to those without this allele — were significantly more likely to be found in the high than the low psychopathology cluster group. In agreement with those findings, Comings et al. [10
] suggested that a DRD2 variant in linkage disequilibrium with the D2A1 allele confers an increased risk to PTSD, and the absence of the variant confers a relative resistance to PTSD. Moreover, Valente et al. [11
] found a statistical association between DAT1 3’UTR VNTR nine repeats and PTSD (OR = 1.82; 95% CI, 1.20–2.76). This preliminary result confirmed previous reports supporting a susceptibility role for allele 9 and PTSD.
van Zuiden et al. [12
] investigated whether glucocorticoid receptor (GR) pathway components assessed in leukocytes before military deployment represent preexisting vulnerability factors for development of PTSD symptoms. In predeployment high GR number, low FKBP5 mRNA expression, and high GILZ mRNA expression were independently associated with increased risk for a high level of PTSD symptoms. Childhood trauma also independently predicted development of a high level of PTSD symptoms. Additionally, the investigators observed a significant interaction effect of GR haplotype BclI and childhood trauma on GR number.
Nuclear factor-κB (NF -κB) is a ubiquitously expressed transcription factor for genes involved in cell survival, differentiation, inflammation, and growth. Cohen et al. examined the role of NF-κB pathway in stress-induced PTSD-like behavioral response patterns in rats. Extreme behavioral responder animals displayed significant upregulation of p50 and p65 with concomitant downregulation of I-κBα, p38, and phospho -p38 levels in hippocampal structures, compared with minimal behavioral responders and controls. Immediate post-exposure treatment with high-dose corticosterone and a selective NF-κB inhibitor (pyrrolidine dithiocarbamate) significantly reduced prevalence rates of extreme responders and normalized the expression of those genes. The authors suggested that stress-induced upregulation of NF-κB complex in the hippocampus may contribute to the imbalance between what are normally precisely orchestrated and highly coordinated physiological and behavioral processes, thus associating it with stress-related disorders.