In the present study we measured the concentrations of cortisol, thyroid hormones, testosterone, and GABA (gamma aminobutyric acid) in am blood plasma samples of combatants with an at least 10 year... Show moreIn the present study we measured the concentrations of cortisol, thyroid hormones, testosterone, and GABA (gamma aminobutyric acid) in am blood plasma samples of combatants with an at least 10 year history of military psychological trauma (N = 74) divided in groups that either suffer from post-traumatic stress disorder (PTSD) (N = 37) or are resistant (N = 37) as well as in a control group without traumatic experience in the anamnesis, (N = 34). PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS). The results show that the am blood cortisol levels of individuals that were exposed to war zone experiences irrespective susceptibility for or resistance to PTSD were significantly higher than the values observed in the controls. Testosterone levels in PTSD patients differed neither from that observed in PTSD resistant nor control groups. In the resistant group testosterone levels were however significantly higher than in controls. The level of all thyroid hormones did not differ between the study groups. GABA level was significantly lower in the PTSD group compared with healthy controls. In the resistant group blood GABA levels were not significantly different from either PTSD patients or controls. In conclusion, the current data show that cortisol and to some extent testosterone may serve as biomarker of war zone stress per se, even if trauma was experienced at least ten years before, rather than of only PTSD or resistance to PTSD. GABA, in contrast, can be considered a potential marker of the protracted nature of PTSD. Show less
Background Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450... Show moreBackground Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. Results Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 x 10(-08)) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. Conclusions This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD. Show less
Exposure to trauma strongly increases the risk to develop stress-related psychopathology, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). In addition, liability to... Show moreExposure to trauma strongly increases the risk to develop stress-related psychopathology, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). In addition, liability to develop these moderately heritable disorders is partly determined by common genetic variance, which is starting to be uncovered by genome-wide association studies (GWASs). However, it is currently unknown to what extent genetic vulnerability and trauma interact. We investigated whether genetic risk based on summary statistics of large GWASs for PTSD and MDD predisposed individuals to report an increase in MDD and PTSD symptoms in a prospective military cohort (N = 516) at five time points after deployment to Afghanistan: one month, six months and one, two and five years. Linear regression was used to analyze the contribution of polygenic risk scores (PRSs, at multiple p-value thresholds) and their interaction with deployment-related trauma to the development of PTSD-and depression-related symptoms. We found no main effects of PRSs nor evidence for interactions with trauma on the development of PTSD or depressive symptoms at any of the time points in the five years after military deployment. Our results based on a unique long-term follow-up of a deployed military cohort suggest limited validity of current PTSD and MDD polygenic risk scores, albeit in the presence of minimal severe psychopathology in the target cohort. Even though the predictive value of PRSs will likely benefit from larger sample sizes in discovery and target datasets, progress will probably also depend on (endo) phenotype refinement that in turn will reduce etiological heterogeneity. (c) 2018 Published by Elsevier B.V. Show less
