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ImportanceDisrupted autonomic nervous system functioning as measured by heart rate variability (HRV) has been associated with posttraumatic stress disorder (PTSD). It is not clear, however, whether reduced HRV before trauma exposure contributes to the risk for development of PTSD.ObjectiveTo examine whether HRV before combat deployment is associated with increased risk of a PTSD diagnosis after deployment when accounting for deployment-related combat exposure.Design, setting, and participantsBetween July 14, 2008, and May 24, 2012, active-duty Marines were assessed 1 to 2 months before a combat deployment and again 4 to 6 months after their return. The first phase of the Marine Resiliency Study (MRS-I) included 1415 male Marines, 59 of whom developed PTSD after deployment. Participants in the second phase of the Marine Resiliency Study (MRS-II) included 745 male Marines, 25 of whom developed PTSD after deployment. Analysis was conducted from November 25, 2013, to April 16, 2015.Main outcomes and measuresPredeployment HRV was measured via finger photoplethysmography during a 5-minute period of rest. Frequency-domain measures of HRV were generated. Diagnosis of PTSD was determined using the Clinician-Administered PTSD Scale.ResultsAfter accounting for deployment-related combat exposure, lower HRV before deployment as measured by an increased low-frequency (LF) to high-frequency (HF) ratio of HRV was associated with risk of PTSD diagnosis after deployment (combined MRS-I and MRS-II cohort meta-analysis odds ratio, 1.47; 95% CI, 1.10-1.98; P = .01). The prevalence of postdeployment PTSD was higher in participants with high predeployment LF:HF ratios (15.8% [6 of 38 participants]) compared with participants who did not have high LF:HF ratios (3.7% [78 of 2122 participants]).Conclusions and relevanceThis prospective longitudinal study provides initial and modest evidence that an altered state of autonomic nervous system functioning contributes to PTSD vulnerability, taking into account other key risk factors. If these findings are replicated, interventions that change autonomic nervous system function may open novel opportunities for prevention and treatment of PTSD.

ImportancePosttraumatic stress disorder (PTSD) has been associated in cross-sectional studies with peripheral inflammation. It is not known whether this observed association is the result of PTSD predisposing to inflammation (as sometimes postulated) or to inflammation predisposing to PTSD.ObjectiveTo determine whether plasma concentration of the inflammatory marker C-reactive protein (CRP) helps predict PTSD symptoms.Design, setting, and participantsThe Marine Resiliency Study, a prospective study of approximately 2600 war zone-deployed Marines, evaluated PTSD symptoms and various physiological and psychological parameters before deployment and at approximately 3 and 6 months following a 7-month deployment. Participants were recruited from 4 all-male infantry battalions imminently deploying to a war zone. Participation was requested of 2978 individuals; 2610 people (87.6%) consented and 2555 (85.8%) were included in the present analysis. Postdeployment data on combat-related trauma were included for 2208 participants (86.4% of the 2555 included) and on PTSD symptoms at 3 and 6 months after deployment for 1861 (72.8%) and 1617 (63.3%) participants, respectively.Main outcomes and measuresSeverity of PTSD symptoms 3 months after deployment assessed by the Clinician-Administered PTSD Scale (CAPS).ResultsWe determined the effects of baseline plasma CRP concentration on postdeployment CAPS using zero-inflated negative binomial regression (ZINBR), a procedure designed for distributions, such as CAPS in this study, that have an excess of zeroes in addition to being positively skewed. Adjusting for the baseline CAPS score, trauma exposure, and other relevant covariates, we found baseline plasma CRP concentration to be a highly significant overall predictor of postdeployment CAPS scores (P = .002): each 10-fold increment in CRP concentration was associated with an odds ratio of nonzero outcome (presence vs absence of any PTSD symptoms) of 1.51 (95% CI, 1.15-1.97; P = .003) and a fold increase in outcome with a nonzero value (extent of symptoms when present) of 1.06 (95% CI, 0.99-1.14; P = .09).ConclusionsAND RELEVANCE A marker of peripheral inflammation, plasma CRP may be prospectively associated with PTSD symptom emergence, suggesting that inflammation may predispose to PTSD.

BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04×10(-9)), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5×10(-6)) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ.ConclusionsThis first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.

BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, ...

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 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 × 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.

Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1 and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.

BackgroundEpigenetic 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.ResultsStage 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 × 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.ConclusionsThis study ...

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 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 ...

BackgroundEpigenetic 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.ResultsStage 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 × 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.ConclusionsThis 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.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n = 93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n = 98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Background Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). Methods In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72). Results The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 x 10(-7), p(adj) = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 x 10(-6)), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 x 10(-5), p(adj) = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 x 10(-6), p(adj) = 0.042). Conclusions The cross replication observed in independent cohorts is evidence that ...

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.