Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.
ABSTRACT: 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.
Project description:BACKGROUND: Research on Vietnam veterans suggests an association between psychological problems, including posttraumatic stress disorder (PTSD), and misconduct; however, this has rarely been studied in veterans of Operation Iraqi Freedom or Operation Enduring Freedom. The objective of this study was to investigate whether psychological problems were associated with three types of misconduct outcomes (demotions, drug-related discharges, and punitive discharges.) METHODS: A population-based study was conducted on all U.S. Marines who entered the military between October 1, 2001, and September 30, 2006, and deployed outside of the United States before the end of the study period, September 30, 2007. Demographic, psychiatric, deployment, and personnel information was collected from military records. Cox proportional hazards regression analysis was conducted to investigate associations between the independent variables and the three types of misconduct in war-deployed (n = 77,998) and non-war-deployed (n = 13,944) Marines. RESULTS: Marines in both the war-deployed and non-war-deployed cohorts with a non-PTSD psychiatric diagnosis had an elevated risk for all three misconduct outcomes (hazard ratios ranged from 3.93 to 5.65). PTSD was a significant predictor of drug-related discharges in both the war-deployed and non-war-deployed cohorts. In the war-deployed cohort only, a specific diagnosis of PTSD was associated with an increased risk for both demotions (hazard ratio, 8.60; 95% confidence interval, 6.95 to 10.64) and punitive discharges (HR, 11.06; 95% CI, 8.06 to 15.16). CONCLUSIONS: These results provide evidence of an association between PTSD and behavior problems in Marines deployed to war. Moreover, because misconduct can lead to disqualification for some Veterans Administration benefits, personnel with the most serious manifestations of PTSD may face additional barriers to care.
Project description:We examined suicidal ideation among 399 active duty Soldiers and Marines engaged in mental health treatment. Using a generalized linear model controlling for demographic and military factors, depression, and positive traumatic brain injury screen, we confirmed our hypothesis that self-report measures of current PTSD symptoms uniquely predicted suicidal ideation. The association between PTSD severity and suicidal ideation was moderated by gender with women at higher risk as PTSD severity increased. Female Soldiers and Marines with high levels of PTSD should receive additional monitoring and intervention. Self-report measures may aid with risk assessment and identify symptom-related distress associated with suicide risk.
Project description: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.
Project description:Heart rate variability (HRV), thought to reflect autonomic nervous system function, is lowered under conditions such as posttraumatic stress disorder (PTSD). The potential confounding effects of traumatic brain injury (TBI) and depression in the relationship between HRV and PTSD have not been elucidated in a large cohort of military service members. Here we describe HRV associations with stress disorder symptoms in a large study of Marines while accounting for well-known covariates of HRV and PTSD including TBI and depression.Four battalions of male active-duty Marines (n = 2430) were assessed 1 to 2 months before a combat deployment. HRV was measured during a 5-minute rest. Depression and PTSD were assessed using the Beck Depression Inventory and Clinician-Administered PTSD Scale, respectively.When adjusting for covariates, including TBI, regression analyses showed that lower levels of high-frequency HRV were associated with a diagnosis of PTSD (? = -0.20, p = .035). Depression and PTSD severity were correlated (r = 0.49, p < .001); however, participants with PTSD but relatively low depression scores exhibited reduced high frequency compared with controls (p = .012). Marines with deployment experience (n = 1254) had lower HRV than did those with no experience (p = .033).This cross-sectional analysis of a large cohort supports associations between PTSD and reduced HRV when accounting for TBI and depression symptoms. Future postdeployment assessments will be used to determine whether predeployment HRV can predict vulnerability and resilience to the serious psychological and physiological consequences of combat exposure.
Project description:A large body of research has been produced in recent years investigating posttraumatic stress disorder (PTSD) among military personnel following deployment to Iraq and Afghanistan, resulting in apparent differences in PTSD prevalence. We compare prevalence estimates for current PTSD between military subgroups, providing insight into how groups may be differentially affected by deployment. Systematic literature searches using the terms PTSD, stress disorder, and acute stress, combined with terms relating to military personnel, identified 49 relevant papers. Studies with a sample size of less than 100 and studies based on data for treatment seeking or injured populations were excluded. Studies were categorized according to theatre of deployment (Iraq or Afghanistan), combat and noncombat deployed samples, sex, enlistment type (regular or reserve and [or] National Guard), and service branch (for example, army, navy, and air force). Meta-analysis was used to assess PTSD prevalence across subgroups. There was large variability in PTSD prevalence between studies, but, regardless of heterogeneity, prevalence rates of PTSD were higher among studies of Iraq-deployed personnel (12.9%; 95% CI 11.3% to 14.4%), compared with personnel deployed to Afghanistan (7.1%; 95% CI 4.6% to 9.6%), combat deployed personnel, and personnel serving in the Canadian, US, or UK army or the navy or marines (12.4%; 95% CI 10.9% to 13.4%), compared with the other services (4.9%; 95% CI 1.4% to 8.4%). Contrary to findings from within-study comparisons, we did not find a difference in PTSD prevalence for regular active-duty and reserve or National Guard personnel. Categorizing studies according to deployment location and branch of service identified differences among subgroups that provide further support for factors underlying the development of PTSD.
Project description:Adult posttraumatic stress disorder (PTSD) has been characterized by altered fear-network connectivity. Childhood trauma is a major risk factor for adult PTSD, yet its contribution to fear-network connectivity in PTSD remains unexplored. We examined, within a single model, the contribution of childhood maltreatment, combat exposure, and combat-related posttraumatic stress symptoms (PTSS) to resting-state connectivity (rs-FC) of the amygdala and hippocampus in military veterans.Medication-free male veterans (n = 27, average 26.6 years) with a range of PTSS completed resting-state fMRI. Measures including the Clinician-Administered PTSD Scale (CAPS), Childhood Trauma Questionnaire (CTQ), and Combat Exposure Scale (CES) were used to predict rs-FC using multilinear regression. Fear-network seeds included the amygdala and hippocampus.Amygdala: CTQ predicted lower connectivity to ventromedial prefrontal cortex (vmPFC), but greater anticorrelation with dorsal/lateral PFC. CAPS positively predicted connectivity to insula, and loss of anticorrelation with dorsomedial/dorsolateral (dm/dl)PFC. Hippocampus: CTQ predicted lower connectivity to vmPFC, but greater anticorrelation with dm/dlPFC. CES predicted greater anticorrelation, whereas CAPS predicted less anticorrelation with dmPFC.Childhood trauma, combat exposure, and PTSS differentially predict fear-network rs-FC. Childhood maltreatment may weaken ventral prefrontal-subcortical circuitry important in automatic fear regulation, but, in a compensatory manner, may also strengthen dorsal prefrontal-subcortical pathways involved in more effortful emotion regulation. PTSD symptoms, in turn, appear to emerge with the loss of connectivity in the latter pathway. These findings suggest potential mechanisms by which developmental trauma exposure leads to adult PTSD, and which brain mechanisms are associated with the emergence of PTSD symptoms.
Project description:Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.
Project description:The etiology of post-traumatic stress disorder (PTSD) likely involves the interaction of numerous genes and environmental factors. Similarly, gene-expression levels in peripheral blood are influenced by both genes and environment, and expression levels of many genes show good correspondence between peripheral blood and brain tissues. In that context, this pilot study sought to test the following hypotheses: (1) post-trauma expression levels of a gene subset in peripheral blood would differ between Marines with and without PTSD; (2) a diagnostic biomarker panel of PTSD among high-risk individuals could be developed based on gene-expression in readily assessable peripheral blood cells; and (3) a diagnostic panel based on expression of individual exons would surpass the accuracy of a model based on expression of full-length gene transcripts. Gene-expression levels in peripheral blood samples from 50 U.S. Marines (25 PTSD cases and 25 non-PTSD comparison subjects) were determined by microarray following their return from deployment to war-zones in Iraq or Afghanistan. The original sample was carved into training and test subsets for construction of support vector machine classifiers. The panel of peripheral blood biomarkers achieved 80% prediction accuracy in the test subset based on the expression of just two full-length transcripts (GSTM1 and GSTM2). A biomarker panel based on 20 exons attained an improved 90% accuracy in the test subset. Though further refinement and replication of these biomarker profiles are required, these preliminary results provide proof-of-principle for the diagnostic utility of blood-based mRNA-expression in PTSD among trauma-exposed individuals.
Project description:The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.
Project description:Posttraumatic stress disorder (PTSD) is a prevalent, serious public health concern, particularly in the military. The identification of genetic risk factors for PTSD may provide important insights into the biological foundation of vulnerability and comorbidity.To discover genetic loci associated with the lifetime risk for PTSD in 2 cohorts from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS).Two coordinated genome-wide association studies of mental health in the US military contributed participants. The New Soldier Study (NSS) included 3167 unique participants with PTSD and 4607 trauma-exposed control individuals; the Pre/Post Deployment Study (PPDS) included 947 unique participants with PTSD and 4969 trauma-exposed controls. The NSS data were collected from February 1, 2011, to November 30, 2012; the PDDS data, from January 9 to April 30, 2012. The primary analysis compared lifetime DSM-IV PTSD cases with trauma-exposed controls without lifetime PTSD. Data were analyzed from March 18 to December 27, 2015.Association analyses for PTSD used logistic regression models within each of 3 ancestral groups (European, African, and Latino American) by study, followed by meta-analysis. Heritability and genetic correlation and pleiotropy with other psychiatric and immune-related disorders were estimated.The NSS population was 80.7% male (6277 of 7774 participants; mean [SD] age, 20.9 [3.3] years); the PPDS population, 94.4% male (5583 of 5916 participants; mean [SD] age, 26.5 [6.0] years). A genome-wide significant locus was found in ANKRD55 on chromosome 5 (rs159572; odds ratio [OR], 1.62; 95% CI, 1.37-1.92; P?=?2.34?×?10-8) and persisted after adjustment for cumulative trauma exposure (adjusted OR, 1.64; 95% CI, 1.39-1.95; P?=?1.18?×?10-8) in the African American samples from the NSS. A genome-wide significant locus was also found in or near ZNF626 on chromosome 19 (rs11085374; OR, 0.77; 95% CI, 0.70-0.85; P?=?4.59?×?10-8) in the European American samples from the NSS. Similar results were not found for either single-nucleotide polymorphism in the corresponding ancestry group from the PPDS sample, in other ancestral groups, or in transancestral meta-analyses. Single-nucleotide polymorphism-based heritability was nonsignificant, and no significant genetic correlations were observed between PTSD and 6 mental disorders or 9 immune-related disorders. Significant evidence of pleiotropy was observed between PTSD and rheumatoid arthritis and, to a lesser extent, psoriasis.In the largest genome-wide association study of PTSD to date, involving a US military sample, limited evidence of association for specific loci was found. Further efforts are needed to replicate the genome-wide significant association with ANKRD55-associated in prior research with several autoimmune and inflammatory disorders-and to clarify the nature of the genetic overlap observed between PTSD and rheumatoid arthritis and psoriasis.