Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

An EWAS of dementia biomarkers and their associations with age, African ancestry, and PTSD.

BACKGROUND: Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this question by assessing the influences of PTSD, APOE ε4 genotypes, DNA methylation, and other variables on the age- and dementia-associated biomarkers Aß40, Aß42, GFAP, NfL, and pTau-181 measured in plasma. Our primary hypothesis was that PTSD would be associated with elevated levels of these markers. METHODS: Analyses were based on data from a PTSD-enriched cohort of 849 individuals. We began by performing factor analyses of the biomarkers, the results of which identified a two-factor solution. Drawing from the ATN research framework, we termed the first factor, defined by Aß40 and Aß42, "Factor A" and the second factor, defined by GFAP, NfL and pTau-181, "Factor TN." Next, we performed epigenome-wide association analyses (EWAS) of the two-factor scores. Finally, using structural equation modeling (SEM), we evaluated (a) the influence of PTSD, age, APOE ε4 genotype and other covariates on levels of the ATN factors, and (b) tested the mediating influence of the EWAS-significant DNAm loci on these associations. RESULTS: The Factor A EWAS identified one significant locus, cg13053408, in FANCD2OS. The Factor TN analysis identified 3 EWAS-significant associations: cg26033520 near ASCC1, cg23156469 in FAM20B, and cg15356923 in FAM19A4. The SEM showed age to be related to both factors, more so with Factor TN (ß = 0.581, p < 0.001) than Factor A (ß = 0.330, p < 0.001). Genotype-determined African ancestry was associated with lower Factor A (ß = 0.196, p < 0.001). Contrary to our primary hypothesis, we found a modest negative bivariate correlation between PTSD and the TN factor scores (r = - 0.133, p < 0.001) attributable primarily to reduced levels of GFAP (r = - 0.128, p < 0.001). CONCLUSIONS: This study identified novel epigenetic associations with ATN biomarkers and demonstrated robust age and ancestral associations that will be essential to consider in future efforts to develop the clinical applications of these tests. The association between PTSD and reduced GFAP, which has been reported previously, warrants further investigation.

Trauma exposure and transdiagnostic distress: Examining shared and posttraumatic stress disorder-specific associations.

We examined transdiagnostic and posttraumatic stress disorder (PTSD)-specific associations with multiple forms of trauma exposure within a nationwide U.S. sample (N = 1,649, 50.0% female) of military veterans overselected for PTSD. A higher-order Distress factor was estimated using PTSD, major depressive disorder (MDD), and generalized anxiety disorder (GAD) symptoms as indicators. A structural equation model spanning three assessment points over an average of 3.85 years was constructed to examine the unique roles of higher-order Distress and PTSD-specific variance in accounting for the associations between trauma exposure, measured using the Life Events Checklist (LEC) and Deployment Risk and Resiliency Inventory Combat subscale (DRRI-C), and psychosocial impairment. The results suggest the association between trauma exposure and PTSD symptoms was primarily mediated by higher-order distress (70.7% of LEC effect, 63.2% of DRRI-C effect), but PTSD severity retained a significant association with trauma exposure independent of distress, LEC: ß = .10, 95% CI [.06, .13]; DRRI-C: ß = .11, 95% CI [.07, .14]. Both higher-order distress, ß = .31, and PTSD-specific variance, ß = .36, were necessary to account for the association between trauma exposure and future impairment. Findings suggest that trauma exposure may contribute to comorbidity across a range of internalizing symptoms as well as to PTSD-specific presentations.

Longitudinal study of traumatic-stress related cellular and cognitive aging.

Traumatic stress is associated with both accelerated epigenetic age and increased risk for dementia. Accelerated epigenetic age might link symptoms of traumatic stress to dementia-associated biomarkers, such as amyloid-beta (Aß) proteins, neurofilament light (NFL), and inflammatory molecules. We tested this hypothesis using longitudinal data obtained from 214 trauma-exposed military veterans (85 % male, mean age at baseline: 53 years, 75 % White) who were assessed twice over the course of an average of 5.6 years. Cross-lagged panel mediation models evaluated measures of lifetime posttraumatic stress disorder and internalizing and externalizing comorbidity (assessed at Time 1; T1) in association with T1 epigenetic age (per the GrimAge algorithm) and T1 plasma markers of neuropathology along with bidirectional temporal paths between T1 and T2 epigenetic age and the plasma markers. Results revealed that a measure of externalizing comorbidity was associated with accelerated epigenetic age (ß = 0.30, p <.01), which in turn, was associated with subsequent increases in Aß-40 (ß = 0.20, p <.001), Aß-42 (ß = 0.18, p <.001), and interleukin-6 (ß = 0.18, p <.01). T1 advanced epigenetic age and the T1 neuropathology biomarkers NFL and glial fibrillary acidic protein predicted worse performance on T2 neurocognitive tasks assessing working memory, executive/attentional control, and/or verbal memory (ps = 0.03 to 0.009). Results suggest that advanced GrimAge is predictive of subsequent increases in neuropathology and inflammatory biomarkers as well as worse cognitive function, highlighting the clinical significance of this biomarker with respect to cognitive aging and brain health over time. The finding that advanced GrimAge mediated the association between psychiatric comorbidity and future neuropathology is important for understanding potential pathways to neurodegeneration and early identification of those at greatest risk.

PTSD and Alcohol Use Disorders Predict the Pace of Cellular Aging.

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression. Results showed that PTSD (ß = .199) and AUD (ß = .186) were associated with a quickened pace of epigenetic aging over time (ps < .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology.

MMPI-2-RF Profiles of Treatment-Seeking Veterans in a VA Pain Clinic and Associations with Markers of Physical Performance.

Chronic pain is a debilitating condition for many military Veterans and is associated with posttraumatic stress disorder (PTSD). This study examined the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) in 144 Veterans (88.2% male, mean age = 57.95 years) recruited from a VA outpatient pain clinic and associations with self-reported pain severity, pain-related interference in daily activities, prescription opioid use, and objective metrics of physical performance on tasks impacted by pain (walking, stair climbing, grip strength, indexed by a single latent variable). Among the cohort with valid responses on the MMPI-2-RF (n = 117) and probable PTSD, mean Somatic Complaints (RC1) and Ideas of Persecution (RC6) scores were clinically elevated. All MMPI-2-RF scales were more strongly correlated with self-reported pain interference than severity. Regressions revealed associations between self-rated pain interference (but not pain or PTSD severity) and physical performance scores (ß = .36, p = .001). MMPI-2-RF overreporting Validity and Higher-Order scales contributed incremental variance in predicting physical performance, including Infrequent Psychopathology Responses (ß = .33, p = .002). PTSD severity was associated with prescription opioid use when accounting for the effects of over-reported somatic and cognitive symptoms (odds ratio 1.05, p ≤ .025). Results highlight the role of symptom overreporting and perceptions of functional impairment to observable behaviors among individuals with chronic pain.

Single-Nucleus Transcriptome Profiling of Dorsolateral Prefrontal Cortex: Mechanistic Roles for Neuronal Gene Expression, Including the 17q21.31 Locus, in PTSD Stress Response.

OBJECTIVE: Multidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution. METHOD: Profiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (∼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (∼160K nuclei; >11K cells per sample). RESULTS: Differential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in excitatory (EX) and inhibitory (IN) neurons and astrocytes, but not in other cell types or bulk tissue. MDD samples had more false discovery rate-corrected significant snDEGs, and PTSD samples had a greater replication rate. In EX and IN neurons, biological pathways that were differentially enriched in PTSD compared with MDD included glucocorticoid signaling. Furthermore, glucocorticoid signaling in induced pluripotent stem cell (iPSC)-derived cortical neurons demonstrated greater relevance in PTSD and opposite direction of regulation compared with MDD, especially in EX neurons. Many snDEGs were from the 17q21.31 locus and are particularly interesting given causal roles in disease pathogenesis and DLPFC-based neuroimaging (PTSD: ARL17B, LINC02210-CRHR1, and LRRC37A2; MDD: LRRC37A and LRP4), while others were regulated by glucocorticoids in iPSC-derived neurons (PTSD: SLC16A6, TAF1C; MDD: CDH3). CONCLUSIONS: The study findings point to cell-type-specific mechanisms of brain stress response in PTSD and MDD, highlighting the importance of examining cell-type-specific gene expression and indicating promising novel biomarkers and therapeutic targets.

Neurobiological and genetic correlates of the dissociative subtype of posttraumatic stress disorder.

Approximately 10%-30% of individuals with posttraumatic stress disorder (PTSD) exhibit a dissociative subtype of the condition defined by symptoms of depersonalization and derealization. This study examined the psychometric evidence for the dissociative subtype of PTSD in a sample of young, primarily male post-9/11-era Veterans (n = 374 at baseline and n = 163 at follow-up) and evaluated its biological correlates with respect to resting state functional connectivity (default mode network [DMN]; n = 275), brain morphology (hippocampal subfield volume and cortical thickness; n = 280), neurocognitive functioning (n = 337), and genetic variation (n = 193). Multivariate analyses of PTSD and dissociation items suggested a class structure was superior to dimensional and hybrid ones, with 7.5% of the sample comprising the dissociative class; this group showed stability over 1.5 years. Covarying for age, sex, and PTSD severity, linear regression models revealed that derealization/depersonalization severity was associated with: decreased DMN connectivity between bilateral posterior cingulate cortex and right isthmus (p = .015; adjusted-p [padj] = .097); increased bilateral whole hippocampal, hippocampal head, and molecular layer head volume (p = .010-.034; padj = .032-.053); worse self-monitoring (p = .018; padj = .079); and a candidate genetic variant (rs263232) in the adenylyl cyclase 8 gene (p = .026), previously associated with dissociation. Results converged on biological structures and systems implicated in sensory integration, the neural representation of spatial awareness, and stress-related spatial learning and memory, suggesting possible mechanisms underlying the dissociative subtype of PTSD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Alzheimer's disease and related dementias among aging veterans: Examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury.

INTRODUCTION: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) confer risk for Alzheimer's disease and related dementias (ADRD). METHODS: This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic. RESULTS: PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles. DISCUSSION: PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.

PTSD, major depression, and advanced transcriptomic age in brain tissue.

BACKGROUND: Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorder with age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex. METHODS: RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male). RESULTS: Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E-05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017). CONCLUSIONS: Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood-brain barrier degradation may play an important role in stress-related accelerated brain aging.

For whom the bell tolls: psychopathological and neurobiological correlates of a DNA methylation index of time-to-death.

Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge ("GrimAge residuals"), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps < 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj < 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj < 0.001; IL-6: padj < 0.001), and immune functioning (padj < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj < 0.001; TNF-α: padj < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.

Conceptualizing traumatic stress and the structure of posttraumatic psychopathology through the lenses of RDoC and HiTOP.

Trauma-related psychopathology, most notably posttraumatic stress disorder (PTSD), poses unique challenges for psychiatric nosology due to the wide range of symptoms and diagnoses associated with trauma and challenges representing the impact of trauma exposure on psychopathology. In this paper, we review the literature on categorical (i.e., Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases systems) versus dimensional conceptualizations of trauma-related symptoms with an emphasis on the Research Domain Criteria (RDoC) and the Hierarchical Taxonomy of Psychopathology (HiTOP) frameworks. We identify strengths of each approach and challenges in accommodating the full range of trauma-related psychopathology and the clinical implications thereof. We discuss several potential approaches for improving the representation of traumatic stress, including the use of PTSD subtypes, trauma-related specifiers for psychiatric diagnoses, and the development of a dimension that we call the traumatic stress spectrum, which spans both adaptive and adverse reactions to trauma. These approaches to representing traumatic stress can be evaluated empirically and further refined. We also discuss how the use of an integrated RDoC-HiTOP approach to reconceptualize traumatic stress might maximize the ability to model valid and reliable trauma-related phenotypes, which would aid in the investigation of clinically relevant biological correlates.

Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood. METHOD: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology. RESULTS: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [padj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, padj = 0.04) controlling for baseline IL-10. CONCLUSIONS: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

Premorbid traumatic stress and veteran responses to the COVID-19 pandemic.

The COVID-19 pandemic has had unprecedented effects on lifestyle stability and physical and mental health. We examined the impact of preexisting posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression on biopsychosocial responses to the pandemic, including psychiatric symptoms, COVID-19 exposure, and housing/financial stability, among 101 U.S. military veterans enrolled in a longitudinal study of PTSD, a population of particular interest given veterans' trauma histories and defense-readiness training. Participants (83.2% male, 79.2% White, Mage  = 59.28 years) completed prepandemic, clinician-administered psychiatric diagnostic interviews and a phone-based assessment between May and September 2020 using a new measure, the Rapid Assessment of COVID-19-Related Experiences (RACE), which was used to assess pandemic responses and its effects on mental and physical health; COVID-19 diagnosis and testing were also extracted from electronic medical records. Multivariate regressions showed that, controlling for demographic characteristics, prepandemic PTSD, ß = .332; p = .003, and AUD symptoms, ß = .228; p = .028, were associated with increased pandemic-related PTSD symptoms. Prepandemic AUD was associated with increased substance use during the pandemic, ß = .391; p < .001, and higher rates of self-reported or medical record-based COVID-19 diagnosis, ß = .264; p = .019. Minority race was associated with pandemic-related housing/financial instability, ß = -.372; p < .001, raising concerns of population inequities. The results suggest that preexisting PTSD and AUD are markers for adverse pandemic-related psychiatric outcomes and COVID-19 illness. These findings carry implications for the importance of targeting prevention and treatment efforts for the highest-risk individuals.

Gene expression in the dorsolateral and ventromedial prefrontal cortices implicates immune-related gene networks in PTSD.

Studies evaluating neuroimaging, genetically predicted gene expression, and pre-clinical genetic models of PTSD, have identified PTSD-related abnormalities in the prefrontal cortex (PFC) of the brain, particularly in dorsolateral and ventromedial PFC (dlPFC and vmPFC). In this study, RNA sequencing was used to examine gene expression in the dlPFC and vmPFC using tissue from the VA National PTSD Brain Bank in donors with histories of PTSD with or without depression (dlPFC n = 38, vmPFC n = 35), depression cases without PTSD (n = 32), and psychopathology-free controls (dlPFC n = 24, vmPFC n = 20). Analyses compared PTSD cases to controls. Follow-up analyses contrasted depression cases to controls. Twenty-one genes were differentially expressed in PTSD after strict multiple testing correction. PTSD-associated genes with roles in learning and memory (FOS, NR4A1), immune regulation (CFH, KPNA1) and myelination (MBP, MOBP, ERMN) were identified. PTSD-associated genes partially overlapped depression-associated genes. Co-expression network analyses identified PTSD-associated networks enriched for immune-related genes across the two brain regions. However, the immune-related genes and association patterns were distinct. The immune gene IL1B was significantly associated with PTSD in candidate-gene analysis and was an upstream regulator of PTSD-associated genes in both regions. There was evidence of replication of dlPFC associations in an independent cohort from a recent study, and a strong correlation between the dlPFC PTSD effect sizes for significant genes in the two studies (r = 0.66, p < 2.2 × 10-16). In conclusion, this study identified several novel PTSD-associated genes and brain region specific PTSD-associated immune-related networks.

Gene expression correlates of advanced epigenetic age and psychopathology in postmortem cortical tissue.

Psychiatric stress has been associated with accelerated epigenetic aging (i.e., when estimates of cellular age based on DNA methylation exceed chronological age) in both blood and brain tissue. Little is known about the downstream biological effects of accelerated epigenetic age on gene expression. In this study we examined associations between DNA methylation-derived estimates of cellular age that range from decelerated to accelerated relative to chronological age ("DNAm age residuals") and transcriptome-wide gene expression. This was examined using tissue from three post-mortem cortical regions (ventromedial and dorsolateral prefrontal cortex and motor cortex, n = 97) from the VA National PTSD Brain Bank. In addition, we examined how posttraumatic stress disorder (PTSD) and alcohol-use disorders (AUD) moderated the association between DNAm age residuals and gene expression. Transcriptome-wide results across brain regions, psychiatric diagnoses, and cohorts (full sample and male and female subsets) revealed experiment-wide differential expression of 11 genes in association with PTSD or AUD in interaction with DNAm age residuals. This included the inflammation-related genes IL1B, RCOR2, and GCNT1. Candidate gene class analyses and gene network enrichment analyses further supported differential expression of inflammation/immune gene networks as well as glucocorticoid, circadian, and oxidative stress-related genes. Gene co-expression network modules suggested enrichment of myelination related processes and oligodendrocyte enrichment in association with DNAm age residuals in the presence of psychopathology. Collectively, results suggest that psychiatric stress accentuates the association between advanced epigenetic age and expression of inflammation genes in the brain. This highlights the role of inflammatory processes in the pathophysiology of accelerated cellular aging and suggests that inflammatory pathways may link accelerated cellular aging to premature disease onset and neurodegeneration, particularly in stressed populations. This suggests that anti-inflammatory interventions may be an important direction to pursue in evaluating ways to prevent or delay cellular aging and increase resilience to diseases of aging.

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: ß = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: ß = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (ß = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (ß = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (ß = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (ß = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Emotion regulation and the association between PTSD, diet, and exercise: a longitudinal evaluation among US military veterans.

Background: Posttraumatic stress disorder (PTSD) is associated with premature onset of chronic health conditions such as cardiovascular disease. Diet and exercise are behavioural contributors to physical health, and research suggests they are influenced by psychiatric symptoms, including PTSD. Objectives: The aim of this study was to examine longitudinal associations between PTSD and exercise and diet quality and to test if emotion regulation strategies contribute to the link between PTSD and these health behaviours. Method: A representative sample of US military veterans (n = 860 at Time 1, n = 503 at Time 2, mean age = 63 years, 91.5% male) were assessed twice over the course of approximately three years. Results: Mediation models revealed that the association between baseline PTSD symptom severity and subsequent diet quality was mediated by emotion suppression (measured at Time 2; indirect B = -.03; 95% CI: -.059 to -.002). Trauma exposure also directly predicted diet quality (B = -.31; p = .003). There were no significant direct or indirect associations between PTSD severity or trauma exposure and exercise engagement. Conclusions: These results suggest that PTSD symptoms are associated with worse diet quality and that the consumption of unhealthy food may be driven by efforts to suppress emotion. This carries implications for understanding and treating medical comorbidities among those with traumatic stress.

Antecedentes: El trastorno de estrés postraumático (TEPT) está asociado con el inicio prematuro de condiciones crónicas de salud, como la enfermedad cardiovascular. La dieta y el ejercicio son contribuyentes conductuales para la salud física y las investigaciones sugieren que están influenciados por los síntomas psiquiátricos, incluyendo al TEPT.Objetivos: El objetivo de este estudio fue el de evaluar las asociaciones longitudinales entre el TEPT y el ejercicio y la calidad de la dieta; asimismo, evaluar si las estrategias de regulación emocional contribuyen al vínculo entre el TEPT y estas conductas de salud.Métodos: Se evaluó a una muestra representativa de veteranos de guerra estadounidenses (n = 860 en el Tiempo 1, n = 503 en el Tiempo 2, edad promedio = 63 años, 91,5% varones) en dos oportunidades en un periodo de tres años.Resultados: Los modelos de mediación mostraron que la asociación entre la severidad de los síntomas del TEPT de base y la calidad subsecuente de la dieta estaba mediada por la supresión de emociones (medidos en el Tiempo 2; B indirecta = −.03; 95% CI: − .059 to − .002). La exposición al trauma también predijo la calidad de la dieta de manera directa (B = = −.31; p = .003). No se encontraron asociaciones, directas o indirectas, entre la severidad del TEPT o la exposición al trauma con el compromiso con el ejercicio.Conclusiones: Estos resultados sugieren que los síntomas del TEPT están asociados a una peor calidad de la dieta y que el consumo de alimentos no saludables puede estar impulsado por esfuerzos para suprimir las emociones. Esto conlleva a implicaciones para comprender y tratar las comorbilidades médicas entre aquellos con estrés traumático.

Klotho, PTSD, and advanced epigenetic age in cortical tissue.

This study examined the klotho (KL) longevity gene polymorphism rs9315202 and psychopathology, including posttraumatic stress disorder (PTSD), depression, and alcohol-use disorders, in association with advanced epigenetic age in three postmortem cortical tissue regions: dorsolateral and ventromedial prefrontal cortices and motor cortex. Using data from the VA National PTSD Brain Bank (n = 117), we found that rs9315202 interacted with PTSD to predict advanced epigenetic age in motor cortex among the subset of relatively older (>=45 years), white non-Hispanic decedents (corrected p = 0.014, n = 42). An evaluation of 211 additional common KL variants revealed that only variants in linkage disequilibrium with rs9315202 showed similarly high levels of significance. Alcohol abuse was nominally associated with advanced epigenetic age in motor cortex (p = 0.039, n = 114). The rs9315202 SNP interacted with PTSD to predict decreased KL expression via DNAm age residuals in motor cortex among older white non-Hispanics decedents (indirect ß = -0.198, p = 0.027). Finally, in dual-luciferase enhancer reporter system experiments, we found that inserting the minor allele of rs9315202 in a human kidney cell line HK-2 genomic DNA resulted in a change in KL transcriptional activities, likely operating via long noncoding RNA in this region. This was the first study to examine multiple forms of psychopathology in association with advanced DNA methylation age across several brain regions, to extend work concerning the association between rs9315202 and advanced epigenetic to brain tissue, and to identify the effects of rs9315202 on KL gene expression. KL augmentation holds promise as a therapeutic intervention to slow the pace of cellular aging, disease onset, and neuropathology, particularly in older, stressed populations.