Leveraging interindividual variability in threat conditioning of inbred mice to model trait anxiety.

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype behavioral marker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.

Can you remember silence? Epigenetic memory and reversibility as a site of intervention.

Just over 20 years ago, molecular biologists Leonie Ringrose and Renato Paro published an article with a provocative title, "Remembering Silence", in BioEssays. The article focused on how epigenetic elements could return to their silent state, operationally defined as their epigenetic status before their modulation by experimental or environmental factors. Though Ringrose and Paro's article was on fruit flies and factors affecting embryological growth, the article asked a question of considerable importance to rapidly expanding research in neuroepigenetics on the correlation between trauma and neuropsychiatric risk: If you experience a traumatic event and, as a result, acquire an epigenetic trait that is considered pathological, can you free yourself of that trait? Ultimately, we are interested in how a return to silence is envisioned in neuroepigenetics research, how interventions purported to bring about that silence might function, and what this might mean for people who live in the aftermath of trauma.

Genetic and non-genetic predictors of risk for opioid dependence.

BACKGROUND: Elucidation of the interaction of biological and psychosocial/environmental factors on opioid dependence (OD) risk can inform our understanding of the etiology of OD. We examined the role of psychosocial/environmental factors in moderating polygenic risk for opioid use disorder (OUD). METHODS: Data from 1958 European ancestry adults who participated in the Yale-Penn 3 study were analyzed. Polygenic risk scores (PRS) were based on a large-scale multi-trait analysis of genome-wide association studies (MTAG) of OUD. RESULTS: A total of 420 (21.1%) individuals had a lifetime diagnosis of OD. OUD PRS were positively associated with OD (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.21-1.66). Household income and education were the strongest correlates of OD. Among individuals with higher OUD PRS, those with higher education level had lower odds of OD (OR 0.92, 95% CI 0.85-0.98); and those with posttraumatic stress disorder (PTSD) were more likely to have OD relative to those without PTSD (OR 1.56, 95% CI 1.04-2.35). CONCLUSIONS: Results suggest an interplay between genetics and psychosocial environment in contributing to OD risk. While PRS alone do not yet have useful clinical predictive utility, psychosocial factors may help enhance prediction. These findings could inform more targeted clinical and policy interventions to help address this public health crisis.

Experiences of racial discrimination and adverse gene expression among black individuals in a level 1 trauma center sample.

Up to 40 % of individuals who sustain traumatic injuries are at risk for posttraumatic stress disorder (PTSD) and the conditional risk for developing PTSD is even higher for Black individuals. Exposure to racial discrimination, including at both interpersonal and structural levels, helps explain this health inequity. Yet, the relationship between racial discrimination and biological processes in the context of traumatic injury has yet to be fully explored. The current study examined whether racial discrimination is associated with a cumulative measure of biological stress, the gene expression profile conserved transcriptional response to adversity (CTRA), in Black trauma survivors. Two-weeks (T1) and six-months (T2) post-injury, Black participants (N = 94) provided a blood specimen and completed assessments of lifetime racial discrimination and PTSD symptoms. Mixed effect linear models evaluated the relationship between change in CTRA gene expression and racial discrimination while adjusting for age, gender, body mass index (BMI), smoking history, heavy alcohol use history, and trauma-related variables (mechanism of injury, lifetime trauma). Results revealed that for individuals exposed to higher levels of lifetime racial discrimination, CTRA significantly increased between T1 and T2. Conversely, CTRA did not increase significantly over time in individuals exposed to lower levels of lifetime racial discrimination. Thus, racial discrimination appeared to lead to a more sensitized biological profile which was further amplified by the effects of a recent traumatic injury. These findings replicate and extend previous research elucidating the processes by which racial discrimination targets biological systems.

Recent advances in the role of miRNAs in post-traumatic stress disorder and traumatic brain injury.

Post-traumatic stress disorder (PTSD) is usually considered a psychiatric disorder upon emotional trauma. However, with the rising number of conflicts and traffic accidents around the world, the incidence of PTSD has skyrocketed along with traumatic brain injury (TBI), a complex neuropathological disease due to external physical force and is also the most common concurrent disease of PTSD. Recently, the overlap between PTSD and TBI is increasingly attracting attention, as it has the potential to stimulate the emergence of novel treatments for both conditions. Of note, treatments exploiting the microRNAs (miRNAs), a well-known class of small non-coding RNAs (ncRNAs), have rapidly gained momentum in many nervous system disorders, given the miRNAs' multitudinous and key regulatory role in various biological processes, including neural development and normal functioning of the nervous system. Currently, a wealth of studies has elucidated the similarities of PTSD and TBI in pathophysiology and symptoms; however, there is a dearth of discussion with respect to miRNAs in both PTSD and TBI. In this review, we summarize the recent available studies of miRNAs in PTSD and TBI and discuss and highlight promising miRNAs therapeutics for both conditions in the future.

Decreased mononuclear cell NR3C1 SKA2 and FKPB5 expression levels among adult survivors of suicide bombing terror attacks in childhood are associated with the development of PTSD.

Life threatening trauma and the development of PTSD during childhood, may each associate with transcriptional perturbation of immune cell glucocorticoid reactivity, yet their separable longer term contributions are less clear. The current study compared resting mononuclear cell gene expression levels of the nuclear receptor, subfamily 3, member 1 (NR3C1) coding the glucocorticoid receptor, its trans-activator spindle and kinetochore-associated protein 2 (SKA2), and its co-chaperon FKBP prolyl isomerase 5 (FKBP5), between a cohort of young adults first seen at the Hadassah Emergency Department (ED) after surviving a suicide bombing terror attack during childhood, and followed longitudinally over the years, and matched healthy controls not exposed to life threatening trauma. While significant reductions in mononuclear cell gene expression levels were observed among young adults for all three transcripts following early trauma exposure, the development of subsequent PTSD beyond trauma exposure, accounted for a small but significant portion of the variance in each of the three transcripts. Long-term perturbation in the expression of immune cell glucocorticoid response transcripts persists among young adults who develop PTSD following life threatening trauma exposure in childhood, denoting chronic dysregulation of immune stress reactivity.

Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders.

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (-T); (2) Trauma, No Symptoms (T - S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the -T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T - S group. There were no differences between the T - S group and - T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment.

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans.

Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.

Relationship between SLC6A2 gene polymorphisms and brain volume in Han Chinese adults who lost their sole child.

BACKGROUND: Norepinephrine transporter (NET) is encoded by the SLC6A2 gene and is a potential target for studying the pathogenesis of PTSD. To the best of our knowledge, no prior investigations have examined SLC6A2 polymorphism-related neuroimaging abnormalities in PTSD patients. METHODS: In 218 Han Chinese adults who had lost their sole child, we investigated the association between the T-182 C SLC6A2 genotype and gray matter volume (GMV). Participants included 57 PTSD sufferers and 161 non-PTSD sufferers, and each group was further separated into three subgroups based on each participant's SLC6A2 genotype (TT, CT, and CC). All participants received magnetic resonance imaging (MRI) and clinical evaluation. To assess the effects of PTSD diagnosis, genotype, and genotype × diagnosis interaction on GMV, 2 × 3 full factorial designs were used. Pearson's correlations were used to examine the association between GMV and CAPS, HAMD, and HAMA. RESULTS: The SLC6A2 genotype showed significant main effects on GMV of the left superior parietal gyrus (SPG) and the bilateral middle cingulate gyrus (MCG). Additionally, impacts of the SLC6A2 genotype-diagnosis interaction were discovered in the left superior frontal gyrus (SFG). The CAPS, HAMA, and HAMD scores, as well as the genotype main effect and diagnostic SLC6A2 interaction, did not significantly correlate with each other. CONCLUSION: These findings indicate a modulatory effect that the SLC6A2 polymorphism exerts on the SPG and MCG, irrespective of PTSD diagnosis. We found evidence to suggest that the SLC6A2 genotype-diagnosis interaction on SFG may potentially contribute to PTSD pathogenesis in adults who lost their sole child.

Causal Associations between Posttraumatic Stress Disorder and COVID-19.

OBJECTIVE: We aimed to evaluate bidirectional genetic relationships between posttraumatic stress disorder (PTSD) and COVID-19. METHODS: We investigated potential causal associations between PTSD and two COVID-19 conditions (COVID-19 hospitalization and SARS-CoV-2 infection) via Mendelian randomization (MR) analyses. Three genome-wide association study (GWAS) summary datasets were used in the study, including PTSD (N = 174,659), SARS-CoV-2 infection (N = 2,597,856), and COVID-19 hospitalization (N = 2,095,324). We performed a literature-based analysis to uncover molecular pathways connecting PTSD and COVID-19. RESULTS: We found that PTSD exerts a causal effect on SARS-CoV-2 infection (odds ratio (OR): 1.10, 95% confidence interval (CI): 1.00-1.21, p = 0.048) and hospitalized COVID-19 (OR: 1.34, 95% CI: 1.07-1.67, p = 0.001). However, both SARS-CoV-2 infection and hospitalized COVID-19 were not associated with the risk of PTSD. Pathway analysis revealed that several immunity-related genes may link PTSD to COVID-19. CONCLUSIONS: Our study suggests that PTSD was associated with increased risks for COVID-19 susceptibility and severity. Early diagnosis and effective treatment of PTSD in individuals infected with the coronavirus may improve the management of the outcomes of COVID-19.

Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort.

The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis-) or distal (trans-) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome-wide genotype and RNA-sequencing data were obtained from 32 trauma-exposed controls and 35 PTSD cases of mixed-ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single-nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP-gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD-dependent manner. However, several known cis-eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non-European, admixed sample population. This study was limited by the cross-sectional design and insufficient statistical power. Overall, this study should encourage further multi-omics approaches towards investigating PTSD in diverse populations.

Gene-based mediation analysis in epigenetic studies.

Mediation analysis has been a useful tool for investigating the effect of mediators that lie in the path from the independent variable to the outcome. With the increasing dimensionality of mediators such as in (epi)genomics studies, high-dimensional mediation model is needed. In this work, we focus on epigenetic studies with the goal to identify important DNA methylations that act as mediators between an exposure disease outcome. Specifically, we focus on gene-based high-dimensional mediation analysis implemented with kernel principal component analysis to capture potential nonlinear mediation effect. We first review the current high-dimensional mediation models and then propose two gene-based analytical approaches: gene-based high-dimensional mediation analysis based on linearity assumption between mediators and outcome (gHMA-L) and gene-based high-dimensional mediation analysis based on nonlinearity assumption (gHMA-NL). Since the underlying true mediation relationship is unknown in practice, we further propose an omnibus test of gene-based high-dimensional mediation analysis (gHMA-O) by combing gHMA-L and gHMA-NL. Extensive simulation studies show that gHMA-L performs better under the model linear assumption and gHMA-NL does better under the model nonlinear assumption, while gHMA-O is a more powerful and robust method by combining the two. We apply the proposed methods to two datasets to investigate genes whose methylation levels act as important mediators in the relationship: (1) between alcohol consumption and epithelial ovarian cancer risk using data from the Mayo Clinic Ovarian Cancer Case-Control Study and (2) between childhood maltreatment and comorbid post-traumatic stress disorder and depression in adulthood using data from the Gray Trauma Project.

Investigating the shared genetic architecture of post-traumatic stress disorder and gastrointestinal tract disorders: a genome-wide cross-trait analysis.

BACKGROUND: Observational studies suggest a correlation between post-traumatic stress disorder (PTSD) and gastrointestinal tract (GIT) disorders. However, the genetic overlap, causal relationships, and underlining mechanisms between PTSD and GIT disorders were absent. METHODS: We obtained genome-wide association study statistics for PTSD (23 212 cases, 151 447 controls), peptic ulcer disease (PUD; 16 666 cases, 439 661 controls), gastroesophageal reflux disease (GORD; 54 854 cases, 401 473 controls), PUD and/or GORD and/or medications (PGM; 90 175 cases, 366 152 controls), irritable bowel syndrome (IBS; 28 518 cases, 426 803 controls), and inflammatory bowel disease (IBD; 7045 cases, 449 282 controls). We quantified genetic correlations, identified pleiotropic loci, and performed multi-marker analysis of genomic annotation, fast gene-based association analysis, transcriptome-wide association study analysis, and bidirectional Mendelian randomization analysis. RESULTS: PTSD globally correlates with PUD (rg = 0.526, p = 9.355 × 10-7), GORD (rg = 0.398, p = 5.223 × 10-9), PGM (rg = 0.524, p = 1.251 × 10-15), and IBS (rg = 0.419, p = 8.825 × 10-6). Cross-trait meta-analyses identify seven genome-wide significant loci between PTSD and PGM (rs13107325, rs1632855, rs1800628, rs2188100, rs3129953, rs6973700, and rs73154693); three between PTSD and GORD (rs13107325, rs1632855, and rs3132450); one between PTSD and IBS/IBD (rs4937872 and rs114969413, respectively). Proximal pleiotropic genes are mainly enriched in immune response regulatory pathways, and in brain, digestive, and immune systems. Gene-level analyses identify five candidates: ABT1, BTN3A2, HIST1H3J, ZKSCAN4, and ZKSCAN8. We found significant causal effects of GORD, PGM, IBS, and IBD on PTSD. We observed no reverse causality of PTSD with GIT disorders, except for GORD. CONCLUSIONS: PTSD and GIT disorders share common genetic architectures. Our work offers insights into the biological mechanisms, and provides genetic basis for translational research studies.

Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption. METHODS: We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes. RESULTS: In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS). CONCLUSIONS: These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

Genetic liability to posttraumatic stress disorder and its association with postpartum depression.

BACKGROUND: Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. METHODS: This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. RESULTS: The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20-1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94-1.30 per standard deviation increase). CONCLUSIONS: Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.

Integrated analysis of proteomics, epigenomics and metabolomics data revealed divergent pathway activation patterns in the recent versus chronic post-traumatic stress disorder.

Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder.

Polygenic Risk for Schizophrenia, Major Depression, and Post-traumatic Stress Disorder and Hippocampal Subregion Volumes in Middle Childhood.

Studies demonstrate that individuals with diagnoses for Major Depressive Disorder (MDD), Post-traumatic Stress Disorder (PTSD), and Schizophrenia (SCZ) may exhibit smaller hippocampal gray matter relative to otherwise healthy controls, although the effect sizes vary in each disorder. Existing work suggests that hippocampal abnormalities in each disorder may be attributable to genetic liability and/or environmental variables. The following study uses baseline data from the Adolescent Brain and Cognitive Development[Formula: see text] Study (ABCD Study[Formula: see text]) to address three open questions regarding the relationship between genetic risk for each disorder and hippocampal volume reductions: (a) whether polygenic risk scores (PGRS) for MDD, PTSD, and SCZ are related to hippocampal volume; (b) whether PGRS for MDD, PTSD, and SCZ are differentially related to specific hippocampal subregions along the longitudinal axis; and (c) whether the association between PGRS for MDD, PTSD, and SCZ and hippocampal volume is moderated by sex and/or environmental adversity. In short, we did not find associations between PGRS for MDD, PTSD, and SCZ to be significantly related to any hippocampal subregion volumes. Furthermore, neither sex nor enviornmental adversity significantly moderated these associations. Our study provides an important null finding on the relationship genetic risk for MDD, PTSD, and SCZ to measures of hippocampal volume.