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.

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.

Platelets bridging the gap between gut dysbiosis and neuroinflammation in stress-linked disorders: A narrative review.

In this narrative review, we examine the association between gut dysbiosis, neuroinflammation, and stress-linked disorders, including depression, anxiety, and post-traumatic stress disorder (PTSD), and investigate whether tryptophan (TRP) metabolism and platelets play a role in this association. The mechanisms underlying the aetiology of stress-linked disorders are complex and not yet completely understood. However, a potential link between chronic inflammation and these disorders may potentially be found in TRP metabolism and platelets. By critically analysing existing literature on platelets, the gut microbiome, and stress-linked disorders, we hope to elicit the role of platelets in mediating the effects on serotonin (5-HT) levels and neuroinflammation. We have included studies specifically investigating platelets and TRP metabolism in relation to inflammation, neuroinflammation and neuropsychiatric disorders. Alteration in microbial composition due to stress could contribute to increased intestinal permeability, facilitating the translocation of microbial products, and triggering the release of pro-inflammatory cytokines. This causes platelets to become hyperactive and secrete 5-HT into the plasma. Increased levels of pro-inflammatory cytokines may also lead to increased permeability of the blood-brain barrier (BBB), allowing inflammatory mediators entry into the brain, affecting the balance of TRP metabolism products, such as 5-HT, kynurenic acid (KYNA), and quinolinic acid (QUIN). These alterations may contribute to neuroinflammation and possible neurological damage. Furthermore, platelets can cross the compromised BBB and interact with astrocytes and neurons, leading to the secretion of 5-HT and pro-inflammatory factors, exacerbating inflammatory conditions in the brain. The mechanisms underlying neuroinflammation resulting from peripheral inflammation are still unclear, but the connection between the brain and gut through the bloodstream could be significant. Identifying peripheral biomarkers and mechanisms in the plasma that reflect neuroinflammation may be important. This review serves as a foundation for further research on the association between the gut microbiome, blood microbiome, and neuropsychiatric disorders. The integration of these findings with protein and metabolite markers in the blood may expand our understanding of the subject.

A network analysis investigating the associations between posttraumatic stress symptoms, markers of inflammation and metabolic syndrome.

Chronic systemic inflammation has been implicated in trauma exposure, independent of a psychiatric diagnosis, and in posttraumatic stress disorder (PTSD) and its highly comorbid conditions, such as metabolic syndrome (MetS). The present study used network analysis to examine the interacting associations between pro-inflammatory cytokines, posttraumatic stress (PTS) symptoms and symptom clusters, and individual components of MetS, in a cohort of 312 participants (n = 139 PTSD cases, n = 173 trauma-exposed controls). Pro-inflammatory cytokines were measured in serum samples using immunoturbidimetric and multiplex assays. Three network models were assessed, and the decision on which model to use was guided by network stability estimates and denseness. Weak negative associations were observed between interleukin one beta (IL-1ß) and detachment (D6) and irritability (E1); tumour necrosis factor alpha (TNFα) and hypervigilance (E3); and C-reactive protein (CRP) and emotional cue reactivity (B4), which could be due to high cortisol levels present in a female-majority cohort. Network models also identified positive associations between CRP and waist circumference, blood pressure, and high-density lipoprotein cholesterol (HDL-C). The strongest association was observed between CRP and waist circumference, providing evidence that central obesity is an important inflammatory component of MetS. Some networks displayed high instability, which could be due to the small pool of participants with viable cytokine data. Overall, this study provides evidence for associations between inflammation, PTS symptoms and components of MetS. Future longitudinal studies measuring pro-inflammatory cytokines in the immediate aftermath of trauma are required to gain better insight into the role of inflammation in trauma-exposure and PTSD.

FKBP5 intron 7 methylation is associated with higher anxiety proneness and smaller right thalamus volume in adolescents.

Dysregulation of stress response systems may mediate the detrimental effects of childhood trauma (CT) on mental health. FKBP5 regulates glucocorticoid receptor sensitivity and exerts pleiotropic effects on intracellular signaling, neurobiology and behavior. We investigated whether CT, alone and in combination with rs1360780 genotype, is associated with altered FKBP5 methylation and whether CT-associated methylation profiles are associated with anxiety proneness (AP) and structural brain volumes. Ninety-four adolescents completed the Childhood Trauma Questionnaire, and a composite AP score was generated from the Childhood Anxiety Sensitivity Index and the State-Trait Anxiety Inventory-Trait measure. Mean methylation values for 12 regulatory regions and 25 individual CpG sites were determined using high-accuracy measurement via targeted bisulfite sequencing. FKBP5 rs1360780 genotype and structural MRI data were available for a subset of participants (n = 71 and n = 75, respectively). Regression models revealed an inverse association between methylation of three intron 7 CpG sites (35558438, 35558566 and 35558710) and right thalamus volume. CpG35558438 methylation was positively associated with AP scores. Our data indicate that an intron 7 methylation profile, consistent with lower FKBP5 expression and elevated high sensitivity glucocorticoid receptor levels, is associated with higher AP and smaller right thalamus volume. Research into the mechanisms underlying the intron 7 methylation-thalamus volume relationship, and whether it confers increased risk for long-term psychopathology by altering the regulatory threshold of stress responding, is required.

Rates of and factors associated with atopy and allergies in posttraumatic stress disorder as compared to controls.

OBJECTIVE: Several studies suggest a relationship between atopy and psychiatric disorders, but few have investigated the association between atopic conditions and posttraumatic stress disorder (PTSD). We sought to compare the rates of atopy and allergies in a South African case-control study of 220 patients with PTSD (mean age 41.7 years, SD = 11.7) and 196 trauma exposed controls (TEC, mean age 45.4 years, SD = 14.7) conducted in Cape Town, South Africa from May 2014 to June 2017. METHODS: Self-reported atopic conditions and allergies were regressed on PTSD, as determined with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), in multivariate logistic regression models, controlling for age, gender, body mass index, physical activity, lifetime and childhood trauma, and time since index trauma. RESULTS: Rates of lifetime atopy (p = 0.03), current asthma (p = 0.04), lifetime allergic rhinitis (p = 0.002), and current allergic rhinitis (p = 0.004) were significantly higher in patients than TEC on bivariate analysis. On multivariate analysis, rates of current atopy (Cohen's d = 0.26, p = 0.04) and current allergic rhinitis (Cohen's d = 0.34, p = 0.012) were significantly higher in patients with PTSD than in TEC. Current eczema (p = 0.24), current asthma (p = 0.26), and allergies (p = 0.59) were not associated with PTSD. CONCLUSIONS: Rates of atopy are higher in participants with PTSD than TEC, and this effect is related to higher rates of allergic rhinitis. Further studies are needed to elucidate the pathways linking allergic rhinitis and PTSD.

RNA-seq analysis of gene expression profiles in posttraumatic stress disorder, Parkinson's disease and schizophrenia identifies roles for common and distinct biological pathways.

Evidence suggests that shared pathophysiological mechanisms in neuropsychiatric disorders (NPDs) may contribute to risk and resilience. We used single-gene and network-level transcriptomic approaches to investigate shared and disorder-specific processes underlying posttraumatic stress disorder (PTSD), Parkinson's disease (PD) and schizophrenia in a South African sample. RNA-seq was performed on blood obtained from cases and controls from each cohort. Gene expression and weighted gene correlation network analyses (WGCNA) were performed using DESeq2 and CEMiTool, respectively. Significant differences in gene expression were limited to the PTSD cohort. However, WGCNA implicated, amongst others, ribosomal expression, inflammation and ubiquitination as key players in the NPDs under investigation. Differential expression in ribosomal-related pathways was observed in the PTSD and PD cohorts, and focal adhesion and extracellular matrix pathways were implicated in PD and schizophrenia. We propose that, despite different phenotypic presentations, core transdiagnostic mechanisms may play important roles in the molecular aetiology of NPDs.

Exploring the relationship between the gut microbiome and mental health outcomes in a posttraumatic stress disorder cohort relative to trauma-exposed controls.

Posttraumatic stress disorder (PTSD) imposes a significant burden on patients and communities. Although the microbiome-gut-brain axis has been proposed as a mediator or moderator of PTSD risk and persistence of symptoms, clinical data directly delineating the gut microbiome's relationship to PTSD are sparse. This study investigated associations between the gut microbiome and mental health outcomes in participants with PTSD (n = 79) and trauma-exposed controls (TECs) (n = 58). Diagnoses of PTSD, major depressive disorder (MDD), and childhood trauma were made using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), MINI International Neuropsychiatric Interview (MINI), and Childhood Trauma Questionnaire (CTQ), respectively. Microbial communities from stool samples were profiled using 16S ribosomal RNA gene V4 amplicon sequencing and tested for associations with PTSD-related variables of interest. Random forest models identified a consortium of four genera, i.e.,  a combination of Mitsuokella, Odoribacter, Catenibacterium, and Olsenella, previously associated with periodontal disease, that could distinguish PTSD status with 66.4% accuracy. The relative abundance of this consortium was higher in the PTSD group and correlated positively with CAPS-5 and CTQ scores. MDD diagnosis was also associated with increased relative abundance of the Bacteroidetes phylum. Current use of psychotropics significantly impacted community composition and the relative abundances of several taxa. Early life trauma may prime the microbiome for changes in composition that facilitate a pro-inflammatory cascade and increase the risk of development of PTSD. Future studies should rigorously stratify participants into healthy controls, TECs, and PTSD (stratified by psychotropic drug use) to explore the role of the oral-gut-microbiome-brain axis in trauma-related disorders.

Childhood trauma, the stress response and metabolic syndrome: A focus on DNA methylation.

Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and well-being. The methylome regulates the transcription of genes involved in the stress response, metabolism and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506-binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT-associated MetS risk.

Disentangling sex differences in the shared genetic architecture of posttraumatic stress disorder, traumatic experiences, and social support with body size and composition.

There is a well-known association of traumatic experiences and posttraumatic stress disorder (PTSD) with body size and composition, including consistent differences between sexes. However, the biology underlying these associations is unclear. To understand the genetic underpinnings of this complex relationship, we investigated genome-wide datasets informative of African and European ancestries from the Psychiatric Genomic Consortium, the UK Biobank, the GIANT Consortium, and the Million Veteran Program. We used genome-wide association statistics to estimate sex-specific genetic correlations (r g ) of traumatic experiences, social support, and PTSD with multiple anthropometric traits. After multiple testing corrections (false discovery rate, FDR q < 0.05), we observed 58 significant r g relationships in females (e.g., childhood physical abuse and body mass index, BMI r g  = 0.245, p = 3.88 × 10-10) and 21 significant r g relationships in males (e.g., been involved in combat or exposed to warzone and leg fat percentage; r g  = 0.405, p = 4.42 × 10-10). We performed causal inference analyses of these genetic overlaps using Mendelian randomization and latent causal variable approaches. Multiple female-specific putative causal relationships were observed linking body composition/size with PTSD (e.g., leg fat percentage→PTSD; beta = 0.319, p = 3.13 × 10-9), traumatic experiences (e.g., childhood physical abuse→waist circumference; beta = 0.055, p = 5.07 × 10-4), and childhood neglect (e.g., "someone to take you to doctor when needed as a child"→BMI; beta = -0.594, p = 1.09 × 10-5). In males, we observed putative causal effects linking anthropometric-trait genetic liabilities to traumatic experiences (e.g., BMI→childhood physical abuse; beta = 0.028, p = 8.19 × 10-3). Some of these findings were replicated in individuals of African descent although the limited sample size available did not permit us to conduct a sex-stratified analysis in this ancestry group. In conclusion, our findings provide insights regarding sex-specific causal networks linking anthropometric traits to PTSD, traumatic experiences, and social support.

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.

A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population.

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10-6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke's pseudo R 2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R 2 = 0.00856, p = 0.0367) and PCL-5 score (R 2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke's pseudo R 2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

The 5-HTTLPR-rs25531 S-A-S-A Haplotype and Chronic Stress Moderate the Association Between Acute Stress and Internalizing Mental Disorders Among HIV+ Children and Adolescents in Uganda.

Background: Internalizing mental disorders (IMDs) among HIV-positive (HIV+) children and adolescents are associated with poor disease outcomes, such as faster HIV disease progression. Although it has been suggested that the development of IMDs is moderated by interaction of stressful life events and vulnerability factors, the underlying etiology is largely unknown. Serotonin transporter gene [solute carrier family 6 member A4 (SLC6A4)] and human tryptophan hydroxylase 2 gene (TPH2) polymorphisms have been implicated in the development of IMDs. This study investigated the association between acute stress and IMDs, and moderation by chronic stress and genetic variants in SLC6A4 and TPH2. Hypothesis: Acute stress acts through genetic and environmental vulnerability factors to increase the risk of developing IMDs. Methods: Polymorphisms in SLC6A4 (5-HTTLPR, rs25531, 5-HTTLPR-rs25531, and STin2 VNTR) and TPH2 (rs1843809, rs1386494, rs4570625, and rs34517220) were genotyped in 368 HIV+ children and adolescents (aged 5-17 years) with any internalizing mental disorder (depression, anxiety disorders, or posttraumatic stress disorder), and 368 age- and sex-matched controls, who were also HIV+. Chronic and acute stress categories were derived by hierarchical cluster analysis. Logistic regression analysis was used to assess the independent moderating effect of chronic stress and each selected polymorphism on the association between acute stress and IMDs. Results: We observed a statistically significant association between severe acute stress and IMDs (p = 0.001). Children and adolescents who experienced severe acute stress were twice as likely to develop IMDs, compared to children and adolescents who experienced mild acute stress (p = 0.001). Chronic stress interacted with severe acute stress to increase the risk of IMDs (p = 0.033). Acute stress was found to interact with 5-HTTLPR-rs25531 S-A-S-A haplotype to increase the risk for IMDs among Ugandan HIV+ children and adolescents (p = 0.049). We found no evidence for a combined interaction of acute stress, chronic stress, and 5-HTTLPR-rs25531 on IMDs. Conclusion: The odds of having an internalizing mental disorder (IMD) were higher among HIV+ children and adolescents who experienced severe acute stress compared to HIV+ children and adolescents who experienced mild acute stress. Chronic stress and 5-HTTLPR-rs25531 independently moderated the association between acute stress and IMDs.

TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda.

BACKGROUND: Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years). RESULTS: We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months. CONCLUSIONS: TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.

Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support.

Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg = 0.16, p = 0.026) and traits related to traumatic events, and the presence of social support (-0.28 < rg < 0.20; p < 0.008). We observed a bidirectional association between CRP and PTSD (CRP → PTSD: ß = 0.065, p = 0.015; PTSD → CRP: ß = 0.008, p = 0.009). CRP also showed a negative association with the "felt loved as a child" trait (UKB, ß = -0.017, p = 0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: ß = -0.22, p = 1.57 × 10-7; multivariate MR: ß = -0.17, p = 0.005) and deprivation index (univariate MR: ß = 0.38, p = 1.63 × 10-9; multivariate MR: ß = 0.27, p = 0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.

DNA methylation and psychotherapy response in trauma-exposed men with appetitive aggression.

Exposure to violence can lead to appetitive aggression (AA), the positive feeling and fascination associated with violence, and posttraumatic stress disorder (PTSD), characterised by hyperarousal, reexperience and feelings of ongoing threat. Psychotherapeutic interventions may act via DNA methylation, an environmentally sensitive epigenetic mechanism that can influence gene expression. We investigated epigenetic signatures of psychotherapy for PTSD and AA symptoms in South African men with chronic trauma exposure. Participants were assigned to one of three groups: narrative exposure therapy for forensic offender rehabilitation (FORNET), cognitive behavioural therapy or waiting list control (n = 9-10/group). Participants provided saliva and completed the Appetitive Aggression Scale and PTSD Symptom Severity Index at baseline, 8-month and 16-month follow-up. The relationship, over time, between methylation in 22 gene promoter region sites, symptom scores, and treatment was assessed using linear mixed models. Compared to baseline, PTSD and AA symptom severity were significantly reduced at 8 and 16 months, respectively, in the FORNET group. Increased methylation of genes implicated in dopaminergic neurotransmission (NR4A2) and synaptic plasticity (AUTS2) was associated with reduced PTSD symptom severity in participants receiving FORNET. Analyses across participants revealed a proportional relationship between AA and methylation of TFAM, a gene involved in mitochondrial biosynthesis.

Shedding Light on the Transcriptomic Dark Matter in Biological Psychiatry: Role of Long Noncoding RNAs in D-cycloserine-Induced Fear Extinction in Posttraumatic Stress Disorder.

Biological psychiatry scholarship on posttraumatic stress disorder (PTSD) is making strides with new omics technologies. In this context, there is growing recognition that noncoding RNAs are vital for the regulation of gene and protein expression. Long noncoding RNAs (lncRNAs) can modulate splicing, influence RNA editing, messenger RNA (mRNA) stability, translation activation, and microRNA-mRNA interactions, are highly abundant in the brain, and have been implicated in neurodevelopmental disorders. The largest subclass of lncRNAs is long intergenic noncoding RNAs (lincRNAs). We report on lincRNAs and their predicted mRNA targets associated with fear extinction induced by co-administration of D-cycloserine and behavioral fear extinction in a PTSD animal model. Forty-three differentially expressed lincRNAs and 190 differentially expressed mRNAs were found to be associated with fear extinction. Eight lincRNAs were predicted to interact with and regulate 108 of these mRNAs, while seven lincRNAs were predicted to interact with 22 of their pre-mRNA transcripts. Based on the functions of their target mRNAs, we inferred that these lincRNAs bind to nucleotides, ribonucleotides, and proteins; subsequently influence nervous system development, morphology, and immune system functioning; and could be associated with nervous system and mental health disorders. We found the quantitative trait loci that overlapped with fear extinction-related lincRNAs included traits such as serum corticosterone level, neuroinflammation, anxiety, stress, and despair-related responses. To the best of our knowledge, this is the first study to identify lincRNAs and their RNA targets with a putative role in transcriptional regulation during fear extinction in the context of an animal model of PTSD.

Natural compulsive-like behaviour in the deer mouse (Peromyscus maniculatus bairdii) is associated with altered gut microbiota composition.

Obsessive-compulsive disorder (OCD) is a psychiatric illness that significantly impacts affected patients and available treatments yield suboptimal therapeutic response. Recently, the role of the gut-brain axis (GBA) in psychiatric illness has emerged as a potential target for therapeutic exploration. However, studies concerning the role of the GBA in OCD are limited. To investigate whether a naturally occurring obsessive-compulsive-like phenotype in a rodent model, that is large nest building in deer mice, is associated with perturbations in the gut microbiome, we investigated and characterised the gut microbiota in specific-pathogen-free bred and housed large (LNB) and normal (NNB) nest-building deer mice of both sexes (n = 11 per group, including three males and eight females). Following baseline characterisation of nest-building behaviour, a single faecal sample was collected from each animal and the gut microbiota analysed. Our results reveal the overall microbial composition of LNB animals to be distinctly different compared to controls (PERMANOVA p < .05). While no genera were found to be significantly differentially abundant after correcting for multiple comparisons, the normal phenotype showed a higher loading of Prevotella and Anaeroplasma, while the OC phenotype demonstrated a higher loading of Desulfovermiculus, Aestuariispira, Peptococcus and Holdemanella (cut-off threshold for loading at 0.2 in either the first or second component of the PCA). These findings not only provide proof-of-concept for continued investigation of the GBA in OCD, but also highlight a potential underlying aetiological association between alterations in the gut microbiota and the natural development of obsessive-compulsive-like behaviours.

The effect of childhood trauma, ApoE genotype and HIV-1 viral protein R variants on change in cognitive performance.

OBJECTIVE: Gene-environment interactions contribute to the development of HIV-associated neurocognitive disorders. We examined whether childhood trauma, apolipoprotein E isoforms and viral protein R (Vpr) variants were associated with change in cognitive performance. Seventy-three seropositive women completed neuropsychological assessments at baseline and 1-year follow-up. We conducted genetic analyses using DNA obtained from blood and calculated risk scores based on Vpr amino acid 37, 41 and 55 variants that were previously associated with cognitive performance. RESULTS: Global cognitive scores declined significantly over the 1-year study period (p = 0.029). A reduction in global cognitive scores was associated with childhood trauma experience (p = 0.039).

Internalizing Mental Disorders and Accelerated Cellular Aging Among Perinatally HIV-Infected Youth in Uganda.

Introduction: Internalizing mental disorders (IMDs) in HIV+ children and adolescents are associated with impaired quality of life and non-adherence to anti-retroviral treatment. Telomere length is a biomarker of cellular aging, and shorter telomere length has been associated with IMDs. However, the nature of this association has yet to be elucidated. Objective: We determined the longitudinal association between IMDs and relative telomere length (rTL) and the influence of chronic stress among Ugandan perinatally HIV-infected youth (PHIY). Methods: IMDs (depressive disorders, anxiety disorders, and post-traumatic stress disorder) and IMDs were assessed using the locally adapted Child and Adolescent Symptom Inventory-5. In 368 PHIY with any IMD and 368 age- and sex-matched PHIY controls without any psychiatric disorder, rTL was assessed using quantitative polymerase chain reaction. Hierarchical cluster analysis was used to generate the three chronic stress classes (mild, moderate, and severe). t-tests were used to assess the difference between baseline and 12 month rTL and the mean difference in rTL between cases and controls both at baseline and at 12 months. Linear regression analysis was used to model the effects of chronic stress on the association between IMDs and rTL, controlling for age and sex. Results: We observed longer rTL among cases of IMDs compared with controls (p < 0.001). We also observed a statistically significant reduction in rTL between baseline and 12 months in the combined sample of cases and controls (p < 0.001). The same statistical difference was observed when cases and controls were individually analyzed (p < 0.001). We found no significant difference in rTL between cases and controls at 12 months (p = 0.117). We found no significant influence of chronic stress on the association between IMDs and rTL at both baseline and 12 months. Conclusion: rTL is longer among cases of IMDs compared with age- and sex-matched controls. We observed a significant attrition in rTL over 12 months, which seems to be driven by the presence of any IMDs. There is a need for future longitudinal and experimental studies to understand the mechanisms driving our findings.