Differential microRNA expression in adolescent anxiety proneness.

Biological mechanisms underlying anxiety proneness (AP), the tendency to react fearfully to stressors due to the belief that experiencing anxiety has harmful consequences, remain unclear. Epigenetic mechanisms, such as microRNAs (small, non-coding RNAs 19-20 nucleotides long), may be contributory. This study investigated AP-associated differences in microRNA expression among South African adolescents with variable exposure to childhood trauma (CT). AP was assessed using a composite score reflecting trait anxiety and anxiety sensitivity, while CT exposure was assessed with the Childhood Trauma Questionnaire. High-quality total RNA (n = 88) extracted from whole blood underwent microRNA-sequencing. Differential microRNA expression analysis was conducted with DESeq2 in R, messenger RNA target prediction analysis was performed using TargetScan and DIANA-microT, and the DIANA mirPATH tool was used for KEGG pathway analysis. The majority of participants were female (75.86%) with an average age of 15 (±1.19) years. MicroRNA expression analysis identified upregulation of hsa-miR-28-5p and downregulation of hsa-miR-502-3p and hsa-miR-500a-3p in high-AP individuals, irrespective of CT. Four KEGG pathways, each with ≥10% of their constituent genes predicted to be targets of the differentially expressed microRNAs, were identified and were enriched for genes involved in calcineurin and glutamate signalling. These findings suggest that epigenetically mediated effects on neuronal function contribute to the molecular aetiology of AP.

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.

Short-read full-length 16S rRNA amplicon sequencing for characterisation of the respiratory bacteriome of captive and free-ranging African elephants (Loxodonta africana).

Hypervariable region sequencing of the 16S ribosomal RNA (rRNA) gene plays a critical role in microbial ecology by offering insights into bacterial communities within specific niches. While providing valuable genus-level information, its reliance on data from targeted genetic regions limits its overall utility. Recent advances in sequencing technologies have enabled characterisation of the full-length 16S rRNA gene, enhancing species-level classification. Although current short-read platforms are cost-effective and precise, they lack full-length 16S rRNA amplicon sequencing capability. This study aimed to evaluate the feasibility of a modified 150 bp paired-end full-length 16S rRNA amplicon short-read sequencing technique on the Illumina iSeq 100 and 16S rRNA amplicon assembly workflow by utilising a standard mock microbial community and subsequently performing exploratory characterisation of captive (zoo) and free-ranging African elephant (Loxodonta africana) respiratory microbiota. Our findings demonstrate that, despite generating assembled amplicons averaging 869 bp in length, this sequencing technique provides taxonomic assignments consistent with the theoretical composition of the mock community and respiratory microbiota of other mammals. Tentative bacterial signatures, potentially representing distinct respiratory tract compartments (trunk and lower respiratory tract) were visually identified, necessitating further investigation to gain deeper insights into their implication for elephant physiology and health.

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.

Exploring the influence of stress on aggressive behavior and sexual function: Role of neuromodulator pathways and epigenetics.

Stress is a complex and multifaceted phenomenon that can significantly influence both aggressive behavior and sexual function. This review explores the intricate relationship between stress, neuromodulator pathways, and epigenetics, shedding light on the various mechanisms that underlie these connections. While the role of stress in both aggression and sexual behavior is well-documented, the mechanisms through which it exerts its effects are multifarious and not yet fully understood. The review begins by delving into the potential influence of stress on the Hypothalamic-Pituitary-Adrenal (HPA) axis, glucocorticoids, and the neuromodulators involved in the stress response. The intricate interplay between these systems, which encompasses the regulation of stress hormones, is central to understanding how stress may contribute to aggressive behavior and sexual function. Several neuromodulator pathways are implicated in both stress and behavior regulation. We explore the roles of norepinephrine, serotonin, oxytocin, and androgens in mediating the effects of stress on aggression and sexual function. It is important to distinguish between general sexual behavior, sexual motivation, and the distinct category of "sexual aggression" as separate constructs, each necessitating specific examination. Additionally, epigenetic mechanisms emerge as crucial factors that link stress to changes in gene expression patterns and, subsequently, to behavior. We then discuss how epigenetic modifications can occur in response to stress exposure, altering the regulation of genes associated with stress, aggression, and sexual function. While numerous studies support the association between epigenetic changes and stress-induced behavior, more research is necessary to establish definitive links. Throughout this exploration, it becomes increasingly clear that the relationship between stress, neuromodulator pathways, and epigenetics is intricate and multifaceted. The review emphasizes the need for further research, particularly in the context of human studies, to provide clinical significance and to validate the existing findings from animal models. By better understanding how stress influences aggressive behavior and sexual function through neuromodulator pathways and epigenetic modifications, this research aims to contribute to the development of innovative protocols of precision medicine and more effective strategies for managing the consequences of stress on human behavior. This may also pave way for further research into risk factors and underlying mechanisms that may associate stress with sexual aggression which finds application not only in neuroscience, but also law, ethics, and the humanities in general.

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.

Prospective Association of Circulating Adipokines with Cardiometabolic Risk Profile Among Women: The Rape Impact Cohort Evaluation Study.

Background: Sexual violence is associated with poor cardiometabolic outcomes, yet the etiopathogenic pathways remain unclear. Adipokines may contribute to pathways in the development of cardiometabolic disease (CMD), including in vulnerable populations. Further investigation of adipokines among sexually traumatized individuals may inform cardiometabolic screening. This study aimed to investigate the association between circulating adipokines, metabolic syndrome (MetS), and longitudinal change in MetS components (namely abdominal obesity, blood pressure, lipid profile, and glycemic status) over a 1-year period in a cohort of rape exposed (RE) and rape unexposed (RUE) females. Materials and Methods: Seven hundred seventy-eight RE and 617 RUE black South African women aged 18-40 years were recruited for the Rape Impact Cohort Evaluation study. Nonfasting blood samples were analyzed for cardiometabolic variables and adipokine levels using enzyme-linked immunosorbent assay. Serum adiponectin was measured in both RE and RUE and resistin, leptin, and leptin/adiponectin (L/A) ratio in RE only. Associations between baseline serum adipokines, MetS, and its components were assessed at baseline and follow-up using adjusted linear and logistic regressions. Results: In the RE group, adiponectin, leptin, and L/A ratio were significantly associated with MetS prevalence cross-sectionally (all p ≤ 0.001). No adipokine marker was related to incident MetS at 12-month follow-up. In the RE group, significant longitudinal associations with high-density lipoprotein cholesterol were shown for adiponectin (ß = 0.146 [0.064], p = 0.022) and leptin (ß = 0.001 [0.002], p = 0.012). Conclusions: Findings suggest that adipokines may have a potential role as biomarkers to identify RE individuals at high risk for CMD.

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.

Prenatal maternal stress and offspring aggressive behavior: Intergenerational and transgenerational inheritance.

Even though studies have shown that prenatal maternal stress is associated with increased reactivity of the HPA axis, the association between prenatal maternal stress and fetal glucocorticoid exposure is complex and most likely dependent on unidentified and poorly understood variables including nature and timing of prenatal insults. The precise mechanisms in which prenatal maternal stress influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. The aim of this review article is to bring comprehensive basic concepts about prenatal maternal stress and mechanisms of transmission of maternal stress to the fetus. This review covers recent studies showing associations between maternal stress and alterations in offspring aggressive behavior, as well as the possible pathways for the "transmission" of maternal stress to the fetus: (1) maternal-fetal HPA axis dysregulation; (2) intrauterine environment disruption due to variations in uterine artery flow; (3) epigenetic modifications of genes implicated in aggressive behavior. Here, we present evidence for the phenomenon of intergenerational and transgenerational transmission, to better understands the mechanism(s) of transmission from parent to offspring. We discuss studies showing associations between maternal stress and alterations in offspring taking note of neuroendocrine, brain architecture and epigenetic changes that may suggest risk for aggressive behavior. We highlight animal and human studies that focus on intergenerational transmission following exposure to stress from a biological mechanistic point of view, and maternal stress-induced epigenetic modifications that have potential to impact on aggressive behavior in later generations.

Serum adiponectin-levels are predictive of probable posttraumatic stress disorder in women.

Background: Accumulative evidence indicates a role for adiponectin, a polypeptide secreted by adipose tissue, in the pathophysiology of posttraumatic disorder (PTSD) via metabolic and inflammatory pathways. This study examined adiponectin as a potential predictive biomarker for PTSD among female rape survivors. Methods: We evaluated the relationship of baseline serum adiponectin levels to the development of probable PTSD at 3- and 6-months post rape-exposure and compared adiponectin levels between 542 rape-exposed (RE) and 593 rape-unexposed women (RUE). Probable PTSD were defined as Davidson Trauma Scale score ≥40. Data were analysed using multivariate regression models and a generalized estimating equation (GEE) model. We adjusted for clinically relevant covariates associated with PTSD, as well as adiposity indices. Results: Participants who were in the mid-and high adiponectin tertile groups versus the lowest tertile group had a significantly reduced risk of probable PTSD among at 6 months follow-up, independent of adiposity(aOR = 0.45[0.22-1.05], p = 0.035; aOR = 0.44[0.22-0.90], p = 0.024). However, there was no effect of group (RE vs. RUE). Limitations: Adiponectin assays were conducted on non-fasting blood samples and information on chronic medication, dietary factors and levels of physical activity were not collected. There was a high attrition rate among rape exposed participants. Conclusions: Our results show that higher serum adiponectin levels are associated with reduced risk of probable PTSD over a 6-month period. This finding supports the hypothesis that serum adiponectin is a potential risk biomarker for PTSD.

Adiponectin gene polymorphisms and posttraumatic stress disorder symptoms among female rape survivors: an exploratory study.

Background: Rape is a common traumatic event which may result in the development of posttraumatic stress disorder (PTSD), yet few studies have investigated risk biomarkers in sexually traumatised individuals. Adiponectin is a novel cytokine within inflammatory and cardiometabolic pathways with evidence of involvement in PTSD. Objective: This prospective exploratory study in a sample of female rape survivors investigated the association of single nucleotide polymorphisms (SNPs) in the adiponectin gene (ADIPOQ) and posttraumatic stress symptom (PTSS) severity, and the interaction of these SNPs of interest with childhood trauma in modifying the association with PTSS severity. Method: The study involved 455 rape-exposed black South African women (mean age (SD), 25.3 years (±5.5)) recruited within 20 days of being raped. PTSS was assessed using the Davidson Trauma Scale (DTS) and childhood trauma was assessed using a modified version of the Childhood Trauma Scale-Short Form Questionnaire. Eight ADIPOQ SNPs (rs17300539, rs16861194, rs16861205, rs2241766, rs6444174, rs822395, rs1501299, rs1403697) were genotyped using KASP. Mixed linear regression models were used to test additive associations of ADIPOQ SNPs and PTSS severity at baseline, 3 and 6 months following rape. Results: The mean DTS score post-sexual assault was high (71.3 ± 31.5), with a decrease in PTSS severity shown over time for all genotypes. rs6444174TT genotype was inversely associated with baseline PTSS in the unadjusted model (ß = -13.6, 95% CI [-25.1; -2.1], p = .021). However, no genotype was shown to be significantly associated with change in PTSS severity over time and therefore ADIPOQ SNP x childhood trauma interaction was not further investigated. Conclusion: None of the ADIPOQ SNPs selected for investigation in this population were shown to be associated with change in PTSS severity over a 6-month period and therefore their clinical utility as risk biomarkers for rape-related PTSD appears limited. These SNPs should be further investigated in possible gene-gene and gene-environment interactions.

Antecedentes: La violación sexual es un evento traumático común que puede resultar en el desarrollo del trastorno de estrés postraumático (TEPT); no obstante, pocos estudios han investigado biomarcadores de riesgo en personas sexualmente traumatizadas. La adiponectina es una citocina recientemente involucrada en vías inflamatorias y cardiometabólicas que tienen evidencia de compromiso en el TEPT.Objetivo: Este estudio prospectivo exploratorio, realizado en una muestra de mujeres sobrevivientes a violación sexual, investigó la asociación entre polimorfismos de nucleótido único (SNPs por sus siglas en inglés) en el gen de la adiponectina (ADIPOQ) y la severidad de los síntomas de estrés postraumático (SEPT), así como también cómo la interacción de estos SNPs sobre el trauma infantil modifica la asociación con la severidad de los SEPT.Método: El estudio incluyó a 455 mujeres sudafricanas de raza negra expuestas a una violación sexual (edad promedio de 25,3 años ± 5,5) reclutadas 20 días después de haber sido violadas sexualmente. Los SEPT se evaluaron empleando la Escala de Trauma de Davidson (DTS por sus siglas en inglés) y el trauma infantil se evaluó empleando una versión modificada de la Escala de Trauma Infantil ­ Cuestionario de versión corta. Se realizó la genotipificación de ocho SNPs del gen ADIPOQ (rs17300539, rs16861194, rs16861205, rs2241766, rs6444174, rs822395, rs1501299, rs1403697) empleando el KASP. Se emplearon modelos de regresión lineal para evaluar las asociaciones aditivas entre los SNPs del gen ADIPOQ y la severidad de los SEPT de base, a los tres y a los seis meses luego de la violación sexual.Resultados: El promedio del puntaje en la DTS luego de una violación sexual fue alto (71,3 ± 31,5) con una disminución en la severidad de los SEPT evidenciada a lo largo del tiempo para todos los genotipos. El genotipo rs6444174TT se encontró inversamente asociado a los SEPT de base en el modelo no ajustado (ß = −13.6, 95% CI [−25.1; −2.1], p = .021). Sin embargo, ningún genotipo mostró estar asociado significativamente con cambios en la severidad de los SEPT a lo largo del tiempo y, por tanto, ya no se investigó la interacción entre los SNPs del gen ADIPOQ y el trauma infantil.Conclusiones: Ninguno de los SNPs del ADIPOQ elegidos para esta investigación mostraron tener alguna asociación entre los cambios en la severidad de los SEPT en un periodo de seis meses y, por tanto, su utilidad clínica como marcadores de riesgo para el TEPT asociado a violación sexual es limitada. Se debería investigar más estos SNPs para evaluar las posibles interacciones gen-gen y gen-ambiente.

Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders.

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire - Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10-4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

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.

Risk and protective factors affecting the symptom trajectory of posttraumatic stress disorder post-rape.

INTRODUCTION: The prevalence of posttraumatic stress disorder (PTSD) in rape survivors is considerably higher than the prevalence in non-sexual trauma survivors. Few studies have investigated risk and protective factors in survivors early-after-rape in a prospective longitudinal design. METHODS: In a sample of 639 rape-exposed women who were assessed within 20 days of rape and over 6 months, baseline data were used to predict PTSD symptom severity scores up to 6 months post-rape. RESULTS: The incidence of PTSD at 3 months was 48.5% and the cumulative incidence at 6 months post-rape was 54.8%. Baseline experience of rape stigma (guilt, shame, self-blame, social devaluation and discredit) and depression were significant predictors of PTSD symptom scores over time, in mixed linear regression models. Higher levels of depression and rape stigma were associated with higher PTSD scores. Assault-related factors were not associated with PTSD scores. LIMITATIONS: We could not measure PTSD symptom trajectories in all rape survivors, some of who may be at greater risk for PTSD e.g. non-disclosing rape survivors, those who declined participation and those who were extremely distressed at the time of recruitment. CONCLUSION: Addressing internalised and externalised stigma and resultant mental health effects on women who present to rape clinics may reduce the long-term adverse effects of rape on mental health outcomes, such as PTSD. Rape survivors who present with high levels of depression soon after a rape should be carefully monitored and appropriately treated in order to reduce PTSD severity.

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.

Associations between telomere length and symptoms of posttraumatic stress disorder and appetitive aggression in trauma-exposed men.

Exposure to community violence is common in South Africa and negatively impacts on biopsychosocial health. Posttraumatic stress disorder (PTSD) is characterised by symptoms of intrusion, avoidance, hypervigilance and negative alterations in cognition and mood, and can develop consequent to trauma exposure. Individuals who repeatedly experience and witness violence may also come to view it as appealing and rewarding. This appetitive aggression (AA) increases the likelihood of perpetrating violence. Telomeres are repetitive nucleotide sequences that protect the ends of chromosomes. Telomere length (TL) attrition is a stress-sensitive marker of biological aging that has been associated with a range of psychiatric disorders. This study investigated the cross-sectional relationship between TL and symptoms of PTSD and AA in South African men residing in areas with high community violence. PTSD and AA symptom severity was assessed in 290 men using the Posttraumatic Stress Disorder Symptom Scale - Interview (PSS-I) and Appetitive Aggression Scale (AAS), respectively. Quantitative polymerase chain reaction was performed on DNA extracted from saliva and used to calculate relative TL (rTL). Regression models were used to assess the relationships between rTL and PSS-I and AAS scores. Network analyses using EBIC glasso methods were performed using rTL and items from each of the AAS and PSS-I measures. Both PSS-I (p = 0.023) and AAS (p = 0.016) scores were positively associated with rTL. Network analyses indicated that rTL was weakly related to two PSS-I and five AAS items but performed poorly on indicators of centrality and was not strongly associated with measure items either directly or indirectly. The positive association between rTL and measures of AA and PTSD may be due to the induction of protective homeostatic mechanisms, which reduce TL attrition, following early life trauma exposure.

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.