Oxidative stress governs mosquito innate immune signalling to reduce chikungunya virus infection in Aedes-derived cells.

Arboviruses such as chikungunya, dengue and zika viruses cause debilitating diseases in humans. The principal vector species that transmits these viruses is the Aedes mosquito. Lack of substantial knowledge of the vector species hinders the advancement of strategies for controlling the spread of arboviruses. To supplement our information on mosquitoes' responses to virus infection, we utilized Aedes aegypti-derived Aag2 cells to study changes at the transcriptional level during infection with chikungunya virus (CHIKV). We observed that genes belonging to the redox pathway were significantly differentially regulated. Upon quantifying reactive oxygen species (ROS) in the cells during viral infection, we further discovered that ROS levels are considerably higher during the early hours of infection; however, as the infection progresses, an increase in antioxidant gene expression suppresses the oxidative stress in cells. Our study also suggests that ROS is a critical regulator of viral replication in cells and inhibits intracellular and extracellular viral replication by promoting the Rel2-mediated Imd immune signalling pathway. In conclusion, our study provides evidence for a regulatory role of oxidative stress in infected Aedes-derived cells.

A Culturally Adapted Perioperative Mental Health Intervention for Older Black Surgical Patients.

OBJECTIVES: Perioperative mental health of older Black surgical patients is associated with poor surgical outcomes; however, evidence-based perioperative interventions are lacking. Our two study objectives included: first, examine factors affecting perioperative care experiences of older Black surgical patients with mental health problems, and second, ascertain design and implementation requirements for a culturally-adapted perioperative mental health intervention. DESIGN SETTING AND PARTICIPANTS: We conducted six focus groups with older Black patients (n = 15; ≥50 years; surgery within the past 5 years and/or interest in mental health research; history of distress, anxiety, or depression coping with surgery/hospitalization/) from a large academic medical center. We engaged study partners, including interventionists and community members, to gather insights on intervention and implementation needs. We followed a hybrid inductive-deductive thematic approach using open coding and the National Institute on Minority Health and Health Disparities Research Framework. RESULTS: Patients reported that their psychological well-being and long-term mental health outcomes were not appropriately considered during perioperative care. Perceived stressors included interpersonal and structural barriers to using mental healthcare services, clinician treatment biases and ageism in care, and lack of healthcare professional connections/resources. Patients utilized various coping strategies, including talk therapy, faith/spirituality, and family and friends. CONCLUSION: This study offers valuable insights into the experiences of older Black surgical patients and the critical elements for developing a personalized perioperative mental health intervention to support their well-being before, during, and after surgery. Our findings demonstrated a need for a patient-centered and culturally adapted intervention targeting the individual/behavioral and interpersonal levels. Informed by the cultural adaptation framework, we propose a multi-component intervention that integrates psychological and pharmacological components.

Sympathetic nervous system functioning during the face-to-face still-face paradigm in the first year of life.

Contemporary theories of early development and emerging child psychopathology all posit a major, if not central role for physiological responsiveness. To understand infants' potential risk for emergent psychopathology, consideration is needed to both autonomic reactivity and environmental contexts (e.g., parent-child interactions). The current study maps infants' arousal during the face-to-face still-face paradigm using skin conductance (n = 255 ethnically-diverse mother-infant dyads; 52.5% girls, mean infant age = 7.4 months; SD = 0.9 months). A novel statistical approach was designed to model the potential build-up of nonlinear counter electromotive force over the course of the task. Results showed a significant increase in infants' skin conductance between the Baseline Free-play and the Still-Face phase, and a significant decrease in skin conductance during the Reunion Play when compared to the Still-Face phase. Skin conductance during the Reunion Play phase remained significantly higher than during the Baseline Play phase; indicating that infants had not fully recovered from the mild social stressor. These results further our understanding of infant arousal during dyadic interactions, and the role of caregivers in the development of emotion regulation during infancy.

Child Maltreatment and Long-Term Physical and Mental Health Outcomes: An Exploration of Biopsychosocial Determinants and Implications for Prevention.

Child maltreatment rates remain unacceptably high and rates are likely to escalate as COVID-related economic problems continue. A comprehensive and evidence-building approach is needed to prevent, detect and intervene where child maltreatment occurs. This review identifies key challenges in definitions, overviews the latest data on prevalence rates, reviews risk and protective factors, and examines common long-term mental health outcomes for children who experience maltreatment. The review takes a systems approach to child maltreatment outcomes through its focus on the overall burden of disease, gene-environment interactions, neurobiological mechanisms and social ecologies linking maltreatment to mental ill-health. Five recommendations relating to the accurate measurement of trends, research on brain structures and processes, improving the reach and impact of teleservices for detecting, preventing and treating child maladjustment, community-based approaches, and building population-focused multidisciplinary alliances and think tanks are presented.

Towards Preventative Psychiatry: Concurrent and Longitudinal Predictors of Postnatal Maternal-Infant Bonding.

Maternal-infant bonding is important for children's positive development. Poor maternal-infant bonding is a risk factor for negative mother and infant outcomes. Although researchers have examined individual predictors of maternal-infant bonding, studies typically do not examine several concurrent and longitudinal predictors within the same model. This study aimed to evaluate the unique and combined predictive power of cross-sectional and longitudinal predictors of maternal-infant bonding. Participants were 372 pregnant women recruited from an Australian hospital. Data were collected from mothers at antenatal appointments (T0), following their child's birth (T1), and at a laboratory assessment when their child was 5-11-months-old (T2). Poorer bonding at T2 was predicted at T0 by younger maternal age, higher education, and higher antenatal depressive symptoms. Poorer bonding at T2 was predicted at T1 by younger maternal age, higher education, and higher postnatal depressive symptoms. Poorer bonding at T2 was predicted at T2 by younger maternal age, higher education, higher postnatal depression symptoms, higher concurrent perceived social support, and more difficult infant temperament, when controlling for child age at T2. To promote positive maternal-infant bonding, global and targeted interventions in the perinatal period may benefit from targeting maternal psychopathology, perceived lack of social support, and coping with difficult infant temperament.

Learning to like triangles: A longitudinal investigation of evaluative conditioning in infancy.

There is tentative evidence that infants can learn preferences through evaluative conditioning to socioemotional stimuli. However, the early development of evaluative conditioning and the factors that may explain infants' capacity to learn through evaluative conditioning are not well understood. Infants (N = 319; 50.2% boys) participated in a longitudinal study where an evaluative conditioning paradigm using socioemotional stimuli was conducted on two occasions (when infants were 7 and 14 months old, on average). We tested whether repeatedly pairing neutral stimuli (triangular and square shapes) with affective stimuli (angry and happy faces) affects infants' preferences for these shapes. At both timepoints, the majority of infants did not choose the shape that was paired with happy faces, indicating that, in general, learning through evaluative conditioning was not present. However, as expected, individual differences were evident such that infants who spent more time fixating on faces compared to shapes (face-preferrers) during the conditioning trials were significantly more likely than non-face-preferrers to choose the shape paired with happy faces, and this effect strengthened with increasing age.

Still connecting the dots: An investigation into infants' attentional bias to threat using an eye-tracking task.

An attentional bias toward threat has been theorized to be a normative aspect of infants' threat and safety learning, and an indicator of risk for internalizing psychopathology in older populations. To date, only four studies have examined this bias using the dot-probe task in infancy and the findings are mixed. We extended the literature by examining patterns of attention to threat in a culturally and linguistically diverse sample of infants aged 5-11 months old (N = 151) using all measures previously employed in the infant dot-probe literature. Given that an attentional bias toward threat is associated with higher risk of developing anxiety disorders later in life, we also examined how negative affect-an early correlate of later anxiety disorders-is related to attentional bias toward threat in infancy. This study was the first to use a consistent measure of negative affect across the whole sample. An eye-tracking dot-probe task was used to examine attentional bias toward threat (i.e., angry faces) relative to positive (i.e., happy faces) stimuli. Results showed that an attention bias to threat was not characteristic of infants at this age, and negative affect did not moderate the putative relationship between attention and emotional faces (angry, happy). These findings therefore suggest that attention biases to socio-emotional threat may not have emerged by 11 months old.

Comparison of effect of etomidate with propofol on hemodynamics during modified electroconvulsive therapy.

Background and Aims: Studies comparing the effect of propofol and etomidate on hemodynamic parameters during electroconvulsive therapy (ECT) have shown ambiguous results. Although some studies observed a larger increase in blood pressure and heart rate during the use of etomidate than propofol in ECT, whereas some studies have shown no difference in hemodynamic parameters with the use of etomidate or propofol. Most of the studies done to compare the hemodynamic effects of etomidate and propofol were limited by small sample size or retrospective in nature. Therefore, we conducted a prospective randomized trial to compare the effects of etomidate and propofol on hemodynamics during ECT. Material and Methods: A prospective randomized crossover study was conducted on 30 patients with American Society of Anesthesiologist physical status I and II, between age 18 and 65 years, suffering from a mental disorder as per International Classification of Diseases-10 and requiring bilateral ECT as per clinical decision of consultant psychiatrist. They were randomized to receive both the drugs for their successive ECT sessions and were subjected to evaluation after clubbing together the ECT sessions of propofol or etomidate as anesthetic agent. Results: Duration of motor seizures was significantly more in patients receiving etomidate, whereas patients receiving propofol had more stable hemodynamics. Conclusion: Though propofol maintains stable hemodynamics during MECT, yet clinical applicability of etomidate outstrips it by a reasonable margin due to its better effect on seizure parameters.

Genetic analysis of endometriosis and depression identifies shared loci and implicates causal links with gastric mucosa abnormality.

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10-4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10-27). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10-8), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCPgene < 2.75 × 10-6). Genes with a nominal gene-based association (Pgene < 0.05) were significantly enriched across endometriosis and depression (Pbinomial-test = 2.90 × 10-4). Also, genes overlapping the two traits at Pgene < 0.1 (Pbinomial-test = 1.31 × 10-5) were significantly enriched for the biological pathways 'cell-cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation.

A Systematic Review of DNA Methylation and Gene Expression Studies in Posttraumatic Stress Disorder, Posttraumatic Growth, and Resilience.

Most people will experience a traumatic event within their lifetime. One commonly recognized response to trauma exposure is posttraumatic stress disorder (PTSD). The biological underpinnings of PTSD, including epigenetic mechanisms of DNA methylation and gene expression, have been studied intensively. However, psychological posttrauma responses vary widely and can include positive outcomes, such as posttraumatic growth (PTG) and, more commonly, resilience. The aim of this systematic review was to summarize the current DNA methylation and gene expression data with respect to three potential posttrauma responses: PTSD, PTG, and resilience. A literature search identified 486 studies, 51 of which were deemed eligible for inclusion (total N = 10,633). All included studies examined PTSD and consistently implicated DNA methylation and gene expression changes in hypothalamic-pituitary-adrenal axis and inflammatory genes. Ten studies acknowledged resilience as a posttrauma response, but only two studies examined epigenetics and gene expression using a scale to measure resilience. Low resilience was associated with gene expression patterns in immune and dopamine genes, and high resilience was associated with a blunted inflammatory response. No studies examined epigenetic or gene expression changes associated with PTG. These findings highlight a focus on pathogenic research, which has failed to adequately acknowledge and measure positive posttrauma outcomes of PTG and resilience. Future research should examine DNA methylation and gene expression changes associated with PTG and resilience in addition to PTSD in order to gain a more comprehensive picture of an individual's well-being following exposure to trauma.

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis.

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins' functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study.

BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations. AIM: Testing if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes. METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa. RESULTS: Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up. CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers. DECLARATION OF INTEREST: V.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.

Quantifying between-cohort and between-sex genetic heterogeneity in major depressive disorder.

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

An integrated -omics analysis of the epigenetic landscape of gene expression in human blood cells.

BACKGROUND: Gene expression can be influenced by DNA methylation 1) distally, at regulatory elements such as enhancers, as well as 2) proximally, at promoters. Our current understanding of the influence of distal DNA methylation changes on gene expression patterns is incomplete. Here, we characterize genome-wide methylation and expression patterns for ~ 13 k genes to explore how DNA methylation interacts with gene expression, throughout the genome. RESULTS: We used a linear mixed model framework to assess the correlation of DNA methylation at ~ 400 k CpGs with gene expression changes at ~ 13 k transcripts in two independent datasets from human blood cells. Among CpGs at which methylation significantly associates with transcription (eCpGs), > 50% are distal (> 50 kb) or trans (different chromosome) to the correlated gene. Many eCpG-transcript pairs are consistent between studies and ~ 90% of neighboring eCpGs associate with the same gene, within studies. We find that enhancers (P < 5e-18) and microRNA genes (P = 9e-3) are overrepresented among trans eCpGs, and insulators and long intergenic non-coding RNAs are enriched among cis and distal eCpGs. Intragenic-eCpG-transcript correlations are negative in 60-70% of occurrences and are enriched for annotated gene promoters and enhancers (P < 0.002), highlighting the importance of intragenic regulation. Gene Ontology analysis indicates that trans eCpGs are enriched for transcription factor genes and chromatin modifiers, suggesting that some trans eCpGs represent the influence of gene networks and higher-order transcriptional control. CONCLUSIONS: This work sheds new light on the interplay between epigenetic changes and gene expression, and provides useful data for mining biologically-relevant results from epigenome-wide association studies.

Lymphocytic choriomeningitis virus infection of dendritic cells interferes with TLR-induced IL-12/IL-23 cytokine production in an IL-10 independent manner.

Dendritic cells produce IL-12 and IL-23 in response to viral and bacterial infection and these cytokines are responsible for successful pathogen clearance. How sequential viral and bacterial infections affect the production of IL-12 and IL-23 is currently not known. Our study demonstrates that in dendritic cells infected with Lymphocytic choriomeningitis virus (LCMV), TLR activation with bacterial PAMPs resulted in reduced IL-12 and IL-23 expression compared to non-infected cells. Furthermore, expression of other proinflammatory cytokines, TNF-α and IL-6, were not inhibited under these conditions. We discovered that TLR-induced phosphorylation of p38 was significantly inhibited in LCMV-infected cells. We detected enhanced expression of suppressor of cytokine signalling (SOCS)-3 and IL-10. Yet, neutralizing IL-10 did not restore IL-12/IL-23 expression. Taken together, these results show that virus infection interferes with the magnitude of TLR-mediated inflammatory responses by repressing specific cytokine expression.

Transcriptome analysis reveals novel genes and immune networks dysregulated in veterans with PTSD.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a serious condition that emerges following trauma exposure and involves long-lasting psychological suffering and health-issues. Uncovering critical genes and molecular networks is essential to understanding the biology of the disorder. We performed a genome-wide scan to identify transcriptome signatures of PTSD. METHODS: Genome-wide peripheral blood transcriptomic data from 380 service personnel were investigated. This included a discovery sample of 96 Australian Vietnam War veterans and two independent pre and post-deployment replication samples of U.S. Marines (N = 188 and N = 96). RESULTS: A total of 60 transcripts were differentially expressed between veterans with and without PTSD, surviving Bonferroni multiple testing correction. Genes within the cytokine-cytokine receptor interaction, Jak-STAT signaling and Toll-like receptor signaling pathways were enriched. For 49% of the genes, gene expression changes were also accompanied by DNA methylation changes. Using replication data from two U.S. Marine cohorts, we observed that of the differentially expressed genes, 71% genes also showed significant gene expression changes between pre and post-deployment. Weighted gene co-expression networks revealed two modules of genes associated with PTSD. The first module (67 genes, p-value = 6e-4) was enriched for genes within the 11p13 locus including BDNF. The second module (266 genes, p-value = 0.01) was enriched for genes in 17q11 including SLC6A4, STAT5A and STAT5B. CONCLUSIONS: We identified novel transcriptomic loci and biological pathways for PTSD in service personnel. Network analysis revealed enrichment of loci harboring key candidate genes in PTSD. These findings highlight the role of transcriptional biomarkers in the molecular etiology of PTSD.

Clinically proven drug targets differentially expressed in the prefrontal cortex of schizophrenia patients.

BACKGROUND: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner. METHODS: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls. RESULTS: We identified 1146 genes that were differentially expressed in schizophrenia, approximately 60% of which were up-regulated and 366 of 1146 (32%) also have aberrant DNA methylation (p=2.46×10-39). The differentially expressed genes were significantly overrepresented in several pathways including inflammatory (p=8.7×10-3) and nitric oxide pathways (p=9.2×10-4). Moreover, these genes were significantly enriched for those with a druggable genome (p=0.04). We identified a number of genes that are significantly up-regulated in schizophrenia as confirmed in other gene expression studies using different brain tissues. Of the 349 genes associated with schizophrenia from the Psychiatric Genomics Consortium we identified 16 genes that are significant from our list of differentially expressed genes. CONCLUSIONS: Our results identified biological functional genes that are differentially expressed in schizophrenia. A subset of these genes are clinically proven drug targets. We also found a strong pattern of differentially expressed immune response genes that may reflect an underlying defect in schizophrenia.

Genetic and serum biomarker evidence for a relationship between TNFα and PTSD in Vietnam war combat veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased inflammation and comorbid medical conditions. However, study findings for individual inflammatory marker levels have been inconsistent. Some research suggests that resilience may play a role in decreased inflammation. A polymorphism in the promoter region of the tumor necrosis factor α gene (TNFα), TNFA -308 (rs1800629) is associated with psychiatric illness but its role in PTSD is yet to be elucidated. OBJECTIVE: This study investigates a key inflammatory marker, TNFα, for its role in PTSD severity. METHOD: In a cohort of trauma-exposed Vietnam War veterans (n=299; 159 cases, 140 controls) TNF α serum levels and TNFα polymorphism rs1800629 were correlated with PTSD severity and resilience scores. RESULTS: The polymorphism was associated with PTSD severity (p=0.045). There were significant group differences between cases and controls with regards to serum TNFα levels (p=0.036). Significant correlations were found between PTSD severity and elevated TNFα levels (r=0.153; p=0.009), and between resilience and decreased TNFα levels at a trend level (p=0.08) across the entire cohort. These relationships were non-significant after controlling for covariates. In the PTSD diagnostic group, a correlation of TNFα and PTSD severity was observed on a trend level (p=0.06), the relationship between TNFα and resilience remained non-significant. CONCLUSIONS: To our knowledge, this is the first time rs1800629 has been investigated in PTSD contributing to a growing body of literature that identifies the GG as a risk genotype for psychiatric disorders in Caucasian cohorts. However, more research is needed to replicate our results in larger, equally well-characterized cohorts. The relationship between serum TNFα levels and PTSD severity and resilience requires further investigation.

Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder.

Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.

Genetic Regulation of Maternal Oxytocin Response and Its Influences on Maternal Behavior.

We interrogated the genetic modulation of maternal oxytocin response and its association with maternal behavior using genetic risk scores within the oxytocin receptor (OXTR) gene. We identified a novel SNP, rs968389, to be significantly associated with maternal oxytocin response after a challenging mother-infant interaction task (Still Face Paradigm) and maternal separation anxiety from the infant. Performing a multiallelic analysis across OXTR by calculating a cumulative genetic risk score revealed a significant gene-by-environment (G × E) interaction, with OXTR genetic risk score interacting with adult separation anxiety to modulate levels of maternal sensitivity. Mothers with higher OXTR genetic risk score and adult separation anxiety showed significantly reduced levels of maternal sensitivity during free play with the infant. The same G × E interaction was also observed for the extended OXTR cumulative genetic risk score that included rs968389. Moreover, the extended cumulative OXTR genetic risk score itself was found to be significantly associated with maternal separation anxiety as it specifically relates to the infant. Our results suggest a complex montage of individual and synergistic genetic mediators of maternal behavior. These findings add to specific knowledge about genetic regulation of maternal oxytocin response in relation to maternal adjustment and infant bonding through the first few months of life.