Associations between Social Adversity and Biomarkers of Inflammation, Stress, and Aging in Children.

BACKGROUND: Prior work has found relationships between childhood social adversity and biomarkers of stress, but knowledge gaps remain. To help address these gaps, we explored associations between social adversity and biomarkers of inflammation (interleukin-1ß [IL-1ß], IL-6, IL-8, tumor necrosis factor-alpha [TNF-α], and salivary cytokine hierarchical "clusters" based on the three interleukins), neuroendocrine function (cortisol, cortisone, dehydroepiandrosterone, testosterone, and progesterone), neuromodulation (N-arachidonoylethanolamine, stearoylethanolamine, oleoylethanolamide, and palmitoylethanolamide), and epigenetic aging (Pediatric-Buccal-Epigenetic clock). METHODS: We collected biomarker samples of children ages 0-17 recruited from an acute care pediatrics clinic and examined their associations with caregiver-endorsed education, income, social risk factors, and cumulative adversity. We calculated regression-adjusted means for each biomarker and compared associations with social factors using Wald tests. We used logistic regression to predict being in the highest cytokine cluster based on social predictors. RESULTS: Our final sample included 537 children but varied based on each biomarker. Cumulative social adversity was significantly associated with having higher levels of all inflammatory markers and with cortisol, displaying a U-shaped distribution. There were no significant relationships between cumulative social adversity and cortisone, neuromodulation biomarkers or epigenetic aging. CONCLUSION: Our findings support prior work suggesting that social stress exposures contribute to increased inflammation in children. IMPACT: Our study is one of the largest studies examining associations between childhood social adversity and biomarkers of inflammation, neuroendocrine function, neuromodulation, and epigenetic aging. It is one of the largest studies to link childhood social adversity to biomarkers of inflammation, and the first of which we are aware to link cumulative social adversity to cytokine clusters. It is also one of the largest studies to examine associations between steroids and epigenetic aging among children, and one of the only studies of which we are aware to examine associations between social adversity and endocannabinoids among children. CLINICAL TRIAL REGISTRATION: NCT02746393.

Maternal social support during and after pregnancy and child cognitive ability: examining timing effects in two cohorts.

BACKGROUND: Maternal anxiety, depression, and stress during and after pregnancy are negatively associated with child cognitive development. However, the contribution of positive maternal experiences, such as social support, to child cognitive development has received less attention. Furthermore, how maternal experience of social support during specific developmental periods impacts child cognitive development is largely unknown. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 5784) and the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction study (PREDO; n = 420), we investigated the associations between maternal perceived social support during and after pregnancy and child's general cognitive ability at 8 years of age, assessed with the Wechsler Intelligence Scale for Children (WISC). Bayesian relevant life course modeling was used to investigate timing effects of maternal social support on child cognitive ability. RESULTS: In both cohorts, higher maternal perceived social support during pregnancy was associated with higher performance on the WISC, independent of sociodemographic factors and concurrent maternal symptoms of depression and anxiety. In ALSPAC, pregnancy emerged as a sensitive period for the effects of perceived social support on child cognitive ability, with a stronger effect of social support during pregnancy than after pregnancy on child cognitive ability. CONCLUSIONS: Our findings, supported from two prospective longitudinal cohorts, suggest a distinct role of maternal perceived social support during pregnancy for cognitive development in children. Our study suggests that interventions aimed at increasing maternal social support during pregnancy may be an important strategy for promoting maternal and child well-being.

Maternal sensitivity and child internalizing and externalizing behavior: a mediating role for glucocorticoid receptor gene (NR3C1) methylation?

The early caregiving environment can have lasting effects on child mental health. Animal models suggest that glucocorticoid receptor gene (NR3C1) DNA methylation plays a mediating role in linking more responsive caregiving to improved behavioral outcomes by its impact on the stress regulatory system. In this longitudinal study, we examined whether children's NR3C1 methylation levels mediate an effect of maternal sensitivity in infancy on levels of child internalizing and externalizing behavior in a community sample. Maternal sensitivity of 145 mothers was rated at infant age 5 weeks, 12 months, and 30 months by observing mother-infant interactions. Buccal DNA methylation was assessed in the same children at age 6 years and maternal-reported internalizing and externalizing behavior was assessed at age 6 and 10 years. Higher sensitivity at age 5 weeks significantly predicted lower DNA methylation levels at two NR3C1 CpG loci, although methylation levels at these loci did not mediate an effect of maternal sensitivity on levels of child internalizing and externalizing behavior. Overall, the study provides evidence that maternal sensitivity in early infancy is associated with DNA methylation levels at loci involved in stress regulation, but the significance of this finding for child mental health remains unclear.

Biological embedding of experience: A primer on epigenetics.

Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

Maternal prenatal depression is associated with dysregulation over the first five years of life moderated by child polygenic risk for comorbid psychiatric problems.

Dysregulation is a combination of emotion, behavior, and attention problems associated with lifelong psychiatric comorbidity. There is evidence for the stability of dysregulation from childhood to adulthood, which would be more fully characterized by determining the likely stability from infancy to childhood. Early origins of dysregulation can further be validated and contextualized in association with environmental and biological factors, such as prenatal stress and polygenic risk scores (PRS) for overlapping child psychiatric problems. We aimed to determine trajectories of dysregulation from 3 months to 5 years (N = 582) in association with maternal prenatal depression moderated by multiple child PRS (N = 232 pairs with available PRS data) in a prenatal cohort. Mothers reported depression symptoms at 24-26 weeks' gestation and child dysregulation at 3, 6, 18, 36, 48, and 60 months. The PRS were for major depressive disorder, attention deficit hyperactivity disorder, cross disorder, and childhood psychiatric problems. Covariates were biological sex, maternal education, and postnatal depression. Analyses included latent classes and regression. Two dysregulation trajectories emerged: persistently low dysregulation (94%), and increasingly high dysregulation (6%). Stable dysregulation emerged at 18 months. High dysregulation was associated with maternal prenatal depression, moderated by PRS for child comorbid psychiatric problems. Males were at greater risk of high dysregulation.

To what extent do social support and coping strategies mediate the relation between childhood maltreatment and major depressive disorder: A longitudinal community-based cohort.

This study aimed to articulate the roles of social support and coping strategies in the relation between childhood maltreatment (CM) and subsequent major depressive disorder (MDD) with a comprehensive exploration of potential factors in a longitudinal community-based cohort. Parallel and serial mediation analyses were applied to estimate the direct effect (DE) (from CM to MDD) and indirect effects (from CM to MDD through social support and coping strategies, simultaneously and sequentially). Sociodemographic characteristics and genetic predispositions of MDD were considered in the modeling process. A total of 902 participants were included in the analyses. CM was significantly associated with MDD (DE coefficient (ß) = 0.015, 95% confidence interval (CI) = 0.002∼0.028). This relation was partially mediated by social support (indirect ß = 0.004, 95% CI = 0.0001∼0.008) and negative coping (indirect ß = 0.013, 95% CI = 0.008∼0.020), respectively. Social support, positive coping, and negative coping also influenced each other and collectively mediated the association between CM and MDD. This study provides robust evidence that although CM has a detrimental effect on later-on MDD, social support and coping strategies could be viable solutions to minimize the risk of MDD. Intervention and prevention programs should primarily focus on weakening negative coping strategies, then strengthening social support and positive coping strategies.

Epigenetic Age Acceleration and Risk for Posttraumatic Stress Disorder following Exposure to Substantiated Child Maltreatment.

OBJECTIVE: Child maltreatment is among the strongest predictors of posttraumatic stress disorder (PTSD). However, less than 40% of children who have been maltreated are ever diagnosed with PTSD, suggesting that exposure to child maltreatment alone is insufficient to explain this risk. This study examined whether epigenetic age acceleration, a stress-sensitive biomarker derived from DNA methylation, explains variation in PTSD diagnostic status subsequent to child maltreatment. METHOD: Children and adolescents (N = 70; 65.7% female), 8-15 years of age (M = 12.00, SD = 2.37) and exposed to substantiated child maltreatment within the 12 months prior to study entry, were enrolled. Participants provided epithelial cheek cells via buccal swab for genotyping and quantification of epigenetic age acceleration within a case-control design. PTSD diagnostic status was determined using the Child PTSD Symptoms Scale according to the DSM-IV-TR algorithm. RESULTS: Epigenetic age acceleration predicted current PTSD status, revealing an effect size magnitude in the moderate range, OR = 2.35, 95% CI: 1.22- 4.51, after adjusting for sample demographics, polygenic risk for PTSD, and lifetime exposure to other childhood adversities. Supplemental analyses demonstrated that epigenetic age acceleration was related to a greater severity of PTSD arousal symptoms (r =.29, p =.015). There were no differential effects for child maltreatment subtype on epigenetic age acceleration or PTSD status. CONCLUSIONS: The biological embedding of child maltreatment may explain variation in PTSD diagnostic status and serve as a novel approach for informing selective prevention or precision-based therapeutics for those at risk for PTSD.

Salivary cytokine cluster moderates the association between caregivers perceived stress and emotional functioning in youth.

Some individuals exposed to early life stress show evidence of enhanced systemic inflammation and are at greater risk for psychopathology. In the current study, caregivers and their offspring (0-17 years) were recruited at a pediatric clinic visit at the University of California, San Francisco (UCSF). Mothers and seven-year-old children from the Growing Up inSingaporeTowards healthy Outcomes (GUSTO) prospective birth cohort were used as a replication cohort. Caregivers perceived stress was measured to determine potential intergenerational effects on the children's functioning and inflammation levels. Children's emotional functioning in the UCSF cohort was evaluated using the Pediatric Quality of Life (PedsQL) inventory. Child emotional and behavioral functioning was measured using the Child Behavior Checklist (CBCL) in GUSTO. Saliva was collected from the children and salivary levels of IL-6, IL-1ß, IL-8 and TNF-α were measured using an electrochemiluminescent cytokine multiplex panel. Child IL-6, IL-1ß, IL-8 cytokine levels were clustered into low, average, and high cytokine cluster groups using hierarchical cluster analysis. We did not find that salivary cytokine clusters were significantly associated with children's emotional or behavioral function. However, cytokine clusters did significantly moderate the association between increased caregiver perceived stress and reduced child emotional functioning (UCSF cohort) and increased Attention-Deficit-Hyperactivity (ADH) problems (GUSTO cohort, uncorrected Cohen's F2 = 0.02). Using a cytokine clustering technique may be useful in identifying those children exposed to increased caregiver perceived stress that are at risk of emotional and attention deficit hyperactivity problems.

DCC gene network in the prefrontal cortex is associated with total brain volume in childhood.

BACKGROUND: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. METHODS: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual's genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. RESULTS: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (ß = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (ß = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. LIMITATIONS: The relatively small sample size and age differences between the main and replication cohorts were limitations. CONCLUSION: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Epigenetics, Development, and Psychopathology.

Epigenetic mechanisms govern the transcription of the genome. Research with model systems reveals that environmental conditions can directly influence epigenetic mechanisms that are associated with interindividual differences in gene expression in brain and neural function. In this review, we provide a brief overview of epigenetic mechanisms and research with relevant rodent models. We emphasize more recent translational research programs in epigenetics as well as the challenges inherent in the integration of epigenetics into developmental and clinical psychology. Our objectives are to present an update with respect to the translational relevance of epigenetics for the study of psychopathology and to consider the state of current research with respect to its potential importance for clinical research and practice in mental health.

Maternal antenatal depression and child mental health: Moderation by genomic risk for attention-deficit/hyperactivity disorder.

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.

Polygenic differential susceptibility to prenatal adversity.

A recent article in this journal reported a number of gene × environment interactions involving a serotonin transporter-gene network polygenic score and a composite index of prenatal adversity predicting several problem behavior outcomes at 48 months (e.g., anxious/depressed, pervasive developmental problems) and at 60 months (e.g., withdrawal, internalizing problems), yet did not illuminate the nature or form these genetic × environment interactions took. Here we report results of six additional analyses to evaluate whether these interactions reflected diathesis-stress or differential-susceptibility related processes. Analyses of the regions of significance and proportion of interaction index are consistent with the diathesis-stress model, seemingly because of the truncated nature of the adversity score (which did not extend to supportive/positive prenatal experiences/exposures); in contrast, the proportion (of cases) affected index favors the differential-susceptibility model. These results suggest the need for future studies to extend measurement of the prenatal environment to highly supportive experiences and exposures.

PRS-on-Spark (PRSoS): a novel, efficient and flexible approach for generating polygenic risk scores.

BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach. RESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%). CONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.

Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk.

This study included 168 and 85 mother-infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRSMDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRSMDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRSMDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRSMDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRSMDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene-environment interdependence in the fetal development of brain regions implicated in cognitive-emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.

Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology-A global perspective.

There is clear evidence that the mother's stress, anxiety, or depression during pregnancy can alter the development of her fetus and her child, with an increased risk for later psychopathology. We are starting to understand some of the underlying mechanisms including the role of the placenta, gene-environment interactions, epigenetics, and specific systems including the hypothalamic-pituitary-adrenal axis and cytokines. In this review we also consider how these effects may be different, and potentially exacerbated, in different parts of the world. There can be many reasons for elevated prenatal stress, as in communities at war. There may be raised pregnancy-specific anxiety with high levels of maternal and infant death. There can be raised interpersonal violence (in Afghanistan 90.2% of women thought that "wife beating" was justified compared with 2.0% in Argentina). There may be interactions with nutritional deficiencies or with extremes of temperature. Prenatal stress alters the microbiome, and this can differ in different countries. Genetic differences in different ethnic groups may make some more vulnerable or more resilient to the effects of prenatal stress on child neurodevelopment. Most research on these questions has been in predominantly Caucasian samples from high-income countries. It is now time to understand more about prenatal stress and psychopathology, and the role of both social and biological differences, in the rest of the world.

The early care environment and DNA methylome variation in childhood.

Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.

funtooNorm: an R package for normalization of DNA methylation data when there are multiple cell or tissue types.

MOTIVATION: DNA methylation patterns are well known to vary substantially across cell types or tissues. Hence, existing normalization methods may not be optimal if they do not take this into account. We therefore present a new R package for normalization of data from the Illumina Infinium Human Methylation450 BeadChip (Illumina 450 K) built on the concepts in the recently published funNorm method, and introducing cell-type or tissue-type flexibility. RESULTS: funtooNorm is relevant for data sets containing samples from two or more cell or tissue types. A visual display of cross-validated errors informs the choice of the optimal number of components in the normalization. Benefits of cell (tissue)-specific normalization are demonstrated in three data sets. Improvement can be substantial; it is strikingly better on chromosome X, where methylation patterns have unique inter-tissue variability. AVAILABILITY AND IMPLEMENTATION: An R package is available at https://github.com/GreenwoodLab/funtooNorm, and has been submitted to Bioconductor at http://bioconductor.org.

Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression.

While many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology.

Stress hormones and posttraumatic stress symptoms following paediatric critical illness: an exploratory study.

In this exploratory case-control study, we investigated basal cortisol regulation in 5-16-year-old children, 3-6 months following PICU (paediatric intensive care) admission. This was nested within a study of child psychological and cognitive function; 47 children were assessed alongside 56 healthy controls. Saliva samples were collected three times per day (immediately after waking, waking +30 min, and waking +12 h) over two consecutive weekdays. In addition, data on posttraumatic stress symptoms were ascertained from 33 PICU admitted children using the Impact of Events Scale-8 (IES-8). Primary analysis revealed no significant differences in basal cortisol concentrations between PICU discharged children and healthy controls (p > 0.05). Secondary analysis in the PICU group identified a significant positive association between posttraumatic stress symptoms and evening (waking +12 h) cortisol concentrations (p = 0.004). However, when subject to multivariate analysis, evening cortisol was a modest independent predictor of IES-8 scores, relative to the presence of septic illness and poor pre-morbid health. We conclude that paediatric critical illness does not appear to result in marked perturbations to basal cortisol at 3-6 month following discharge. There was evidence of a link between evening cortisol and symptoms of PTSD, but this was not a robust effect and requires further elucidation.