Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Behavioral and neurostructural correlates of childhood physical violence victimization: Interaction with family functioning.

Violence victimization may cause child behavior problems and neurostructural differences associated with them. Healthy family environments may buffer these effects, but neural pathways explaining these associations remain inadequately understood. We used data from 3154 children (x̅age  = 10.1) to test whether healthy family functioning moderated possible associations between violence victimization, behavior problems, and amygdala volume (a threat-responsive brain region). Researchers collected data on childhood violence victimization, family functioning (McMaster Family Assessment Device, range 0-3, higher scores indicate healthier functioning), and behavior problems (Achenbach Child Behavior Checklist [CBCL] total problem score, range 0-117), and they scanned children with magnetic resonance imaging. We standardized amygdala volumes and fit confounder-adjusted models with "victimization × family functioning" interaction terms. Family functioning moderated associations between victimization, behavior problems, and amygdala volume. Among lower functioning families (functioning score = 1.0), victimization was associated with a 26.1 (95% confidence interval [CI]: 9.9, 42.4) unit higher CBCL behavior problem score, yet victimized children from higher functioning families (score = 3.0) exhibited no such association. Unexpectedly, victimization was associated with higher standardized amygdala volume among lower functioning families (y = 0.5; 95% CI: 0.1, 1.0) but lower volume among higher functioning families (y = -0.4; 95% CI: -0.7, -0.2). Thus, healthy family environments may mitigate some neurobehavioral effects of childhood victimization.

Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Connecting the dots: social networks in the classroom and white matter connections in the brain.

BACKGROUND: Peer connections in school classrooms play an important role in social-emotional development and mental health. However, research on the association between children's peer relationships and white matter connections in the brain is scarce. We studied associations between peer relationships in the classroom and white matter structural connectivity in a pediatric population-based sample. METHODS: Bullying and victimization, as well as rejection and acceptance, were assessed in classrooms in 634 children at age 7. White matter microstructure (fractional anisotropy (FA), mean diffusivity (MD)) was measured with diffusion tensor imaging at age 10. We examined global metrics of white matter microstructure and used Tract-Based Spatial Statistics (TBSS) for voxel-wise associations. RESULTS: Peer victimization was associated with higher global FA and lower global MD and peer rejection was associated with lower global MD; however, these associations did not remain after multiple testing correction. Voxel-wise TBSS results for peer victimization and rejection were in line with global metrics both in terms of direction and spatial extent of the associations, with associated voxels (pFWE <.05) observed throughout the brain (including corpus callosum, corona radiata, sagittal stratum and superior longitudinal fasciculi). CONCLUSIONS: Although based only on cross-sectional data, the findings could indicate accelerated white matter microstructure maturation in certain brain areas of children who are victimized or rejected more often. However, repeated measurements are essential to unravel this complex interplay of peer connections, maturation and brain development over time.

Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.

Low prosocial behavior in childhood has been consistently linked to later psychopathology, with evidence supporting the influence of both genetic and environmental factors on its development. Although neonatal DNA methylation (DNAm) has been found to prospectively associate with a range of psychological traits in childhood, its potential role in prosocial development has yet to be investigated. This study investigated prospective associations between cord blood DNAm at birth and low prosocial behavior within and across four longitudinal birth cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. We examined (a) developmental trajectories of "chronic-low" versus "typical" prosocial behavior across childhood in a case-control design (N = 2,095), and (b) continuous "low prosocial" scores at comparable cross-cohort time-points (N = 2,121). Meta-analyses were performed to examine differentially methylated positions and regions. At the cohort-specific level, three CpGs were found to associate with chronic low prosocial behavior; however, none of these associations was replicated in another cohort. Meta-analysis revealed no epigenome-wide significant CpGs or regions. Overall, we found no evidence for associations between DNAm patterns at birth and low prosocial behavior across childhood. Findings highlight the importance of employing multi-cohort approaches to replicate epigenetic associations and reduce the risk of false positive discoveries.

Prenatal Maternal Stress and Child IQ.

The evidence for negative influences of maternal stress during pregnancy on child cognition remains inconclusive. This study tested the association between maternal prenatal stress and child intelligence in 4,251 mother-child dyads from a multiethnic population-based cohort in the Netherlands. A latent factor of prenatal stress was constructed, and child IQ was tested at age 6 years. In Dutch and Caribbean participants, prenatal stress was not associated with child IQ after adjustment for maternal IQ and socioeconomic status. In other ethnicities no association was found; only in the Moroccan/Turkish group a small negative association between prenatal stress and child IQ was observed. These results suggest that prenatal stress does not predict child IQ, except in children from less acculturated minority groups.

Childhood Adversity and Incident Psychotic Experiences in Early Adulthood: Cognitive and Psychopathological Mediators.

BACKGROUND AND HYPOTHESIS: Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood. STUDY DESIGN: We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula. STUDY RESULTS: In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results. CONCLUSIONS: Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences.

No robust evidence for an interaction between early-life adversity and protective factors on global and regional brain volumes.

Childhood adversity is associated with brain morphology and poor psychological outcomes, and evidence of protective factors counteracting childhood adversity effects on neurobiology is scarce. We examined the interplay of childhood adversity with protective factors in relation to brain morphology in two independent longitudinal cohorts, the Generation R Study (N = 3008) and the Mannheim Study of Children at Risk (MARS) (N = 179). Cumulative exposure to 12 adverse events was assessed across childhood until age 9 years in Generation R and 11 years in MARS. Protective factors (temperament, cognition, self-esteem, maternal sensitivity, friendship quality) were assessed at various time-points during childhood. Global brain volumes and volumes of amygdala, hippocampus, and the anterior cingulate, medial orbitofrontal and rostral middle frontal cortices were assessed with anatomical scans at 10 years in Generation R and at 25 years in MARS. Childhood adversity was related to smaller cortical grey matter, cerebral white matter, and cerebellar volumes in children. Also, no buffering effects of protective factors on the association between adversity and the brain outcomes survived multiple testing correction. We found no robust evidence for an interaction between protective factors and childhood adversity on broad brain structural measures. Small interaction effects observed in one cohort only warrant further investigation.

Harsh Parenting and Child Brain Morphology: A Population-Based Study.

Evidence suggests that maltreatment shapes the child's brain. Little is known, however, about how normal variation in parenting influences the child neurodevelopment. We examined whether harsh parenting is associated with the brain morphology in 2,410 children from a population-based cohort. Mothers and fathers independently reported harsh parenting at child age 3 years. Structural and diffusion-weighted brain morphological measures were acquired with MRI scans at age 10 years. We explored whether associations between parenting and brain morphology were explained by co-occurring adversities, and whether there was a joint effect of both parents' harsh parenting. Maternal harsh parenting was associated with smaller total gray (ß = -0.05 (95%CI = -0.08; -0.01)), cerebral white matter and amygdala volumes (ß = -0.04 (95%CI = -0.07; 0)). These associations were also observed with the combined harsh parenting measure and were robust to the adjustment for multiple confounding factors. Similar associations, although non-significant, were found between paternal parenting and these brain outcomes. Maternal and paternal harsh parenting were not associated with the hippocampus or the white matter microstructural metrics. We found a long-term association between harsh parenting and the global brain and amygdala volumes in preadolescents, suggesting that adverse rearing environments common in the general population are related to child brain morphology.

Are all threats equal? Associations of childhood exposure to physical attack versus threatened violence with preadolescent brain structure.

BACKGROUND: Neurodevelopmental studies of childhood adversity often define threatening experiences as those involving harm or the threat of harm. Whether effects differ between experiences involving harm ("physical attack") versus the threat of harm alone ("threatened violence") remains underexplored. We hypothesized that while both types of experiences would be associated with smaller preadolescent global and corticolimbic brain volumes, associations with physical attack would be greater. METHODS: Generation R Study researchers (the Netherlands) acquired T1-weighted scans from 2905 preadolescent children, computed brain volumes using FreeSurfer, and asked mothers whether their children ever experienced physical attack (n = 202) or threatened violence (n = 335). Using standardized global (cortical, subcortical, white matter) and corticolimbic (amygdala, hippocampus, anterior cingulate cortex, orbitofrontal cortex) volumes, we fit confounder-adjusted models. RESULTS: Physical attack was associated with smaller global volumes (ßcortical=-0.14; 95% CI: -0.26, -0.02); ßwhite matter= -0.16; 95% CI: - 0.28, - 0.03) and possibly some corticolimbic volumes, e.g., ßamygdala/ICV-adjusted= -0.10 (95% CI: -0.21, 0.01). We found no evidence of associations between threatened violence and smaller volumes in any outcome; instead, such estimates were small, highly uncertain, and positive in direction. CONCLUSIONS: Experiences of physical attack and threatened violence may have quantitively different neurodevelopmental effects. Thus, differences between types of threatening experiences may be neurodevelopmentally salient.

Observed infant-parent attachment and brain morphology in middle childhood- A population-based study.

Poor quality of the early infant-parent bond predicts later child problems. Infant-parent attachment has been suggested to influence brain development, but this association has hardly been examined. In adults, larger amygdala volumes have been described in relation to early attachment disorganization; neuroimaging studies of attachment in children, however, are lacking. We examined the association between infant-parent attachment and brain morphology in 551 children from a population-based cohort in the Netherlands. Infant-parent attachment was observed with the Strange-Situation Procedure at age 14 months and different brain measures were collected with magnetic resonance imaging at mean age 10 years. Children with disorganized infant attachment had larger hippocampal volumes than those with organized attachment patterns. This finding was robust to the adjustment for confounders and consistent across hemispheres. The association was not explained by cognitive or emotional and behavioral problems. Disorganized attachment did not predict any other difference in brain morphology. Moreover, children with insecure organized infant attachment patterns did not differ from those who were securely attached in any brain outcome. Causality cannot be inferred, but our findings in this large population-based study provide novel evidence for a long-term association between the quality of infant-parent attachment and specific brain differences in childhood.

Frequent Bullying Involvement and Brain Morphology in Children.

Background: Over the past few decades, bullying has been recognized as a considerable public health concern. Involvement in bullying is associated with poor long-term social and psychiatric outcomes for both perpetrators and targets of bullying. Despite this concerning prognosis, few studies have investigated possible neurobiological correlates of bullying involvement that may explain the long-term impact of bullying. Cortical thickness is ideally suited for examining deviations in typical brain development, as it has been shown to detect subtle differences in children with psychopathology. We tested associations between bullying involvement and cortical thickness using a large, population-based cohort. Methods: The study sample consisted of 2,602 participants from the Generation R Study. When children were 8 years old, parents and teachers reported on common forms of child bullying involvement (physical, verbal, and relational). Questions ascertained whether a child was involved as a perpetrator (n = 82), a target of bullying (n = 92), as a combined perpetrator and target of bullying (n = 47), or uninvolved in frequent bullying (n = 2,381). High-resolution structural MRI was conducted when children were 10 years of age. Cortical thickness estimates across the cortical mantle were compared among groups. Results: Children classified as frequent targets of bullying showed thicker cortex in the fusiform gyrus compared to those uninvolved in bullying (B = 0.108, p corrected < 0.001). Results remained consistent when adjusted for socioeconomic factors, general intelligence, and psychiatric symptoms. Children classified as frequent perpetrators showed thinner cortex in the cuneus region; however, this association did not survive stringent correction for multiple testing. Lastly, no differences in cortical thickness were observed in perpetrator-targets. Discussion: Bullying involvement in young children was associated with differential cortical morphology. Specifically, the fusiform gyrus, often involved in facial processing, showed thicker cortex in targets of frequent bullying. Longitudinal data are necessary to demonstrate the temporality of the underlying neurobiology associated with bullying involvement.