Amygdala 5-HTT gene network moderates the effects of postnatal adversity on attention problems : anatomo-functional correlation and epigenetic changes

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.Peer reviewe

Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Early intervention to prevent adverse child emotional and behavioural development following maternal depression in pregnancy: study protocol for a randomised controlled trial

Abstract Background Substantial evidence indicates that maternal depression during pregnancy (i.e., antenatal depression) is associated not only with maternal wellbeing but also with child emotional and behavioural development. Children of antenatally depressed women are at risk of emotional and behavioural problems, including internalising problems (e.g., anxiety and depression) and externalising problems (e.g., attention problems), that may last at least to adolescence. These enduring effects also constitute an enormous economic cost. Despite the seriousness of this problem, until recently there existed very few controlled studies evaluating whether active psychological treatment for antenatal depression can prevent adverse child outcomes. Our previous pilot randomised controlled trial (RCT) exploring the effect of cognitive behavioural therapy (CBT) for antenatal depression on child outcomes showed promising results. We aim to assess whether treating antenatal depression with an evidence-based 8-week structured CBT program can prevent or ameliorate adverse child developmental outcomes at 2 years of age. Methods Pregnant women ≤ 30 weeks gestation diagnosed with a depressive disorder are recruited and randomised to CBT or treatment as usual (TAU). The target sample size is 230 and the primary outcome measure is the infant Internalising scale of the Child Behaviour Checklist (CBCL) at 24 months of age. Secondary infant outcome measures at 24 months are the Externalising scale of the CBCL and the motor and cognitive development subscales of the Ages & Stages Questionnaire (ASQ-3). Additional secondary outcome measures are subscales of the Revised Infant Behaviour Questionnaire (IBQ-R), ASQ-3 and the ASQ-Socio-Emotional (ASQ-SE) at 3 and 12 months of age and the quality of mother-infant interaction at 3 and 24 months. Maternal measures, including demographic data, depression diagnosis, depressive and anxiety symptoms, perceived stress and parenting stress, are collected across all time points. Discussion The trial is ongoing and recruitment was slowed due to the COVID-19 pandemic. If results suggest a beneficial effect of antenatal depression treatment on infant outcomes, the project could have repercussions for standard antenatal care, for maternal and infant health services and for preventing the intergenerational transmission of mental health disorders. Trial registration Australia and New Zealand Clinical Trials Register: ACTRN12618001925235 Date Registered: 27 November 2018

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

BackgroundPrior 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-1β [IL-1β], 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).MethodsWe 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.ResultsOur 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.ConclusionOur findings support prior work suggesting that social stress exposures contribute to increased inflammation in children.ImpactOur 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 registrationNCT02746393

Amygdala 5-HTT gene network moderates the effects of postnatal adversity on attention problems : anatomo-functional correlation and epigenetic changes

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children

Genetic and environmental factors predict multivariate trajectories of maternal distress after birth

Background: Maternal distress influences her own wellbeing and shapes her offspring’s psychosocial adjustment and neurodevelopment across childhood. The aim of this study was to analyze multivariate trajectories of maternal postpartum distress using a latent class modeling approach and to find genetic and psychosocial factors that predict membership within a given group (latent class). Methods: Maternal self-reports of depressive symptoms, parenting stress, general stress, and marital stress were measured at regular intervals during the first six years postpartum in 261 mothers participating in the Maternal Adversity, Vulnerability and Neurodevelopment Study. Genetic risk was determined by calculating a polygenic risk score for Major Depressive Disorder (MDD-PRS). Additionally, we assessed maternal history of early life adversity (mELA), educational level, and prenatal symptoms of depression as psychosocial risk factors. Using Latent Gold® Software, we identified latent classes of mothers based on their 1) average levels of distress and 2) change in distress over time. Results: We identified four latent classes based on average levels of distress and found that class membership probability was influenced by an interaction between MDD-PRS and prenatal depressive symptoms (WaldInteraction(3)=13.19, p=0.004; WaldMDD-PRS(3)=6.02, p=0.11; WaldDepression(3)=41.96; p<0.001), mELA (Wald(3)=8.64, p=0.035), and educational level (Wald(3)=11.61, p=0.009). Furthermore, we found five classes of mothers with distinct across- time trajectories, which were associated with mELA (Wald(3)=12.67, p=0.013). Conclusions: Our findings might become relevant in the clinical setting, e.g. for identifying pregnant women at risk for distress in the postpartum based on her prenatal symptoms of depression and genetic risk, mELA, and educational level