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Maternal trauma influences infant and adult health outcomes and may impact future generations through epigenetic modifications such as DNA methylation (DNAm). Research in humans on the intergenerational epigenetic transmission of trauma effects is limited. In this study, we assessed DNAm signatures of war-related violence by comparing germline, prenatal, and direct exposures to violence across three generations of Syrian refugees. We compared families in which a pregnant grandmother versus a pregnant mother was exposed to violence and included a control group with no exposure to war. We collected buccal swab samples and survey data from mothers and 1-2 children in each of 48 families (n = 131 participants). Based on an epigenome-wide association study (EWAS), we identified differentially methylated regions (DMPs): 14 were associated with germline and 21 with direct exposure to violence. Most DMPs showed the same directionality in DNAm change across germline, prenatal, and direct exposures, suggesting a common epigenetic response to violence. Additionally, we identified epigenetic age acceleration in association with prenatal exposure to violence in children, highlighting the critical period of in utero development. This is the first report of an intergenerational epigenetic signature of violence, which has important implications for understanding the inheritance of trauma. 

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT , and catechol-O-methyltransferase, COMT ) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents. 

Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p < 1.95 × 10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10-7 and 8.3 × 10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM. 

Abstract Enhanced production of dehydroepiandrosterone (DHEA) by the foetal hypothalamic‐pituitary‐adrenal (HPA) axis enables maturational events critical for labour induction and neonatal adaptation. Despite knowledge of the interconnected nature of maternal and foetal physiology and dramatic changes in DHEA production after birth, few studies have examined DHEA levels in newborns and none have examined DHEA’s response to acute stress. Understanding normative patterns of early DHEA activity is needed to accurately assess functioning of the biological stress system with relevance for health and development. The present study analysed DHEA concentrations and change after stress among 93 newborns and associations with pregnancy, delivery and demographic risk factors. Three saliva samples, collected prior to and following a blood draw stressor, were used to determine baseline and stress reactive DHEA levels. Mothers self‐reported on health behaviours during pregnancy. Data on obstetric factors were obtained from medical records. DHEA levels declined from pre‐ to post‐stressor assessments. Results also showed that post‐stressor DHEA change was significantly associated with administration of medications used to treat pain and accelerate labour. However, there was no significant variation in DHEA pre‐stress levels or change after stress as a function of time after birth. By capturing DHEA levels after birth, the present study provides a window into prenatal health of the HPA system. The study also advances knowledge of DHEA in newborns by providing data on reference levels and important covariates. This information on basic adrenal physiology provides a foundation that can be expanded on to enhance understanding of early hypothalamic‐pituitary‐adrenal axis activity.