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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.