Childhood adversity, DNA methylation, and risk for depression: A longitudinal study of protective factors and sensitive periods in development

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Project Summary. Exposure to childhood adversity is one of the strongest risk factors for depression across the life course, increasing risk by at least twofold. Although these exposures are clearly harmful, there is substantial variation in how people respond to adversity; not all children who experience early-life adversity go on to develop mental health problems. This finding raises the question: Are there modifiable factors early in life that protect against the effects of adversity, contribute to resilient biological processes, and prevent new onsets of depression? Family- and community-level factors, including maternal social support, parenting behaviors, grandparent involvement, peer support, and school quality, are established promotive factors for depression, even among children with a history of adversity. Emerging research also suggests DNA methylation (DNAm), a well-studied epigenetic modification, may function as a pathway to explain the biological embedding of these promotive factors. Yet, prior studies in this field have been small, cross-sectional, and focused mostly on candidate genes. As such, our interdisciplinary team seeks to considerably advance these insights by identifying the extent to which DNAm mediates, or partially explains, the effect of these positive life experiences on risk for depression across childhood to adulthood. We will study these relationships in two birth cohorts: the US-based Fragile Families and Child Wellbeing Study (FFCWS) and the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC). Both cohorts are rare in containing repeated measures of positive life experiences, childhood adversities, DNAm, symptom and/or diagnostic markers of depression risk, and indicators of positive adaptation. Leveraging our team’s track-record of identifying adversity-linked sensitive periods for DNAm and depression, we will capitalize on these data to pursue three aims. In all aims, we will model risk (i.e., childhood adversity exposure) and positive life experiences simultaneously, which few studies have done before. In Aim 1, we will characterize the time-dependent effects of positive life experiences on depression from childhood to adulthood. In Aim 2, we will investigate the time-varying impacts of positive life experiences on DNAm patterns and trajectories. For Aims 1 and 2, we will use a two-stage structured life-course modeling approach (SLCMA) our team developed for high-dimensional data. In Aim 3, we will evaluate the extent to which these DNAm patterns explain the relationship between positive life experiences and depression using statistical mediation. In sum, this study will: 1) identify modifiable positive life experiences that shape DNAm and depression patterns, 2) determine if there are sensitive periods when these experiences are more influential in shaping these outcomes, and 3) generate insights about promotive and protective biological mechanisms that could lead to new targeted interventions that benefit all children and mitigate the effects of adversity for those who are exposed.