Sensitive periods for prenatal alcohol exposure: a longitudinal study of DNA methylation and subsequent mental health

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ABSTRACT: Prenatal alcohol exposure (PAE) can lead to a variety of cognitive, behavioral, and health deficits falling under the umbrella of fetal alcohol spectrum disorder (FASD). FASD is estimated to affect 2-7% of children in the USA and 23% worldwide. Importantly, people with FASD have much higher rates of mental health problems than the general population. In particular, up to 50% of people with FASD suffer from depression, making it one of the most prevalent mental illnesses linked to PAE. Although the biological mechanisms underlying this increased vulnerability remain unknown, DNA methylation (DNAm) – a type of epigenetic modification – has emerged as a prime candidate to explain the long-term effects of PAE and its links to depression. However, most human studies of PAE and its effects on DNAm and depression are cross- sectional, and thus, have not investigated if the timing of PAE influences these relationships. Here, we propose to determine the extent to which the timing of PAE influences DNAm and depressive symptoms in childhood and adolescence, as well as assess the role of DNAm in mediating the link between PAE and increased depression risk. We will analyze data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a longitudinal birth cohort that collected repeated, prospective measures of PAE during pregnancy, DNAm and genetic data, and measures of depression collected almost yearly from age 4 to 16.5. We will replicate findings in Generation R (GenR), a longitudinal birth cohort with similar metrics to ALSPAC from children followed for 17 years. In Aim 1, we will assess the extent to which the timing of PAE influences parent-reported, child depressive symptom trajectories from age 4 to 16.5. Trajectories will be characterized using growth mixture modeling with structured residuals, a method we previously used to identify six classes of depression trajectories in ALSPAC. Causal relationships will be tested through Mendelian Randomization and negative control analyses (i.e., partner drinking in pregnancy). In Aim 2, we will identify the DNAm patterns at birth that are influenced by the timing of PAE and determine the extent to which these DNAm profiles mediate, or partially explain, the relationship between PAE and depressive symptom trajectories using statistical mediation methods. Both aims leverage a two-stage structured life course modeling approach previously used by our team to identify age periods when early-life exposures have greater effects on DNAm and depression. In sum, this study will identify: (1) periods when PAE has larger effects on depressive symptoms and DNAm; (2) specific patterns of depression in childhood and adolescence driven by PAE; and (3) epigenetic alterations that link PAE to depression. These findings will highlight developmental windows and biological mechanisms that could be targeted in interventions that reduce depression risk among people with FASD and maximize their well-being. The proposed research will also generate preliminary evidence towards future grant applications focused on socio-biological factors that link PAE to mental health across the life course.