Epigenetic biomarkers for the risk and progression of depression among young adolescents

About This Grant

Project Summary Adolescent internalizing problems—including anxiety, withdrawal, and depression—present an urgent public health concern, affecting a substantial proportion of U.S. adolescents aged 12-17. Early life stress (ELS), such as childhood adversity and trauma, amplifies the risk of developing internalizing problems, with affected children having approximately 2.5 times higher odds than peers without such experiences. Although the effects of ELS may not be immediately apparent, they can have a lasting impact on long-term quality of life, underscoring the importance of early identification of at-risk individuals. DNA methylation (DNAm) and microRNA (miRNA) expression regulate gene activity in response to environmental stress. While previous studies suggest that DNAm changes during childhood and adolescence are linked to mental health outcomes, large-scale validation in long-term, population-based cohorts remain a critical gap. Similarly, miRNAs, which regulate gene expression and play a pivotal role in stress responses, are underexplored in human studies linking ELS to internalizing problems. This project aims to identify epigenetic biomarkers—specifically miRNAs and DNAm—that mediate the effects of ELS on adolescent internalizing problems. We hypothesize that miRNA expression, in combination with DNAm, serves as a powerful, synergistic predictor of internalizing problems. To test this, we will apply advanced computational techniques, including longitudinal mediation analysis and machine learning, utilizing data from two robust, long-term population-based cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and Generation R. Our specific aims are: (1) Investigate the impact of dynamic changes in DNAm on the risk of internalizing problems, with a focus on individual-level variability and the role of ELS; (2) Identify the link between ELS, miRNA expression, and internalizing problems; and (3) Estimate the synergistic contribution of DNAm and miRNAs in predicting internalizing problems through the creation of a composite epigenetic risk score. By integrating multi-omics data and leveraging extensive follow- up from birth through adolescence, this project will offer groundbreaking insights into how ELS shapes the biological risk for internalizing problems. These findings will significantly enhance our ability to detect early biomarkers of internalizing difficulties, paving the way for tailored, preventive interventions aimed at reducing the burden of adolescent internalizing problems.