Dimensions of early-life adversity and SLC6A4 methylation in emerging adults

Growing evidence suggests that epigenetic pathways, including DNA methylation (DNAm), play a role in the biological embedding of early-life adversity (ELA) and life-course health, but how remains unclear. We explore epigenetic pathways indicated by DNAm of the stress-regulating gene, SLC6A4, including how DNAm is shaped by distinct life-course dimensions of ELA, including developmental contexts characterized by threat and deprivation. We investigate whether and how life-course dimensions of ELA are associated with SLC6A4 methylation (SLC6A4m) using data from 370 cohort members from the Youth Emotion Project. Participants were recruited from two US high schools and followed prospectively, with DNA collection in early adulthood and ELA measures based on coded responses from the Childhood Trauma Interview. Adjusted linear regressions of mean SLC6A4m across 71 CpG sites on ELA reveal a strong and robust association, including a dose-response relationship between SLC6A4m and increased ELA severity. Each additional high-severity event was associated with a 0.052 percentage point increase in mean percent SLC6A4m (p<0.001). When modeled separately, both childhood and adolescent ELA predict SLC6A4m, and when modeled jointly, adolescent ELA alone predicts SLC6A4m. Additionally, the ELA- SLC6A4m relationship varies by ELA type. Across childhood and adolescence, deprivation is positively associated with greater SLC6A4m. Adolescent threat is also positively associated with SLC6A4m, but the association is not statistically significant. Results suggest prioritizing early-life interventions for promoting healthy stress regulation, including preventing adversity and its harmful effects, with close attention to adolescence and high-deprivation development settings.