DNA methylation as a possible causal mechanism linking childhood adversity and health: Results from two-sample mendelian randomization study

Abstract Childhood adversity is an important risk factor for adverse health across the life course. Epigenetic modifications, such as DNA methylation (DNAm), are a hypothesized mechanism linking adversity to disease susceptibility. Yet, few studies have determined whether adversity-related DNAm alterations are causally related to future health outcomes or if their developmental timing plays a role in these relationships. Here, we used 2-sample mendelian randomization to obtain stronger causal inferences about the association between adversity-associated DNAm loci across development (ie, birth, childhood, adolescence, and young adulthood) and 24 mental, physical, and behavioral health outcomes. We identified particularly strong associations between adversity-associated DNAm and attention-deficit/hyperactivity disorder, depression, obsessive-compulsive disorder, suicide attempts, asthma, coronary artery disease, and chronic kidney disease. More of these associations were identified for birth and childhood DNAm, whereas adolescent and young adulthood DNAm were more closely linked to mental health. Childhood DNAm loci also had primarily risk-suppressing relationships with health outcomes, suggesting that DNAm might reflect compensatory or buffering mechanisms against childhood adversity rather than acting solely as an indicator of disease risk. Together, our results suggest adversity-related DNAm alterations are linked to both physical and mental health outcomes, with particularly strong impacts of DNAm differences emerging earlier in development.