Association between DNA methylation at birth and cognitive outcomes from early childhood to adolescence: A systematic...

The Developmental Origins of Health and Disease (DOHaD) framework underscores the significance of early-life environmental exposures in shaping long-term neurodevelopmental outcomes. DNA methylation has emerged as a potential mechanism mediating these effects, yet the extent to which neonatal epigenetic variation is associated with cognitive trajectories remains unclear. In this systematic review, we synthesize findings from studies that examine the association between DNA methylation at birth and later cognitive outcomes in childhood and adolescence. Findings related to adolescence were sparse and should be interpreted as exploratory due to the limited evidence base. We identified seven studies through a comprehensive search, including prospective cohorts, cross-sectional studies, and randomised controlled trials. These studies used diverse approaches from candidate gene analyses to epigenome-wide association studies (EWAS) and assessed DNA methylation in tissues such as cord blood and buccal swabs. Notable findings include associations between methylation at genes such as HES1, GNG4, and NEGR1 and cognitive or neurobehavioral outcomes; however, results across studies were inconsistent. Methodological heterogeneity including differences in tissue source, array platform, timing and domain of outcome measurement, and analytical approaches contributed to mixed findings and limited comparability. Despite these limitations, current evidence is consistent with a potential association between DNA methylation at birth and later cognitive development. We emphasize the need for future research to adopt harmonized protocols, larger and more diverse longitudinal cohorts; particularly twin studies to advance mechanistic understanding and reproducibility in this emerging field.