Multi-Dimensional Natural and Social Environmental Factors, Genetic Components, and the Brain Health of Young Adolescents

Developing children encounter a diverse array of dimensional environmental exposures that collectively shape their brain health. However, studies are mainly limited to single-exposure or single-domain levels. We investigated the comprehensive relationships of youth multi-dimensional growth environmental factors with their brain structural signatures, cognitive performance, mental health, and the moderation effects of genetic components, in over 10,000 US participants from the Adolescent Brain and Cognitive Development (ABCD) study. Using environmental Exposome-Wide Association Study (ExWAS), linear mixed-effect association models (LMM) and principal component analysis (PCA), we found that the 4 main environmental domains were significantly correlated with their brain health indices to varying degrees. The contribution of the (I) family environmental domain ranked first, followed by (II) residential-community level socioeconomic status, (III) school and peer environment, and (IV) natural pollution indices, which ranked fourth. The associations of environmental domains with youth mental health and cognition were significantly mediated by brain cortical structure signatures and moderated by individuals’ genetic architecture components, identified through structural function and moderated mediation analysis. Our study revealed that the identified core environment components were closely linked to cognition and specific mental and behavior symptoms, including attention, social and conduct problems. These links were mediated through distinct brain cortical structural differences, which encompass intricate interaction mechanisms between genetic and environmental components.