Abstract
Brain structure and function show substantial individual differences, finely controlled by genes, environments, and their interactions. Despite the increasing knowledge about genetic and environmental main effects, gene-environment interaction effects on brain phenotypes remain elusive. This study investigates genome-wide by environment (41 exposures) interactions on 598 brain imaging phenotypes in 7084 healthy young adults. Both univariate and multivariate analyses identify 486 significant gene-environment interactions, scattered across the genome, exposome, and phenome. These interactions explain more variances of phenotypes than genetic and environmental main effects (100% of genetic and 96% of environmental main effects are non-significant). Variants with interactions are enriched in intronic and intergenic regions, comprising 79 regulatory variants and 145 associated with brain gene expression. Protein-protein interaction network analyses reveal distinct interaction networks for genes associated with air pollution (hubs: H4C6, SMARCA4, and RPS11) and urbanicity (hubs: CCND1, CALM3, and CDK2) exposures. Genes that interacted with air pollution exposures exhibit enrichment in pathways related to metal ion detoxification and homeostasis. For time-varying exposures, 144 interactions demonstrate sensitive periods, predominantly in childhood (ages 4-7) and adolescence (ages 12-15). These findings highlight the value of genome-wide by exposome-wide interaction studies, which may offer crucial information for optimizing brain health outcomes.