Genome‐Wide by Lifetime Environment Interaction Studies of Brain Imaging Phenotypes

This study explores genome‐wide by lifetime environment interactions on brain imaging phenotypes. Gene‐environment interactions explain more phenotypic variance than main effects, pinpoint regulatory variants, and reveal exposure‐specific biological pathways. Critical sensitive periods are identified in childhood and adolescence, offering novel insights for optimizing brain health. 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. This study explores genome-wide by lifetime environment interactions on brain imaging phenotypes. Gene-environment interactions explain more phenotypic variance than main effects, pinpoint regulatory variants, and reveal exposure-specific biological pathways. Critical sensitive periods are identified in childhood and adolescence, offering novel insights for optimizing brain health. 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. Advanced Science, EarlyView.