A mesocorticolimbic dopamine gene network moderates the effect of early adversity on the risk for metabolic and psychiatric comorbidities

Abstract

Exposure to early adversity increases the risk for non-transmittable diseases, but also psychiatric conditions, and these common developmental risk factors suggest overlapping underlying mechanisms. The dopamine neurons constitute a system underlying the brain response to environmental conditions and functional variations of this system may be linked to long-term unfavorable outcomes in response to early adversity. We created an expression-based polygenic score for the dopamine transporter gene network (ePRS-DAT1) on the prefrontal cortex and striatum, to explore the role of dopamine on the long-term effects of early life adversity on these outcomes. The ePRS-DAT1 reflects genes co-expressed with DAT1 gene in the PFC and STR in a combined manner, being calculated using the effect size of the association between the individual SNPs from those genes and gene expression (GTEx). Using large datasets (UKBiobank for adulthood and ALSPAC for childhood/adolescence), we demonstrate that the ePRS-DAT1 moderates the impact of early life adversity on the risk for both psychiatric and cardiometabolic comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the ePRS suggesting these regions as critical dopaminergic targets for psychiatric/metabolic comorbidities. These results reveal that psychiatric and metabolic comorbidities showed share common developmental pathways and underlying biological mechanisms.