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

Abstract

AbstractPsychiatric and cardio-metabolic conditions are commonly comorbid, being a leading cause of disability. Early adversity is a risk factor for both conditions, however, biological pathways remain unknown. The dopamine (DA) system is sensitive to early adversity and influences the development of comorbidities. We hypothesized that early life adversity would functionally link these conditions with the mesocorticolimbic dopamine system as a critical moderator pathway. We computed a co-expression based polygenic score (ePRS) reflecting variations in the function of the dopamine transporter (DAT) gene network in the prefrontal cortex and striatum, the final targets of the mesocorticolimbic pathway. We explored the interaction effects of the ePRS with a score of early life adversity on presence of psychiatric and cardio-metabolic comorbidities in adults (UK Biobank, N= 60016) and adolescents (ALSPAC, N= 910). In adults we also explored genetic and environment effects on gray matter density variations. As predicted, the mesocorticolimbic DAT1 ePRS significantly moderated the impact of early life adversity on the risk for both psychiatric (schizophrenia, neuroticism, mood and substance use disorders) and cardio-metabolic (type 2 diabetes, atherosclerosis, cardiovascular disease) comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the DAT1 ePRS implicating these regions as critical dopaminergic targets for psychiatric/cardio-metabolic comorbidities. These results reveal that psychiatric and cardio-metabolic comorbidities share common developmental pathways and underlying biological mechanisms.