Mitochondria-associated gene network-environment interaction effect on the risk for impulsive behavior and substance dependence over the life course

Childhood adversities have been associated with the development of a third of all adult psychopathologies and affect individuals across their lifespan. Early life adversity (ELA) has been found to be a significant risk factor for a range of behavioral problems, including attention deficit and hyperactivity disorder (ADHD) in children and substance use disorders (SUD) and alcohol dependence in adulthood; however, not all individuals develop pathologies after ELA. Recent evidence points towards a mediating role of mitochondrial dysfunction between psychosocial stress and disorder development. In this work, we investigated if individual differences related to the environment-responsive mitochondria-associated gene network interact with early adversity resulting in these behavioral outcomes over the life course in different cohorts. Using our translational model of differential susceptibility, we selected 22 nuclear genes related to mitochondrial function and responsive to both positive and negative environmental exposures in mice. Homologous genes were identified in humans, and the resulting gene network was used to calculate an expression-based polygenic score (ePRS). Interaction effects between environmental and genetic (ePRS) factors were investigated on behavioral outcomes across one children cohort (MAVAN) and two adult cohorts (UKBiobank and SAGE). Additional replication cohorts are currently being explored (e.g., ABCD). In childhood (MAVAN), results showed significant interactions in two different tools measuring hyperactivity at 60 months old (Child Behavior Checklist, Subscale: Attention Deficit/Hyperactivity Problems, p=0.03, β=0.189, N=139; Strength and Difficulties Questionnaire, Hyperactivity score, p= 0.0459, β=0.169, N=141). In adulthood, results from the UK Biobank showed significant SUD-related interactions (Ever addicted to any substance or behavior, p= 0.01, β=-0.02, N=3,826; Ever addicted to alcohol, p=0.04, β= 0.03, N=1,454; Ever addicted to a behavior or miscellaneous, p=0.003, β=0.05, N=958; Ongoing behavioral or miscellaneous addiction, p=0.046, β=0.05, N=448). These results were replicated in the SAGE cohort, where an ePRS-environment interaction was associated significantly with the presence of alcohol dependence (p=0.02, β=0.06, N=1,911). While all interactions were significant, further inspection revealed differences in the interactions presented. In both MAVAN and SAGE, a lower ePRS resulted in a higher likelihood of presenting negative outcomes after exposure to an adverse environment. On the other hand, the opposite pattern is present in UK Biobank, whereby a higher ePRS resulted in a higher likelihood of presenting negative outcomes in individuals exposed to an adverse environment. We are currently carrying out additional replications with other cohorts to better understand these observed variations. Our findings suggest that individual differences in mitochondrial function are relevant for early signs of altered impulse control and contribute to the later development of substance use disorders in response to variations in the early environment. Through this research, we identified a significant core group mechanism that could be affecting the incidence and trajectories of addiction and warrants more attention. By identifying individuals with stronger responses to adversity, we can inform disorder management and aid in developing targeted responses for individuals.