Neurogenetic Mechanisms of Risk for ADHD: Examining Associations of Functionally-Annotated Polygenic Scores and Brain Volumes in a Population Cohort

Background: ADHD polygenic scores (PGS) are reliably predictive of ADHD outcomes across studies. However, traditional PGS are statistical indices of genetic liability, predictive of ADHD but uninformed by biological information. The objective of our study was to determine whether a novel, biologically-informed, functionally annotated ADHD PGS can reveal specific brain mechanisms of risk for ADHD. Methods: Data were from the Philadelphia Neurodevelopmental Cohort (n=555). Multiple mediation models were tested to examine the indirect effects of ADHD PGS (including one using a functionally annotated approach, i.e., AnnoPred) on ADHD inattention (IA) and hyperactivity-impulsivity (HI) symptoms, via gray matter volumes in the cingulate gyrus, angular gyrus, caudate, dorsolateral prefrontal cortex (DLPFC), and inferior temporal lobe. Age-stratified analyses (children, adolescents, and young adults) were also conducted to account for developmental differences. Results: A direct effect was detected between AnnoPred PGS and IA symptoms in adolescents only. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, ADHD PGS were consistently associated with the DLPFC. Conclusions: A biologically-informed PGS yielded a more powerful (and developmentally-specific) signal in detecting a direct effect of ADHD PGS on adolescent IA symptoms. However, no indirect effects between ADHD PGS and ADHD symptomology via the brain emerged. ADHD will become increasing predictive as discovery sample sizes climb. Studies that integrate both genetic and neuroimaging information are critical to advancing our understanding of the biological mechanisms underlying ADHD.