Title: Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort
Legend: Figure A. Multiple mediation paths between AnnoPred ADHD PGS and ADHD Inattention Symptoms via brain regions in adolescents in PNC. Figure B & C. Multiple mediation paths between AnnoPred ADHD PGS and ADHD symptoms via brain regions in the full sample of children, adolescents, and young adults in PNC
Citation: He, Q., Keding, T. J., Zhang, Q., Miao, J., Russell, J. D., Herringa, R. J., Lu, Q., Travers, B. G., & Li, J. J. (2023). Neurogenetic mechanisms of risk for ADHD: Examining associations of polygenic scores and brain volumes in a population cohort. Journal of neurodevelopmental disorders, 15(1), 30. https://doi.org/10.1186/s11689-023-09498-6
Abstract: Background – ADHD polygenic scores (PGSs) have been previously shown to predict ADHD outcomes in several studies. However, ADHD PGSs are typically correlated with ADHD but not necessarily reflective of causal mechanisms. More research is needed to elucidate the neurobiological mechanisms underlying ADHD. We leveraged functional annotation information into an ADHD PGS to (1) improve the prediction performance over a non-annotated ADHD PGS and (2) test whether volumetric variation in brain regions putatively associated with ADHD mediate the association between PGSs and ADHD outcomes.
Methods = Data were from the Philadelphia Neurodevelopmental Cohort (N = 555). Multiple mediation models were tested to examine the indirect effects of two ADHD PGSs—one using a traditional computation involving clumping and thresholding and another 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.
Results – A direct effect was detected between the AnnoPred ADHD PGS and IA symptoms in adolescents. No indirect effects via brain volumes were detected for either IA or HI symptoms. However, both ADHD PGSs were negatively associated with the DLPFC.
Conclusions – The AnnoPred ADHD PGS was a more developmentally specific predictor of adolescent IA symptoms compared to the traditional ADHD PGS. However, brain volumes did not mediate the effects of either a traditional or AnnoPred ADHD PGS on ADHD symptoms, suggesting that we may still be underpowered in clarifying brain-based biomarkers for ADHD using genetic measures.
Keywords: ADHD, Polygenic scores, Brain volume, Functional annotation, Multiple mediation
Investigator: James J. Li, PhD
About the Lab: James Li’s lab (the Social and Behavioral Development Lab) investigates genetic and environmental factors that contribute to the development of child externalizing disorders (e.g., attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder). Research in the lab utilizes molecular genetic approaches (e.g., genome-wide association scans, gene-pathway analysis) to advance understanding about the genetic architecture underlying complex developmental phenomena. They also focus on rigorous measurements of early environmental influences as they relate to child behavioral problems, not only for risk factors such as negative parenting and maltreatment, but also for enriched factors such as positive parenting and social support. The goal of this research is to understand how genes and environments independently and interactively influence variation in child social and behavioral development, and to ultimately bridge the substantial gap between genetics/neuroscience and prevention/intervention.