Translating Discoveries in Attention-Deficit/Hyperactivity Disorder Genomics to an Outpatient Child and Adolescent Psychiatric Cohort

• Published in: Journal of the American Academy of Child and Adolescent Psychiatry Vol. 59; no. 8; pp. 964 - 977
• Main Authors: Vuijk, Pieter J., Martin, Joanna, Braaten, Ellen B., Genovese, Giulio, Capawana, Michael R., O’Keefe, Sheila M., Lee, B. Andi, Lind, Hannah S., Smoller, Jordan W., Faraone, Stephen V., Perlis, Roy H., Doyle, Alysa E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2020; Elsevier BV; Elsevier
• Subjects: Academic achievement; Achievement tests; ADHD; Adolescent; Adult; Anxiety disorders; Associations; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Autism; Behavior; Child; Child & adolescent psychiatry; Children; Children & youth; clinical translation; Cognition; Discriminant validity; Educational Planning; Genetic testing; Genome-wide association studies; Genome-Wide Association Study; Genomes; genomic medicine; Genomics; Humans; Hyperactivity; Intellectual disabilities; Longitudinal Studies; Outpatients; Phenotypes; polygenic risk; Principal components analysis; Psychopathology; Public health; Regression analysis; Short term memory; Youth; ADHD; genomic medicine; clinical translation; polygenic risk
• ISSN: 0890-8567; 1527-5418
• DOI: 10.1016/j.jaac.2019.08.004

Genomic discoveries should be investigated in generalizable child psychiatric samples in order to justify and inform studies that will evaluate their use for specific clinical purposes. In youth consecutively referred for neuropsychiatric evaluation, we examined 1) the convergent and discriminant validity of attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) in relation to DSM-based ADHD phenotypes; 2) the association of ADHD PRSs with phenotypes beyond ADHD that share its liability and have implications for outcome; and 3) the extent to which youth with high ADHD PRSs manifest a distinctive clinical profile. Participants were 433 youth, ages 7–18 years, from the Longitudinal Study of Genetic Influences on Cognition. We used logistic/linear regression and mixed effects models to examine associations with ADHD-related polygenic variation from the largest ADHD genome-wide association study to date. We replicated key findings in 5,140 adult patients from a local health system biobank. Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R2 values ∼2%–3%), as well as cross-diagnostic variation in aggression and working memory. In adults, ADHD PRSs were associated with ADHD and phenotypes beyond the condition that have public health implications. Finally, youth with a high ADHD polygenic burden showed a more severe clinical profile than youth with a low burden (β coefficients ∼.2). Among child and adolescent outpatients, ADHD polygenic risk was associated with ADHD and related phenotypes as well as clinical severity. These results extend the scientific foundation for studies of ADHD polygenic risk in the clinical setting and highlight directions for further research.