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

Abstract

Objective 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. Method 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. Results Among referred youth, ADHD PRSs were associated with ADHD diagnoses, cross-diagnostic ADHD symptoms and academic impairment (odds ratios ∼1.4; R 2 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). Conclusion 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.

Polygenic Risk and the Course of Attention-Deficit/Hyperactivity Disorder From Childhood to Young Adulthood: Findings From a Nationally Representative Cohort

“…These findings are similar to a study of a clinical ADHD population that found a larger difference in levels of hyperactivity symptoms than inattention symptoms between high and low PRS groups. 11 One explanation for this could be that genetic risk identified by the PRS derived from the current ADHD GWAS is more related to hyperactivity/impulsivity symptoms than inattention symptoms. Children exhibiting externalizing-type problems are more likely to come to clinical attention, leading to a higher likelihood of these children being included in pediatric clinical populations.…”

“…That a relatively small amount of variance in symptoms is explained by the PRS has been found in other studies; for example, a recent study in a clinical ADHD cohort found the PRS explained 1.8%–2.9% of variance in ADHD symptom level. 11 …”

“…That a relatively small amount of variance in symptoms is explained by the PRS has been found in other studies; for example, a recent study in a clinical ADHD cohort found the PRS explained 1.8%-2.9% of variance in ADHD symptom level. 11 Separately examining hyperactivity/impulsivity and inattention symptoms showed that the association with ADHD PRS was slightly stronger for hyperactivity/impulsivity symptoms than for inattention symptoms. These findings are similar to a study of a clinical ADHD population that found a larger difference in levels of hyperactivity symptoms than inattention symptoms between high and low PRS groups.…”

“…These scores have been shown to explain about 5% of the variance of ADHD case-control status in independent samples 1 and are associated with dimensional measures of ADHD symptoms in both clinical and population-based studies. 11 , 12 , 13 However, less is known about how ADHD PRS is associated with the longitudinal course of the disorder and whether people with a high genetic burden, as reflected in higher PRSs, may be more likely to show a more persistent course.…”

The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

“…For example, ADHD-PRS was found to associate with symptoms of hyperactivity-impulsivity and to be mediated by white matter microstructure in brain regions that have been suggested to have a role in ADHD pathology 51,52 . In addition, ADHD-PRS was found to predict educational achievement 53 , to be linked with the severity of the clinical profile in those with high PRS 54 , and even to predict MPH response 55 . Although the etiology and pathways involved in ADHD cannot be revealed by using PRS only, this approach seems to be a powerful tool studying endophenotypes of the heterogeneous disorder.…”