Moderators of neuropsychological mechanism in attention-deficit hyperactivity disorder

Neuropsychological measures have been proposed as both a way to tap mechanisms and as endophenotypes for child ADHD. However, substantial evidence supporting heterogeneity in neuropsychological performance among youth with ADHD as well as apparent effect differences by sex, age, and comorbidity have slowed progress. To address this, it is important to understand sibling effects in relation to these moderators. 461 youth ages 6-17 years (54.8 % male, including 251 youth with ADHD, 107 of their unaffected biological siblings, and 103 non-ADHD controls) completed diagnostic interviews and a theoretically informed battery of neuropsychological functioning. A structural equation model was used to consolidate neuropsychological domains. Group differences between unaffected siblings of youth with ADHD and controls across each domain were first examined as the primary endophenotype test for ADHD. Moderation of these effects was evaluated via investigation of interactions between diagnostic group and both proband and individual level characteristics, including sex, age, and comorbidity status. Unaffected siblings performed worse than control youth in the domains of inhibition, response time variability, and temporal information processing. Individual age moderated these effects, such that differences between controls and unaffected siblings were pronounced among younger children (ages 6-10 years) but absent among older youth (ages 11-17 years). Evidence for moderation of effects by proband sex and comorbidity status produced more variable and smaller effects. Results support the utility of inhibition, response time variability, and temporal processing as useful endophenotypes for ADHD in future genetic associations studies of the disorder, but suggest this value will vary by age among unaffected family members.