The adrenergic receptor α-2A gene (ADRA2A) and neuropsychological executive functions as putative endophenotypes for childhood ADHD

There is resurgent interest in the psychiatric literature in endophenotypes, variables thought to more strongly reflect the effects of candidate genes than do manifest disorders. In a sample of 176 children with attention deficit hyperactivity disorder (ADHD) and 52 of their siblings, we examined the validity of several putative endophenotypes for ADHD that represent commonly used clinical measures of multiple cognitive/neuropsychological domains of executive functions (EFs). We review their distributional normality, their relations to ADHD symptoms in probands and unaffected siblings relative to nonADHD controls, and their correlation in siblings. We also tested the EF measures' associations with the ADRA2A gene and whether they mediated or moderated the associations between ADHD and ADRA2A. Several EF measures showed association with ADRA2A, as well as moderation, but not mediation, of its association with ADHD. Implications of the results for evaluating the validity and utility of putative endophenotype measures and for finding candidate gene effects on ADHD are discussed.