Context: As genes associated with common disorders are increasingly identified, we need to progress from observing associations to identifying risk pathways. The high-activity COMT genotype, in the presence of attention-deficit/hyperactivity disorder (ADHD), has previously been shown to be associated with extreme antisocial behavior. The same genotype has also been implicated in affecting cognitive function in healthy individuals. Impaired cognitive function might therefore lie on the risk pathway from genotype to clinical outcome.
Objectives: To replicate the association between COMT genotype and antisocial behavior in ADHD and to then test whether (1) impaired executive control or (2) impaired social understanding act as intermediate phenotypes for this association and lie on the risk pathway between COMT genotype and antisocial behavior.
Design: Prospective epidemiological cohort sample.
Setting: The Avon Longitudinal Study of Parents and Children.
Participants: Four thousand three hundred sixty-five children with data on COMT Val¹⁵⁸Met genotype, ADHD symptoms and diagnoses, and measures of social cognition/understanding and executive control.
Main outcome measures: Antisocial behavior at age 7.5 years assessed using DSM-IV conduct disorder symptoms.
Results: We replicated the association of the high-activity COMT genotype, in the presence of ADHD, with extreme antisocial behavior (odds ratio, 2.82; 95% confidence interval, 2.02-3.94; P < .001 for the most severe antisocial behavior). The high-activity COMT genotype was associated with both executive control and impaired social understanding. The strength of the association between genotype and antisocial behavior was unchanged by including executive control in the model but dropped when impaired social understanding was included (odds ratio, 1.87; 95% confidence interval, 1.26-2.76; P = .002).
Conclusions: The high-activity COMT genotype in ADHD is associated with antisocial behavior in part via impaired social understanding. Impaired executive control was also associated with the high-activity COMT genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.