• Anita Thapar, Kate Langley, Tom Fowler, Frances Rice, Darko Turic, Naureen Whittinger, John Aggleton, Marianne Van den Bree, Michael Owen, and Michael O'Donovan.
• Department of Psychological Medicine, College of Medicine, School of Psychology, Cardiff University, Heath Park, Cardiff, Wales. thapar@cardiff.ac.uk
• Arch Gen Psychiat. 2005 Nov 1; 62 (11): 1275-8.

ContextEarly-onset antisocial behavior accompanied by attention-deficit/hyperactivity disorder is a clinically severe variant of antisocial behavior that is associated with a particularly poor outcome. Identifying early predictors is thus important. Genetic and prenatal environmental risk factors and prefrontal cortical function are thought to contribute. Recent evidence suggests that prefrontal cortical function is influenced by a valine/methionine variant in the catechol O-methyltransferase (COMT) gene.ObjectiveTo test the a priori hypothesis that this genetic variant predicts early-onset antisocial behavior in a high-risk sample and further examine the effects of birth weight, an environmentally influenced index of prenatal adversity previously linked to childhood disruptive behaviors and genotype x birth weight interaction.Design, Setting, And ParticipantsA family-based genetic study was undertaken between 1997 and 2003. Participants were prospectively recruited from child and adolescent psychiatry and child health clinics in the United Kingdom and included 240 clinic children who met diagnostic criteria for attention-deficit/hyperactivity disorder or hyperkinetic disorder. Participants underwent comprehensive standardized assessments including measures of antisocial behavior and IQ. Main Outcome Measure DSM-IV symptoms of childhood-onset conduct disorder rated by trained interviewers using a standard diagnostic interview.ResultsThe results show main effects of the COMT gene variant (P = .002), birth weight (P = .002), and a significant gene x environment (COMT x birth weight) interaction (P = .006).ConclusionsEarly-onset antisocial behavior in a high-risk clinical group is predicted by a specific COMT gene variant previously linked with prefrontal cortical function and birth weight, and those possessing the val/val genotype are more susceptible to the adverse effects of prenatal risk as indexed by lower birth weight.

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