ADHD is a highly heritable
psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the
catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for
ADHD. The high-activity
valine variant of this polymorphism degrades prefrontal
dopamine three to four times more quickly than the low-activity
methionine variant and could therefore contribute to the proposed hypodopaminergic state in
ADHD. Here we tested for association of this polymorphism with
ADHD and examined its influence on prefrontal cognition in
ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish
ADHD families (Hawi et al. (2000) Am J Med Genet 96:282-284). Here we re-examined this finding with an extended sample of 179
ADHD cases using a family control design. We also examined the performance of children and adolescents with
ADHD (n = 61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of
ADHD. COMT genotype, however, affected prefrontal cognition in
ADHD:
ADHD children who were homozygous for the
valine variant had significantly better sustained attention than those
ADHD children possessing at least one copy of the
methionine variant. Children possessing the
methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the
methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in
ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of
dopamine associated with the
methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in
ADHD.