Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): Association of the high-enzyme activity val allele with ADHD impulsive-hyperactive phenotype

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and com bined type. Both environmental and genetic factors contribute to the etiolo gy of this complex disease. In the current investigation, a cat-echol-O-met hyltransferase (COMT) polymorphism that codes for a high versus low enzyme COMT activity was examined using family-based methods for a role in ADHD. U sing a haplotype relative risk design and a parent-to-proband allele transm ission test with 48 ADHD triads, we found an association between COMT and i llness (chi(2) = 4.72,p = 0.03, df = 1). In particular, the impulsive-hyper active type of ADHD (excluding inattention) ascertained by Diagnostic and S tatistical Manual of Mental Disorders (DSM IV), criteria (chi(2) = 8.34, P = 0.004, df = 1), by the Conners Teaching Rating Hyperactivity scale (Pears on chi(2) = 5.32, p = 0.02, df = 1) as well as by the Continuous Performanc e Test False Alarm scale (chi(2) = 2.78, P = 0.096, df = 1) were associated with the high enzyme activity COMT val allele. Similar results were obtain ed if genotype frequencies were compared. It should be noted that the assoc iation between the high-enzyme activity COMT val allele that increases CNS dopamine (and norepinephrine) clearance is consistent with the use of methy lphenidate, an agent that increases dopamine (and norepinephrine) turnover, in the treatment of this disorder. These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD. (C) 1999 Wiley-Liss, Inc.