Family-based candidate gene association studies in ADHD

Recent genetic studies in ADHD have focused on possible associations between ADHD and common monoamine polymorphisms. We have examined the following polymorphisms for association with this disorder: dopamine D4 exon III 7 repeat (DRD4), catechol-O-methyltransferase val/ met (COMT) and the serotonin transporter promoter region 44 bp deletion (5-HTTLPR). (1) We attempted to replicate our early report of an association between COMT and ADHD in an independently recruited group of 70 nuclear families using the haplotype relative risk design. However, we found no evidence for association of the COMT polymorphism and ADHD (or any of the DSM IV subtypes) in the current cohort or the expanded cohort of 118 Israeli triads. (2) We also failed to observe an association between the DRD4 7 repeat and ADHD in a group of 98 triads. (3) A significant decrease (10.29 % versus 30.88%) in the short/ short 5-HTTLPR genotype was observed in the ADHD DSM IV combined subtype compared to the HRR derived control group (Likelihood ratio = 9.62, P=0.008, N=68 triads). Since the short/short 5-HTTLPR genotype is predicted to result in less efficient clearance of serotonin, a deficit in this genotype as currently observed in the type III ADHD group, is predicted to produce lower than normal serotonin brain levels consistent with an impulsive phenotype.