EVIDENCE THAT THE DOPAMINE-D4 RECEPTOR IS A SUSCEPTIBILITY GENE IN ATTENTION-DEFICIT HYPERACTIVITY DISORDER

Attention deficit hyperactivity disorder (ADHD) is a common neurobehav ioral problem afflicting 5-10% of children and adolescents and persist ing into adulthood in 30-50% or more of cases.(1,2) Family, twin, and adoption studies suggest genetic factors contribute to ADHD and sympto ms of inattention, impulsivity, and hyperactivity.(3-5) Because stimul ant intervention is effective in reducing ADHD symptoms in about 70-80 % of cases, molecular genetic investigations of genes involved in dopa mine regulation are currently underway by many groups.(6-8) In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hos te and colleagues(9) found an increase of a 7-repeat variant of a 48-b p VNTR in exon 3(10) among ADHD subjects compared to controls. Swanson and colleagues(11) replicated this finding in a sample of 52 ADHD pro bands and their biological parents using a haplotype relative risk ana lysis. Here, we describe linkage investigations of the VNTR and ADHD i n affected sibling pair (ASP) families and singleton families using bo th the transmission disequilibrium test (TDT)(12) and a mean test of i dentity-by-descent (IBD) sharing. Using the TDT in the total sample, t he 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing amon g ASPs. In the current sample, the 7 allele attributes a 1.5-fold risk for developing ADHD over non-carriers of the allele estimated under a model described by Risch and Merikangas.(13).