Evidence that the dopamine D4 receptor is a susceptibility gene in attention deficit hyperactivity disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral problem afflicting 5–10% of children and adolescents and persisting into adulthood in 30–50% or more of cases.^1,2 Family, twin, and adoption studies suggest genetic factors contribute to ADHD and symptoms of inattention, impulsivity, and hyperactivity.^3–5 Because stimulant intervention is effective in reducing ADHD symptoms in about 70–80% of cases, molecular genetic investigations of genes involved in dopamine regulation are currently underway by many groups.^6–8 In a case control study of the dopamine D4 receptor gene (DRD4) and ADHD, La Hoste and colleagues⁹ found an increase of a 7-repeat variant of a 48-bp VNTR in exon 3¹⁰ among ADHD subjects compared to controls. Swanson and colleagues¹¹ replicated this finding in a sample of 52 ADHD probands and their biological parents using a haplotype relative risk analysis. Here, we describe linkage investigations of the VNTR and ADHD in affected sibling pair (ASP) families and singleton families using both the transmission disequilibrium test (TDT)¹² and a mean test of identity-by-descent (IBD) sharing. Using the TDT in the total sample, the 7 allele is differentially transmitted to ADHD children (P = 0.03) while the mean test revealed no evidence of increased IBD sharing among 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