Association and linkage of the dopamine transporter gene (DAT1) and cognitive deficits attributed to attention deficit hyperactivity disorder

Efforts to identify genetic factors in psychiatric disorders have been particularly challenging, in part because of the very complex nature of the disorders themselves, but also due to the limitations of nosological and statistical tools available to researchers. Within the last few years, however, molecular and statistical genetic advances have cast new light on the search for the genetic bases of complex traits, and a number of researchers have cited associations between specific genes (i.e., DAT1 and DRD4) with specific psychiatric conditions (i.e., ADHD or Tourette syndrome). The purpose of the present investigation was to determine whether or not recent findings relating DAT1 to behavioral ratings of ADHD would generalize to other indicators of the disorder. Neuropsychological tests of executive function were used as 'behavioral markers' of ADHD. Between-family association analyses and within-family logistic regression analsyes, were employed in the present study (1) to examine whether executive functions such as attention and impulse control show association and linkage with the DAT1 gene, and (2) to examine whether the executive function measures would help to define the phenotype for ADHD and thus better detect linkage with the DAT1 gene. 92 children were evaluated, using symptom rating scales and a battery of executive function tests. DNA samples were collected from the children and from their parents using a buccal brush procedure. The results of the study offer corroborating evidence for linkage and association of DATI with tests of executive function. However, of the two DAT1 alleles most commonly seen in the population (viz., 480-bp and 440-bp), it was the low-risk 440-bp allele that showed linkage and association with the executive function measures. The direction of these results diverges from earlier investigations and suggests that, rather than predisposing individuals to greater impairment, the 480-bp allele instead protects against impairment. Limitations and implications of the current research are addressed.