Dopamine system genes and ADHD: a review of the evidence

Abstract

The search for genes influencing the development of attention-deficit/hyperactivity disorder (ADHD) has identified a number of associated genes within, or influencing, the dopamine neurotransmitter system. The focus on this system as the site of genetic susceptibility was prompted by information from animal models, particularly transgenics, as well as the mechanism of action of the psychostimulants, the primary pharmacological treatment for ADHD. Thus far, genes in the dopamine system reported as associated with ADHD, by at least one study, include the dopamine transporter, the dopamine receptors D1, D4 and D5, as well as genes encoding proteins that control the synthesis, degradation and release of dopamine. For some of these genes, replication across studies provides evidence supporting the relationship; however, for others, the data is far from conclusive and further work is needed. The quick progress in the genetic findings was initially surprising given the complexity of the phenotype and the relatively small sample sizes used in the initial studies. However, the high heritability of ADHD, as indicated by twin studies, may have contributed to the success. The genes studied so far are estimated to contribute only weakly or moderately to the risk for the development of ADHD. This may be because these genes, in fact, make only a small contribution. However, few studies have comprehensively examined the genetic information across the gene. This will lead to underestimates of risk if the polymorphism(s) tested is/are not the functional change(s) actually contributing to the genetic susceptibility and if linkage disequilibrium between tested marker(s) and causal variant(s) is weak, or if there is substantial allelic heterogeneity. While the studies thus far are very promising, virtually nothing is known on precisely how genetic variation in these genes actually contributes to risk; thus, functional studies are now required.