A role for neurotransmission and neurodevelopment in attention-deficit/hyperactivity disorder

Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is not completely understood, it is well known that the disorder has a moderate to high genetic component, with an estimated heritability of 76% [1]. The mode of transmission is likely to be due to many susceptibility genes with small effects. Moreover, recent research findings have highlighted the relevance of gene-gene and gene-environment interactions in explaining the heterogeneous ADHD phenotype [2-4]. Several susceptibility genes have been proposed in almost 15 years of molecular research on ADHD, mainly on the basis of neurobiological hypotheses for ADHD. However, the success of these investigations can be considered as limited, because many studies were not able to replicate the positive results [1,4]. Here, we review the main results obtained so far in the ADHD molecular genetics field and suggest new ways of investigation that might help to clarify the genetic component of ADHD.The dopaminergic theory proposed to explain the neurobiology of the disorder [5], initially largely based on pharmacological evidence, states that abnormal levels of dopamine cause ADHD. This led in 1995 to the first association study by Cook et al. [6], who investigated a 40 bp variable number tandem repeat (VNTR) in the 3' untranslated region of the dopamine transporter gene (DAT1) in ADHD families. Using the family-based approach called 'haplotype relative risk', an association with the ten-repeat allele was detected. In the following year, LaHoste et al. [7] investigated another dopaminergic gene, the dopamine D4 receptor gene (DRD4). In this study [7], the frequency of a 48 bp VNTR in exon 3 was compared between ADHD cases and controls and an association with the seven-repeat allele was observed. These two genes, specifically through these variants, became the most studied genes in ADHD molecular genetics, with some positive and some negative results. Other polymorphisms in the two genes and in genes codin