DRD4 and DAT1 in ADHD: Functional neurobiology to pharmacogenetics

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common and potentially very impairing neuropsychiatric disorder of childhood. Statistical genetic studies of twins have shown ADHD to be highly heritable, with the combination of genes and gene by environment interactions accounting for around 80% of phenotypic variance. The initial molecular genetic studies where candidates were selected because of the efficacy of dopaminergic compounds in the treatment of ADHD were remarkably successful and provided strong evidence for the role of DRD4 and DAT1 variants in the pathogenesis of ADHD. However, the recent application of non-candidate gene strategies (eg, genome-wide association scans) has failed to identify additional genes with substantial genetic main effects, and the effects for DRD4 and DAT1 have not been replicated. This is the usual pattern observed for most other physical and mental disorders evaluated with current state-of-the-art methods. In this paper we discuss future strategies for genetic studies in ADHD, highlighting both the pitfalls and possible solutions relating to candidate gene studies, genome-wide studies, defining the phenotype, and statistical approaches.

Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders

“…Effects vary as a function of DRD4 and DAT1 variants and these 2 genes are the main candidate genes for pharmacogenetic investigation [69]. Several studies suggested that DRD4 7R variant is associated with lower response to stimulants, and patients with 7R require higher doses of methylphenidate (e.g.…”

DAT1 Gene Polymorphism in Children with Attention Deficit Hyperactivity Disorder

“…It is observed that controlling the concentration and duration of dopamine neurotransmission is performed through its reabsorption in the synaptic space (18). Immuno -histochemical studies have shown that DAT1 gene mRNA is expressed in dopaminergic neurons in the brain substantia nigra and ventral tegmental area and the protein is active in areas of the brain with dopaminergic innervation, including ventral mesencephalon and dorsal and ventral parts of corpus striatum (19,20).…”

Self-government of complex reading and writing brains informed by cingulo-opercular network for adaptive control and working memory components for language learning

“…Given the evidence that many of the working memory phenotype measures have been shown to have a genetic basis, not only specialized instruction but also genetic risk factors may mediate response to instruction and influence development of the brain’s mental government. There is substantial evidence that genetic variants in the dopamine receptor D4 gene ( DRD4 ) confer increased risk for ADHD [53–55]. However, the cognitive behavioral deficits in ADHD and reading disabilities are not the same [56].…”