Abstract
The genetic mechanisms involved in attention deficit hyperactivity disorder (ADHD) are being studied with considerable success by several centres worldwide. These studies confirm prior hypotheses about the role of genetic variation within genes involved in the regulation of dopamine, norepinephrine and serotonin neurotransmission in susceptibility to ADHD. Despite the importance of these findings, uncertainties remain due to the very small effects sizes that are observed. We discuss possible reasons for why the true strength of the associations may have been underestimated in research to date, considering the effects of linkage disequilibrium, allelic heterogeneity, population differences and gene by environment interactions.With the identification of genes associated with ADHD, the goal of ADHD genetics is now shifting from gene discovery towards gene functionality – the study of intermediate phenotypes ('endophenotypes'). We discuss methodological issues relating to quantitative genetic data from twin and family studies on candidate endophenotypes and how such data can inform attempts to link molecular genetic data to cognitive, affective and motivational processes in ADHD.The International Multi-centre ADHD Gene (IMAGE) project exemplifies current collaborative research efforts on the genetics of ADHD. This European multi-site project is well placed to take advantage of the resources that are emerging following the sequencing of the human genome and the development of international resources for whole genome association analysis. As a result of IMAGE and other molecular genetic investigations of ADHD, we envisage a rapid increase in the number of identified genetic variants and the promise of identifying novel gene systems that we are not currently investigating, opening further doors in the study of gene functionality.
Highlights
Research into the etiology of attention deficit hyperactivity disorder (ADHD) exemplifies the way that inter-disciplinary research fosters collaboration and opens up new avenues of investigation
We subsequently reported a similar pattern of findings using the stage I sample of 680 families from the International Multi-centre ADHD Gene project [17]
With the primary emphasis on delineating causal pathways, the study of cognitive endophenotypes represents a second stage in molecular genetic research on ADHD: once genetic associations are identified in the International Multi-centre ADHD Gene (IMAGE) and other ADHD samples, the functionality of the risk genes – the mechanisms by which the genes increase the risk for the disorder – becomes a key research focus
Summary
Research into the etiology of attention deficit hyperactivity disorder (ADHD) exemplifies the way that inter-disciplinary research fosters collaboration and opens up new avenues of investigation. More recently the SNP consortium was established to identify single nucleotide polymorphisms (SNPs) that occur far more frequently, approximately one every 500 base pairs and are useful for high-density association mapping These are key to current studies since association, unlike linkage, can only be detected by markers that are correlated with functional variants in the population and are informative over very small distances. With the primary emphasis on delineating causal pathways, the study of cognitive endophenotypes represents a second stage in molecular genetic research on ADHD: once genetic associations are identified in the IMAGE and other ADHD samples, the functionality of the risk genes – the mechanisms by which the genes increase the risk for the disorder – becomes a key research focus Such investigation of the cognitive and motivational processes in ADHD within a genetic design is at its early stages (for reviews of initial findings, (see [38,39,40,41]). We can look forward to new insights and potential advances in our treatment of ADHD throughout the lifespan
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