Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies

Background

We reviewed systematically the results of genetic studies investigating associations between putative susceptibility genes for attention-deficit hyperactivity disorder (ADHD) and neuropsychological traits relevant for this disorder.

Methods

We identified papers for review through the PubMed database.

Results

Twenty-nine studies examined 10 genes (DRD4, DAT1, COMT, DBH, MAOA, DRD5, ADRA2A, GRIN2A, BDNF and TPH2) in relation to neuropsychological traits relevant for ADHD. For DRD4, the continuous performance test (CPT) and derived tasks were the most used tests. Association of high reaction time variability with the 7-repeat allele absence appears to be the most consistent result and seems to be specific to ADHD. Speed of processing, set-shifting and cognitive impulsiveness were less frequently investigated but seem to be altered in the 7-repeat allele carriers. No effect of genotype was found on response inhibition (the stop and go/no-go tasks). For DAT1, 4 studies provide conflicting results in relation to omission and commission errors from CPT and derived tasks. High reaction time variability seems to be the most replicated cognitive marker associated with the 10-repeat homozygosity. The other genes have attracted fewer studies, and the reported findings need to be replicated.

Limitations

Although we aimed to perform a formal meta-analysis, this was not possible because the number of studies using the same neurocognitive endophenotypes was limited. We referred only minimally to the various theoretical frameworks in this field of research; more detail would have been beyond the scope of our systematic review. Finally, sample sizes in most of the studies we reviewed were small. Thus, some negative findings could be attributed to a lack of statistical power, and positive results should be considered preliminary until they are replicated in extended samples.

Conclusion

Several methodological issues, including measurement errors, developmental changes in cognitive abilities, sex, psychostimulant effects and presence of comorbid conditions, represent confounding factors and may explain conflicting results.