Putative genetic and environmental factors influencing Attention-Deficit/Hyperactivity Disorder (ADHD) in a South African sample
Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent childhood onset externalising disorder for which the negative ramifications have been well documented. Although the disorder has been shown to be highly heritable, molecular genetic studies into the aetiology of the disorder have been plagued by conflicting findings. The aim of this thesis was to find reasons for the mixed findings, focusing particularly on the heterogeneous nature of the disorder. This was done to provide future researchers with tools that would enable them to not only select more homogeneous samples, but to also take pertinent confounding factors into account when studying the aetiology of ADHD. The ultimate aim was to reduce the conflicting findings regarding the aetiology of ADHD, and in doing so enabling a better understanding of the disorder to be gained. In addition, this study aimed to provide information on genetic and environmental factors influencing ADHD in a South African sample, a country where there is a dearth of knowledge in this regard. The possibility of genetic factors playing a role in ADHD in South Africa was first confirmed through a family study examining whether ADHD symptoms aggregate in families. Results showed that inattention and total ADHD symptoms do aggregate in families, and is therefore influenced by additive genetic and/or shared environmental factors. In subsequent chapters, reasons for the mixed findings were tested. Findings showed that neither the ADHD subtypes, nor ADHD comorbid with ODD, represent distinct disorders. Rather, the subtypes were found to be variations of the same underlying disorder, whilst the frequent co-occurrence of ADHD and ODD was found to be due to shared environmental factors influencing both. The study did, however, show aetiological differences in ADHD between males and females, although these differences were more quantitative than qualitative in nature. Females required a greater liability of risk factors before manifesting the disorder compared to males. Moreover, delivery complications were found to influence ADHD symptoms in families where only one child was diagnosed with the disorder (simplex ADHD), but not in families with more than one diagnosed family member (multiplex ADHD). Finally, two molecular genetic studies were conducted to determine the effect of gene-environment interactions on ADHD, as well as examine the possibility that rare genetic variants influence the disorder. The first study showed a significant interaction effect between pregnancy and/or delivery complications and a variable number of tandem repeats polymorphism in the dopamine transporter gene (DAT1 3’ uVNTR) on ADHD symptom severity. Pregnancy and/or delivery complications played a role in ADHD symptom severity, but only in individuals homozygous for the 10-repeat allele of the DAT1 3’ uVNTR. This result points to the DAT1 3’ uVNTR having an indirect rather than a direct effect on ADHD symptom severity, and serves as a possible explanation for the mixed findings. The second molecular genetic study tested whether any rare genetic variants of the monoamine oxidase A variable number of tandem repeats polymorphism (MAOA-uVNTR) could be found in a sample of children diagnosed with ADHD. Results from this study showed a rare deletion of 12 base pairs at the tail-end of the fourth repeat of the 30 base pair sequence in two siblings diagnosed with ADHD. In conclusion, findings showed that a reduction in conflicting findings may result if researchers distinguish between the sexes, as well as between simplex and multiplex ADHD, prior to conducting research into the aetiology of the disorder. Moreover, a further reduction in the conflicting findings may result if researchers take gene-environment interactions into account when studying genetic and environmental factors influencing ADHD. Finally, it may be worthwhile for researchers to search for rare mutations in well-known polymorphisms when studying the genetic aetiology of ADHD.