The current results extend our understanding of different elements of impulsive choice, their genetic underpinnings and by extension their putative neurobiological basis. By providing evidence for differential genetic associations the results further validate the distinction between IDIR and delay aversion in models of impulsive choice (1). Using a hypothesis testing approach we predicted that IDIR (as measured by percentage of choices for the small-sooner reward in the post reward
condition) would be associated with DAT1
. This was based on the notion that IDIR is the result of altered signaling of delayed rewards modulated by dopamine function, which is affected by functional polymorphisms in the DAT1
gene. The result was negative and so the findings were at odds with the previous studies linking DAT1 genotype to impulsive choice, delayed responding (18
), delay discounting and trait impulsivity (56
). However bearing in mind the nature of the current sample it may be that effects of DAT1
on impulsive choice are sample specific and in particular may not underpin impulsive choice specifically in ADHD. The 10R allele may confer risk for ADHD only in combination with additional DNA variants in the DAT1 gene. Thus, we had found that a specific haplotype of the DAT1
gene is associated with combined-type ADHD (57
), replicating a previous report from a different sample (58
); additional DAT1
genetic variants from the 5′ region of the gene have also been reported to be associated with ADHD (59
). In general, it has been difficult to identify robust and consistent associations between specific dopamine genotypes, including DAT1
and putative neuropsychological endophenotypes (60
). The current result therefore adds to this rather fragmented picture, although it is not possible, of course, to rule out the effects of variations in dopamine genes, other than DAT1, involved in dopamine neurotransmission on IDIR.
Our second hypothesis was that delay aversion (the additional effect of linking small-sooner reward choices to delay reduction) would be associated with 5-HTTLPR genotype. This was based on the view that delay aversion was a specific case of a more general avoidant response to aversive events and therefore would be mediated by similar neurobiological mechanisms linked to serotonin function (34
). As predicted, 5-HTTLPR genotype was associated with delay aversion with s-allele carriers more delay averse than non-carriers. This finding should be interpreted in relation to a more general link between 5-HTTLPR and impulsive choice seen in tryptophan depletion studies suggesting serotonin status affects waiting behavior and delay-related choice in other populations (26
). However, it presents the first study to extend this to the effects of 5-HTTLPR genotype on impulsive choice behavior on laboratory tasks. It also represents one of the first studies implicating this genotype in ADHD neuropsychology.
Although not ideally placed to explore the moderation of these effects by ADHD status given the familial relations between affected and unaffected cases we conducted separate exploratory analyses for these groups. This confirmed the observation of a rather different pattern of results for the two groups and an unexpected heterosis effect in the ADHD group (the s/l group being the most delay averse). This raises the possibility that 5-HTTLPR genotype effects on impulsive behaviour may be dependent on disorder status or more generally on participant characteristics. This possibility has not been investigated systematically as most studies of 5-HTTLPR s-allele effects on amygdala reactivity have typically been in samples of healthy volunteers with no history of affective or other psychiatric disorders.
Although most studies have not specifically tested for it, a number of studies have found group-specific evidence of molecular heterosis at the 5HTT
gene. Heterozygote subjects have shown lower [I125]beta-citalopram serotonin transporter binding in cocaine users (62
), increased white-matter lesions among depressed patients (63
), higher cognitive function in elderly adults (64
) and lower availability of central 5HTT (16
). In a recent study, Malmberg et al. (65
) found associations between disruptive behaviour disorder and s/l genotype. Explanations for these effects include; (i) an inverted U-shaped response curve in which either too little or too much gene expression is deleterious; (ii) an independent third factor causing a hidden stratification of the sample such that both the two homozygote genotype (s/s and l/l) are independently associated with the highest phenotype score relative to the heterozygote (e.g., s/l); (iii) greater fitness in heterozygotes because they show a broader range of gene expression than both homozygotes (for a review see [(66
)]). Clearly, although intriguing, our finding showing a disorder specific heterosis effect in families with ADHD children needs to be confirmed in other large independent samples with non-related controls.
The current results may take us further in understanding heterogeneity in ADHD. Previous studies (6
) found that only a sub-set of ADHD children show impulsive responding on the MIDA. This may therefore be a marker of a sub-type of ADHD in which 5-HTTLPR polymorphisms play a particularly important role in the pathogenesis of the condition. This may explain the inconsistency in results relating to the association between ADHD and this genotype. The expectation is that effects would be larger for 5-HTTLPR genotypes in a refined delay averse sample of ADHD children. If this were the case it may be possible to isolate a sub-group whose ADHD is mediated by delay averse and might respond to serotonergic drugs (39
) as a component of their treatment on the one hand or delay training on the other (25
). The results of Zepf et al. (67
) demonstrating that ADHD children with comorbid anxious-depression and/or aggression were sensitive to tryptophan depletion, highlights the possibility that a delay averse sub-group might be more likely to have these comorbidities.
The current study had many strengths. These included the large sample and the use of an experimental paradigm to dissect different elements of impulsive choice; however, there were a number of limitations. First, the skewed distribution of the IDIR measure and the need to dichotomize it for the analysis rather than use it as a continuous measure might have reduced its sensitivity compared with the delay aversion measure, the negative finding therefore needs to be interpreted with caution, although the effects were very far from significant. Second, the study did not include direct measures or manipulations of serotonin or dopamine levels which would have helped resolve issues around the functional significance of the different allelic combinations. Third, there were insufficient affected girls in this subset of the IMAGE sample to provide power to include gender as a factor in the analysis. Finally, the current sample with genotypic information did not include unrelated controls - this means that it remains uncertain how specific the role of these genotypes might be to ADHD because of the familial link and associated genetic overlap between probands and their unaffected sibs. Future studies should include biologically unrelated controls and groups of patients with other disorders to examine this issue.