In a large sample of children and adults with ADHD, a polymorphism in a DRD4 gene was found to have an effect on the course of ADHD. Specifically, a survival function indicated that subjects with at least one copy of the DRD4 7-repeat allele had a significantly more persistent course of ADHD compared to subjects with ADHD without this risk allele. These results suggest that the DRD4 7-repeat allele genotype is associated with a more persistent course of ADHD.
Our results are consistent with recent findings by Langley and colleagues (2008)
showing that the DRD4
7-repeat allele was associated with a more persistent course of ADHD. However, Johansson et al. (2007)
did not find an association between DRD4
and adult ADHD. Our DRD4
finding also stands in contrast to those of Shaw and colleagues (2007)
who found that subjects with the DRD4
7-repeat allele were less likely to have persistent course of ADHD. Although the reasons for these discrepant findings are unclear, they could be due to Shaw et al.’s requirement that subjects meet full diagnostic criteria for ADHD combined-type to be considered persistent. In fact, if Shaw and colleagues had used any DSM-IV ADHD subtype to define persistence there would have been no effect of the DRD4
Although more work is needed to clarify this issue, this discrepancy raises the possibility that DRD4
may have a differential effect on inattentive and hyperactive symptoms. For example, Rowe et al. (1998)
, McCracken et al. (2000)
, and Lasky-Su et al. (2007
found the DRD4
7-repeat allele had a significant association with inattentive symptoms but not hyperactive-impulsive symptoms. On the other hand, a link between the DRD4
7-repeat allele and hyperactivity was implicated by a knockout mouse study. When that study disabled DRD4
in a knockout mouse model, dopamine synthesis increased in the dorsal striatum and the mice showed locomotor supersensitivity to ethanol, cocaine, and methamphetamine (Rubinstein et al., 1997
knockout mice also showed reduced novelty-related exploration (Dulawa et al., 1999
), which is consistent with human data suggesting a role for DRD4
in novelty seeking behaviors. However, a recent study of knockout mice by Helms et al. (2008)
suggests that the absence of dopamine receptors is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking.
Our finding that subjects with the DAT1
10/10 genotype were not at higher risk for a persistent course of ADHD are inconsistent with those of Mill et al. (2006)
who found that the DAT1
10/10 genotype was associated with a worse adult prognosis. It is important to note that Mill et al. (2006)
relied on a range of negative outcomes in subjects with ADHD including criminal conviction, substance dependence, and unemployment, as adulthood outcome measures while we relied on the persistence of the clinical diagnosis of ADHD, which may account for the difference in findings. Our findings are also inconsistent with findings reported by Barkley and colleagues (2006a)
who found that the DAT1
9/10 polymorphism was associated with poorer adult outcomes compared to the 10/10 homozygous condition. Our findings suggest that DAT1
is not associated with a persistent or remittent course of ADHD, and are consistent with recent findings by Johansson et al. (2007)
showing no association between DAT1
and adult ADHD. More work is needed to help reconcile these discrepant findings.
Although meta-analyses suggest that DRD4
represents a small risk factor for the development of ADHD (Faraone et al., 2001
; Faraone et al., 2005
; Li et al., 2006
; Maher et al., 2002
), the present findings indicate that this gene may also play a role in the persistence of the condition. Additionally, if a persistent course of ADHD is associated with genetic variants, then persistent ADHD may be a more powerful phenotype for identifying susceptibility genes. Our group has previously put forth such a hypothesis (Faraone et al., 2000
) based on the fact that persistent ADHD cases have a higher relative risk for the disorder in parents and siblings (19.7 and 17.2) than non-persistent cases (5.4 and 4.0).
The findings reported here should be viewed in light of some methodological limitations. Our borderline significant finding for DRD4 would not have survived any correction for multiple comparisons. However, our sound a priori hypothesis and the testing of only three polymorphisms alleviate this concern somewhat. The majority of our subjects did not have follow-up assessments and ages of offset of ADHD for remittent cases were made retrospectively. Because many persistent cases of ADHD were young children, it is unclear how long the ADHD would persist. However, the use of survival analysis assured that the estimated rates of persistence accounted for the wide range of subjects’ ages. We truncated our survival analyses at age 25 years due to the few remitting cases beyond this age. Future adult studies of ADHD should examine the effect of DRD4 after age 25. Because all of the subjects were Caucasian, the present results may not generalize to other populations. While not all subjects were referred, they were all derived from families of a referred child, so results may not generalize to non-referred samples. We did not investigate the persistence of ADHD subtypes, mainly because a third of the sample was first assessed with DSM-III-R. Future studies should investigate the role of these genes on the persistence of inattentive versus hyperactive/impulsive symptoms. Although we did not find any effect of psychotropic medications on the course of ADHD, our measures of medication assessment may have been too crude to find significant relationships. Future studies should investigate the relationships between medication, genotype, and course of ADHD. Despite these limitations, our findings suggest that the DRD4 7-repeat allele is associated with a more persistent course of ADHD.