The main aim of this study was to examine the association between attention-deficit hyperactivity disorder (ADHD)-associated genes and the course of ADHD. Subjects were derived from identically designed case-control family studies of boys and girls with ADHD and a genetic linkage study of families with children with ADHD. Caucasian probands and family members with ADHD and with available genetic data were included in this analysis (N = 563). The course of ADHD was compared in subjects with and without putative risk alleles (DRD4 7-repeat allele, DAT1 10-repeat allele, and 5HTTLPR long allele). The persistence of ADHD (full or subthreshold diagnosis in the last month) was plotted using Kaplan-Meier survival functions and tested with Cox proportional hazard models. Survival analyses revealed that by 25 years of age 76% of subjects with a DRD4 7-repeat allele were estimated to have significantly more persistent ADHD compared with 66% of subjects without the risk allele. In contrast, there were no significant associations between the course of ADHD and the DAT1 10-repeat allele (P = 0.94) and 5HTTLPR long allele. Our findings suggest that the DRD4 7-repeat allele is associated with a more persistent course of ADHD.
Behavioral and molecular genetic studies indicate that attention-deficit hyperactivity disorder (ADHD) is a complex phenotype influenced by multiple genes of small effect. Multiple candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder (Faraone et al., 2005, Li et al., 2006, Purper-Ouakil et al., 2005 and Yang et al., 2007). For the eight genes for which the same variant has been studied in three or more case— control or family-based studies, seven have shown statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies (DRD4, DRD5, DAT1 [SLC6A3], DBH, HTT [SLC6A4], HTR1B, and SNAP25) ( Faraone et al., 2005 and Mick and Faraone, 2008). Maher et al.'s (2002) meta-analysis of dopamine system genes showed positive associations of ADHD with DRD4 and DRD5, while DAT1 did not reach significance (P = 0.06). However, the functional implications of these genes remain unclear.
One possibility of the putative functional effect of ADHD-associated genes could be on their impact on the course of ADHD. Prior work suggests that persistent ADHD may have a higher familial loading than remitting forms of the disorder (Biederman et al., 1995 and Manshadi et al., 1983): the risk of ADHD among children of ADHD adults was much higher than the risk for ADHD among relatives of children with ADHD (Biederman et al., 1995). This high familial loading in persistent cases of ADHD suggests that genes may play a role in persistent ADHD.
Two studies have examined the effects of genes on functional outcomes into adulthood and have produced inconsistent results. Mill and colleagues (2006) showed longitudinal evidence that risk variants in DRD4 (7-repeat allele in exon 3 VNTR) and DAT1 3′-untranslated region 40 base-pair VNTR (10/10 genotype) predicted poor adult outcomes such as a criminal conviction, evidence of aggression, or long-term unemployment. Barkley et al. (2006b) found that the DAT1 9/10 genotype was associated with greater symptoms of ADHD, externalizing scores, and family, educational, and occupational deficits into adulthood. Additionally, the two studies that have examined the effects of genes on the persistence of an ADHD diagnosis have also produced inconsistent results. Shaw and colleagues (2007) found that subjects with at least one copy of the DRD4 7-repeat allele were significantly less likely to retain the diagnosis of combined-type ADHD after 6 years. Langley and colleagues (2009) found that the DRD4 7-repeat allele was associated with persistent ADHD. Most recently, Franke et al. (2008) found that a 9-6 DAT1 haplotype was associated with adult ADHD, and Johansson et al. (2007) showed an association between adult ADHD and DRD5 but not DAT1 or DRD4. The inconsistencies among these findings call for additional studies on the molecular genetics of persistence of ADHD.
The main aim of this study was to examine the association between ADHD-associated genes and the course of the disorder. To this end we examined data from large samples of well-characterized youth with ADHD and their affected first-degree relatives who had been genotyped at three loci in three genes implicated in the risk for ADHD: DRD4, DAT1, and HTT. Based on the evidence from longitudinal twin studies that show a strong genetic influence on the stability of ADHD symptoms ( Kuntsi et al., 2005, Larsson et al., 2004 and Price et al., 2005), we hypothesized that variants in these genes would predict a more persistent course of ADHD.
