Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3 0 -untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3 0 -UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta-analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3'UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148-bp allele consistent with recent meta-analyses. The strongest overall association (P = 0.02) and increased risk for the 148-bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00-1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long-term clinical outcome.

BackgroundThe Attention Network Test (ANT) generates measures of different aspects of attention/executive function. In the present study we investigated whether adults with ADHD performed different from controls on measures of accuracy, variability and vigilance as well as the control network. Secondly, we studied subgroups of adults with ADHD, expecting impairment on measures of the alerting and control networks in a subgroup with additional symptoms of affective fluctuations.MethodsA group of 114 adults (ADHD n = 58; controls n = 56) performed the ANT and completed the Adult ADHD Rating Scale (ASRS) and the Mood Disorder Questionnaire (MDQ). The latter was used to define affective fluctuations.ResultsThe sex distribution was similar in the two groups, but the ADHD group was significantly older (p = .005) and their score on a test of intellectual function (WASI) significantly lower than in the control group (p = .007). The two groups were not significantly different on measures of the three attention networks, but the ADHD group was generally less accurate (p = .001) and showed a higher variability through the task (p = .033).The significance was only retained for the accuracy measure when age and IQ scores were controlled for. Within the ADHD group, individuals reporting affective fluctuations (n = 22) were slower (p = .015) and obtained a lower score on the alerting network (p = .018) and a higher score on the conflict network (p = .023) than those without these symptoms. The significance was retained for the alerting network (p = .011), but not the conflict network (p = .061) when we controlled for the total ASRS and IQ scores.DiscussionAdults with ADHD were characterized by impairment on accuracy and variability measures calculated from the ANT. Within the ADHD group, adults reporting affective fluctuations seemed to be more alert (i.e., less impacted by alerting cues), but slower and more distracted by conflicting stimuli than the subgroup without such fluctuations. The results suggest that the two ADHD subgroups are characterized by distinct patterns of attentional problems, and that the symptoms assessed by MDQ contribute to the cognitive heterogeneity characterizing groups of individuals with ADHD.

It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.

Difficulties related to inhibition and set-shifting have been suggested as possible endophenotypes of Attention Deficit Hyperactivity Disorder (ADHD). However, such difficulties have not been consistently found in studies using standard neuropsychological tests. This has been partly explained by the complexity of these tests and the need to include contrast measures which control for more basic functions. The purpose of the present study was to examine whether difficulties related to inhibition and set-shifting in adult ADHD patients could be revealed by the Color Word Interference Test (CWIT) from the Delis Kaplan Executive Function System (D-KEFS). A clinically recruited group of adults with ADHD (n = 60) obtained significantly lower scores than population derived controls (n = 60) on both primary summary (p < .001) and contrast measures (p = .004) of set-shifting. The differences between the groups remained statistically significant after controlling for intellectual function and working memory (p = .003). However, no significant differences between the groups were observed on any measure of inhibition. The study indicates that adults with ADHD have specific difficulties with set-shifting as measured by the CWIT, difficulties that probably also reflect problems related to executive function in their daily life.