The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3'-UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (chi(2)=10.8, 1 d.f., p=0.001, OR=2.9, 95% CI 1.4-6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.     

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.     

Effects of source of DNA on genotyping success rates and allele percentages in the Preschoolers with Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS)

OBJECTIVE: In children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and their parents, who were participants of the Preschool ADHD Treatment Study (PATS), we assessed the effect of source of DNA (from buccal or blood cells) on the genotyping success rate and allele percentages for the five polymorphisms in three candidate genes (DAT1, DRD4, and SNAP 25) investigated in the PATS pharmacogenetic study of response to stimulant medication. METHOD: At baseline assessment, 241 individuals (113 probands and 128 parents) consented to participate; 144 individuals (52 probands and 92 parents) provided blood samples from venipuncture, and 97 individuals (61 probands and 36 parents) provided buccal samples from cheek swab as specimens for isolation of DNA. Three types of polymorphisms-variable number of tandem repeat (VNTR) polymorphism, tandem duplication polymorphism (TDP), and single nucleotide polymorphism (SNP)-were evaluated, including the DRD4 gene 48-bp VNTR in exon III, the DAT1 gene 40-bp VNTR in 3'-untranslated region, the DRD4 gene TDP 120-bp duplication in the promoter region, the SNAP-25 gene TC-1069 SNP, and the SNAP-25 gene TG-1065 SNP. Standard procedures were used to genotype individuals for each of these five polymorphisms. RESULTS: Using the methods available in 2004, the genotyping success rate was on the average much greater for DNA from blood cells than buccal cells (e.g., 91% vs. 54% in probands). For some polymorphisms (DRD4-VNTR, DRD4-TDP, and SNAP25-TC SNP), allele proportion also varied by blood versus buccal source of DNA (e.g., 26.5% vs. 18.6% for the 7-repeat allele of the DRD4 gene). CONCLUSIONS: The much lower success rate for genotyping based on DNA from buccal than blood cells is likely due to the quality of DNA derived from these two sources. The observed source differences in allele proportion may be due to self-selection related to choice of how specimens were collected (from cheek swab or venipuncture), or to a selective detection of some alleles based on differences in DNA quality.     

Attention deficit hyperactivity disorder (ADHD) and the dopamine D4 receptor gene: evidence of association but no linkage in a UK sample.

Recent studies report association and linkage between attention deficit hyperactivity disorder (ADHD) and the 7-repeat allele of a 48 base-pair repeat in the dopamine D4 receptor gene (DRD4). We examined the frequency of this allele in a sample of probands with DSM-IV ADHD using a case-control design, as well as the transmission disequilibrium test (TDT) and haplotype-based haplotype relative risk (HHRR) in the subset of probands with DNA available from both parents. One hundred and thirty-two ADHD probands were compared with 189 controls (chi(2) = 6.17, 1 df, P = 0.01, OR = 1.73, 95% CI = 1.11--2.71). A total of 85 complete trios were available for within-family tests of association and linkage. Fifty-two heterozygous parents carrying one copy of the 7-repeat were informative for the TDT (29 transmitted vs 23 non-transmitted, chi(2) = 0.69). Analysis of the entire sample of 132 probands using TRANSMIT provided no additional evidence for excess transmission of the 7-repeat allele (58 transmitted vs 54 non-transmitted). HHRR gave similar results. We conclude that the case-control findings are likely to be falsely positive, resulting from genetic stratification. However we can not rule out alternative explanations of low statistical power and gene-environment correlation.     

Two dopamine genes related to reports of childhood retrospective inattention and conduct disorder symptoms.

The 7-repeat allele of the dopamine receptor D4 gene (DRD4) and the 10 repeat allele of the dopamine transporter gene (DAT1) have shown association and linkage with symptoms of attention deficit hyperactivity disorder (ADHD) in childhood. The parents of ADHD children (clinic group, n = 80 fathers and 107 mothers) and control children (control group, n = 42 fathers and 51 mothers) were the focus of this study. These parents reported retrospectively on their level of ADHD Inattention and Conduct Disorder symptoms in adolescence. In analyses of the relation of symptom levels to the DRD4 and DAT1 genotypes, fathers possessing the 7 repeat DRD4 allele had greater levels of both inattention and conduct disorder symptoms. Mothers with the 10/10 genotype had higher levels of inattention symptoms. Thus, genetic associations found in children may be replicable in their parents.     

The dopamine transporter gene and the impulsivity phenotype in attention deficit hyperactivity disorder: a case-control association study in a Korean sample

The dopamine transporter gene (DAT1) has been extensively studied as one of the candidate genes in attention-deficit/hyperactivity disorder (ADHD). Several studies have reported on the association between the DAT1 10-repeat allele and cognitive variables in ADHD. However, few studies have been designed to ascertain the association between DAT1 genotypes other than the 10-repeat allele and cognitive endophenotypes in ADHD. The aim of this study was to examine the relationship between the DAT1 genotypes and the candidate endophenotypes, inattention and impulsivity symptoms, as measured by the continuous performance test (CPT), in a Korean sample of 85 children diagnosed with DSM-IV ADHD. Compared to the normal control group, the frequencies of the 9/10 genotype were significantly higher in the ADHD probands (χ² = 13.45, p = 0.02, OR = 4.12, 95% CI: 2.21–12.34) and parents of probands (χ² = 11.60, p = 0.03). The 9-repeat allele frequencies were significantly higher in the ADHD probands (χ² = 11.55, p = 0.03, OR = 4.43, 95% CI: 1.55–11.78) and parents of probands (χ² = 12.70, p = 0.03) than the normal control group. Compared to the ADHD probands without the 9-repeat allele (n = 74), the mean T-score, with regard to the commission errors of the CPT, was significantly higher (p < 0.05) in the ADHD probands with the 9-repeat allele (n = 11). Compared to the ADHD probands with other DAT1 genotypes, the mean T-score, with respect to the commission errors of the CPT, was significantly higher in the ADHD probands with the 9/10 genotype (p < 0.05). The results of this study suggest the possibility of an association between the DAT1 9-repeat allele and the impulsivity phenotype of ADHD.     

Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (chi(2)=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.     

Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D4 receptor (DRD4) gene has been frequently implicated in its pathogenesis. OBJECTIVE: To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D1 receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele. DESIGN: Longitudinal cohort study. SETTING: National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years). MAIN OUTCOME MEASURES: Cortical thickness across the cerebrum and presence of DSM-IV-defined ADHD at follow-up. RESULTS: Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development. CONCLUSIONS: The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.     

Role of gene-gene/gene-environment interaction in the etiology of eastern Indian ADHD probands

Associations between attention deficit hyperactivity disorder (ADHD) and genetic polymorphisms in the dopamine receptors, transporter and metabolizing enzymes have been reported in different ethnic groups. Gene variants may affect disease outcome by acting synergistically or antagonistically and thus their combined effect becomes an important aspect to study in the disease etiology. In the present investigation, interaction between ten functional polymorphisms in DRD4, DAT1, MAOA, COMT, and DBH genes were explored in the Indo-Caucasoid population. ADHD cases were recruited based on DSM-IV criteria. Peripheral blood samples were collected from ADHD probands (N = 126), their parents (N = 233) and controls (N = 96) after obtaining informed written consent for participation. Genomic DNA was subjected to PCR based analysis of single nucleotide polymorphisms and variable number of tandem repeats (VNTRs). Data obtained was examined for population as well as family-based association analyses. While case-control analysis revealed higher occurrence of DAT1 intron 8 VNTR 5R allele (P = 0.02) in cases, significant preferential transmission of the 7R-T (DRD4 exon3 VNTR-rs1800955) and 3R-T (MAOA-u VNTR-rs6323) haplotypes were noticed from parents to probands (P = 0.02 and 0.002 respectively). Gene-gene interaction analysis revealed significant additive effect of DBH rs1108580 and DRD4 rs1800955 with significant main effects of DRD4 exon3 VNTR, DAT1 3′UTR and intron 8 VNTR, MAOA u-VNTR, rs6323, COMT rs4680, rs362204, DBH rs1611115 and rs1108580 thereby pointing towards a strong association of these markers with ADHD. Correlation between gene variants, high ADHD score and low DBH enzymatic activity was also noticed, especially in male probands. From these observations, an impact of the studied sites on the disease etiology could be speculated in this ethnic group.     

Is there a role for rare variants in DRD4 gene in the susceptibility for ADHD? Searching for an effect of allelic heterogeneity

Although several studies have demonstrated an association between the 7-repeat (7R) allele in the 48-bp variable number of tandem repeats (VNTRs) in the exon 3 at dopamine receptor D4 (DRD4) gene and attention-deficit/hyperactivity disorder (ADHD), others failed to replicate this finding. In this study, a total of 786 individuals with ADHD were genotyped for DRD4 exon 3 VNTR. All 7R homozygous subjects were selected for VNTR re-sequencing. Subjects homozygous for the 4R allele were selected paired by age, ancestry and disorder subtypes in order to have a sample as homogeneous as possible with 7R/7R individuals. Using these criteria, 103 individuals (66 with ADHD and 37 control individuals) were further investigated. An excess of rare variants were observed in the 7R alleles of ADHD patient when compared with controls (P=0.031). This difference was not observed in 4R allele. Furthermore, nucleotide changes that predict synonymous and non-synonymous substitutions were more common in the 7R sample (P=0.008 for total substitutions and P=0.043 for non-synonymous substitutions). In silico prediction of structural/functional alterations caused by these variants have also been observed. Our findings suggest that not only repeat length but also DNA sequence should be assessed to better understand the role of DRD4 exon 3 VNTR in ADHD genetic susceptibility.     

Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. METHODS: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. RESULTS: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. CONCLUSIONS: Our results support previous findings of an association between the DAT1 gene and ADHD.     

Prenatal smoking exposure and dopaminergic genotypes interact to cause a severe ADHD subtype.

BACKGROUND: In utero exposure to smoking and alcohol are common risk factors that have been associated with attention-deficit/hyperactivity disorder (ADHD) in human beings and animal models. Furthermore, molecular studies have focused on the association between ADHD and DNA polymorphisms in dopamine pathway-related genes. We examined the joint effects of genetic and prenatal substance exposures on DSM-IV and population-defined subtypes of ADHD. METHODS: Logistic regression was used to assess the relationship between ADHD subtypes, DAT1 and DRD4 polymorphisms, and prenatal substance exposures in a birth-record sample of male and female twin pairs, aged 7-19 years. RESULTS: Interactions between prenatal exposure to smoking and variations in the DAT1 and DRD4 loci were observed in children with either the DSM-IV or population-defined ADHD combined subtypes. The odds of a diagnosis of DSM-IV combined subtype was 2.9 times greater in twins who had inherited the DAT1 440 allele and who were exposed, than in unexposed twins without the risk allele. The OR was 2.6 in the population-defined subtype. Odds ratios for the DRD4 seven-repeat allele were 3.0 (2.8) in the population-defined (DSM-IV) combined ADHD subtypes. The OR for exposed children with both alleles was 9.0 (95% confidence interval=2.0-41.5) for the population-defined combined subtypes. CONCLUSIONS: Results indicate that smoking during pregnancy is associated with specific subtypes of ADHD in genetically susceptible children.     

Susceptibility genes for a trait measure of attention deficit hyperactivity disorder: a pilot study in a non-clinical sample of twins

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach.     

A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric syndromes affecting 5%–10% of school-age children worldwide. Distortions in the catecholaminergic system seem to be responsible for this condition. Within this system there are several candidate genes, the dopamine receptor D₄ (DRD4) and the dopamine transporter 1 (DAT1), with common polymorphism which might be associated with ADHD. We performed a family based association study with 36 trios and 19 parent proband pairs. All diagnoses were confirmed by the “Hypescheme” diagnostic computer program. In this study we did not observe an association of ADHD with DRD4 and DAT1 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method. The odds ratio for the DRD4 7-allele was 1.01 and 0.94 for both statistical tests, respectively, and the respective odds ratio for the DAT1 6-allele were 0.91 and 0.88.     

Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: no higher DAT availability in patients with homozygosity for the 10-repeat allele.

In 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability was assessed by [(99m)Tc]TRODAT-1 SPECT and correlated with 3' VNTR polymorphism of the DAT gene on chromosome 5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 were heterozygous (9-10). No statistically significant difference in DAT availability was found between patients with 10-10 carriers (DAT 1.28 +/- 0.34) and with at least one 9 allele (DAT 1.31 +/- 0.27); when smokers were excluded, DAT availability was 1.38 +/- 0.28 in the 10-10 carriers (n = 12) and 1.42 +/- 0.19 in the 9-10 and 9-9 carriers (n = 7). In conclusion, no higher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These results differ from a study in 11 Korean children with ADHD, in which 10-10 carriers showed higher DAT availability in [(123)I]IPT SPECT. Discrepancies may be explained by differences in patient's age, ethnical differences, different imaging techniques or the limited number of patients included in both studies.     

Association between the dopamine transporter gene and the inattentive subtype of attention deficit hyperactivity disorder in Taiwan

Attention deficit hyperactivity disorder (ADHD) is a common heritable childhood psychiatric disorder. Since methylphenidate, one of the main drugs used to treat ADHD, targets the dopamine transporter, this study examined the linkage disequilibrium (LD) structure of the dopamine transporter gene (DAT1) and investigated whether the DAT1 gene was associated with ADHD. This Chinese family-based association sample consisted of 273 DSM-IV diagnosed ADHD probands and their family members (n = 906). We screened 15 polymorphisms across the DAT1 gene, including 14 single nucleotide polymorphism (SNP) markers and the variable number of tandem repeat (VNTR) polymorphism in 3′-untranslated region (3′UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs): HB1 (intron 2 through intron 6), HB2 (intron 8 through intron 11), and HB3 (3′UTR). Family-Based Association Tests showed that no allele was significantly more transmitted than expected to the ADHD children for these 15 markers. Haplotype-Based Association Tests showed that a haplotype rs27048 (C)/rs429699 (T) was significantly associated with the inattentive subtype (P = 0.008). In quantitative analyses, this haplotype also demonstrated significant association with the inattention severity (P = 0.012). Our finding of the haplotype rs27048 (C)/rs429699 (T) as a novel genetic marker in the inattentive ADHD subtype suggests that variation in the DAT1 gene may primarily affect the inattentive subtype of ADHD.     

<Emphasis Type="Italic">DAT1</Emphasis> and <Emphasis Type="Italic">DRD4</Emphasis> genes involved in key dimensions of adult ADHD

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3′UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10^?4) and trait anger scores (p = 7.66 × 10^?4). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.     

Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder.

OBJECTIVE: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. METHOD: Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. RESULTS: For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. CONCLUSIONS: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.     

The dopamine D4 receptor and the hyperactivity phenotype: a developmental-epidemiological study

Attention-deficit hyperactivity disorder (ADHD) affects 2-6% of school-age children and is a precursor of behavioural problems in adolescence and adulthood. Underlying the categorical definition of ADHD are the quantitative traits of activity, impulsivity, and inattention which vary continuously in the population. Both ADHD and quantitative measures of hyperactivity are heritable, and influenced by multiple genes of small effect. Several studies have reported an association between clinically defined ADHD and the seven-repeat allele of a 48-bp tandem repeat polymorphism in the third exon of the dopamine D4 receptor gene (DRD4). We tested this association in a large, unselected birth cohort (n = 1037) using multiple measures of the hyperactivity phenotype taken at multiple assessment ages across 20 years. This longitudinal approach allowed us to ascertain whether or not DRD4 has a general effect on the diagnosed (n = 49) or continuously distributed hyperactivity phenotype, and related personality traits. We found no evidence to support this association.