Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele.

There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.     

No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset syndromes affecting 3%-6% of school-age children worldwide. Although the biological basis of ADHD is unknown, a dopaminergic abnormality has long been suggested. The dopamine D4 receptor gene (DRD4) has been mapped to chromosome 11p15.5 and has been implicated in predisposition to ADHD. Several independent genetic association studies have demonstrated increased frequency of the DRD4 7-repeat allele in ADHD cases compared with controls or excess transmission of the 7-repeat allele from parents to affected offspring. However, there have also been few negative studies. In this study we investigated 78 ADHD parent proband trios and 21 parent proband pairs for the transmission of the DRD4 alleles in HHRR and case control design. We found no significant differences in the frequency of the DRD4 alleles transmitted or not transmitted to ADHD cases from their parents nor when comparing case allele frequencies to ethnically matched controls. Therefore, it is unlikely that the DRD4 7-repeat allele is associated with ADHD in the Irish population.     

Association of dopamine D4 receptor (DRD4) polymorphisms with attention deficit hyperactivity disorder in Indian population.

Attention deficit hyperactivity disorder (ADHD) is a childhood onset neurobehavioral disorder. Several studies worldwide have implicated a possible association between ADHD and transmission of different polymorphisms of the dopamine D4 receptor gene (DRD4) in different ethnic groups. However, this is the first report on the transmission of different polymorphisms of DRD4 in Indian subjects. Association of 5' flanking 120-bp duplication, exon 1 12-bp duplication, and exon 3 48-bp variable numbers of tandem repeats (VNTR) were analyzed in 50 ADHD cases. Haplotype-based haplotype relative risk (HHRR) analysis and transmission disequilibrium test (TDT) were carried out to ascertain the association of these polymorphisms with the disorder. Linkage disequilibria (LD) between the polymorphisms were calculated using EH+ and 2LD programs. Our preliminary data showed lack of association between ADHD and transmission of the 5' flanking 120-bp duplication and exon 1 12-bp duplication. But, the transmissions of 6 and 7 repeat alleles of exon 3 48-bp VNTR showed significant association with ADHD. We have also examined the haplotype frequencies and biased transmission of one haplotype was observed in ADHD probands. LD analysis showed very strong disequilibrium between exon 1 12-bp duplication and exon 3 48-bp VNTR. Strong LD was also observed between the 5' flanking 120-bp duplication and exon 1 12-bp duplication. The observed association between higher repeat alleles of exon 3 48-bp VNTR and Indian ADHD children is consistent with some of the earlier reports.     

Exon 3 polymorphisms of dopamine D4 receptor (DRD4) gene and attention deficit hyperactivity disorder in Chinese children.

Dopamine D4 receptor (DRD4) gene is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). The 7-repeat allele of the variable-number-of-tandem-repeat (VNTR) polymorphism in exon 3 has been reported to be associated with ADHD. However, studies in Chinese populations have yielded conflicting results. We therefore perform another study to investigate the association between ADHD and DRD4 gene polymorphism in Chinese children in Hong Kong. In this prospective family-based and case-control study during January-June 2004, we recruited consecutive Chinese children diagnosed with ADHD by DSM-IV and sex-matched controls admitted for acute upper respiratory infection, excluding those with perinatal brain insults, mental retardation, or neurological deficits. VNTR polymorphisms of the DRD4 gene were determined by standard PCR followed by agarose gel electrophoresis. Sixty-four ADHD cases (52 boys, 12 girls), their family members, and 64 normal controls were recruited. The 4-repeat allele (84.4%) and the 4/4-repeat genotype (70.3%) were the most prevalent. Both family-based and case-control analyses showed no association between ADHD and DRD4 gene polymorphisms (transmission dysequilibrium test (TDT): P = 0.91 and P = 0.33 for the 7-repeat and 4-repeat alleles, respectively; OR for the 7-repeat allele = 2.01 (95% CI 0.07-60.4, P = 0.66), OR for the 4-repeat allele = 1.51 (95% CI 0.80-2.85, P = 0.2)). However, the longer repeat alleles had a positive trend association with ADHD (P = 0.01) in the case-control analysis. We concluded that ADHD is not associated with a particular VNTR polymorphism of the DRD4 gene. Further studies are needed to clarify the role of repeat length of the VNTR region of the DRD4 gene in the pathogenesis of ADHD.     

Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians: haplotype characterization and relevance of the 2-repeat allele.

The relationship of the dopamine D4 receptor gene (DRD4) to the behavioral trait of novelty seeking has not been uniformly consistent. A methodological shortcoming in previous studies may relate to the way different DRD4 variants were categorized. Because of evolutionary and functional (e.g., diminished potency to reduce cAMP) similarities between the 2- and 7-repeat (2R, 7R) alleles of the DRD4, we suggest grouping of these two alleles together may facilitate detection of biologically meaningful and reproducible association findings with behavioral traits. We measured novelty seeking with the Tridimensional Personality Questionnaire (TPQ) in a community sample of Caucasian, Korean, and Filipino subjects (N = 171) who were subsequently characterized for the DRD4 variable number of tandem repeats (VNTR). In the Korean sample, those with a 2R and/or 7R allele scored significantly higher on novelty seeking scale (P < 0.05). By contrast, grouping the VNTR alleles by size (2, 3, 4 vs. 5, 6, 7), as has been done in similar studies of Asian subjects, was not significant. Using the extreme discordant phenotype (EDP) strategy in the pooled sample and selecting the individuals within the upper and lower decile, we observed a trend for association with higher novelty seeking in individuals who carry the 2R and/or 7R alleles (P = 0.06). We also confirmed that the 2R allele in the Korean and Filipino subjects was the result of a one-step recombination event between the 4R and 7R alleles. This study suggests that genetic association analyses can benefit by consideration of the shared functional and evolutionary attributes of the DRD4 2R and 7R alleles.     

Investigation of the dopamine D5 receptor gene (DRD5) in adult attention deficit hyperactivity disorder

Several lines of evidence from neuroimaging, pharmacology and genetics support the involvement of the dopaminergic system in the etiology of Attention Deficit Hyperactivity Disorder (ADHD). Previous candidate gene studies have investigated the association between a dinucleotide (CA)(n) repeat polymorphism, located 18.5 kb from the start codon of the DRD5 gene, and ADHD. Association between the 148 bp allele and ADHD has been reported in some studies, however replication of the finding has not been consistent. We tested for an association between the (CA)(n) repeat and adult ADHD in a sample comprised of 119 families with adult ADHD probands and 88 unrelated adult ADHD cases with a corresponding number of controls matched for age, ethnicity and sex. In the family sample we found a non-significant trend for association between the 148 bp allele and ADHD (Z=1.91, p=0.055). An excess of non-transmissions was detected for the 150 and 152bp alleles (Z=-2.26, p=0.023; Z=-2.20, p=0.028). Quantitative analysis performed using the Brown Attention Deficit Disorder Scale (BADDS) showed association between the 150 bp allele and lower total score (p=0.011), and lower effort (p=0.008), activation (p=0.008) and attention (p=0.01) cluster scores. We did not replicate association findings in the case-control group, likely due to the lack of statistical power of this sample. Our findings add to the literature suggesting DRD5 (CA)(n) repeat has a modest effect in modulating susceptibility to adult ADHD but further studies are required.     

A haplotype relative risk study of the dopamine D4 receptor (DRD4) exon III repeat polymorphism and attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is a developmental syndrome expressed along three domains: inattention, hyperactive-impulsive, and combined type. Several investigations have recently examined the role of the dopamine DRD4 exon III repeat polymorphism in ADHD. The long 7 repeat allele of this receptor was shown in three family-based studies, but not in one case control design, to be a risk factor for this disorder. We now report an additional family-based study of DRD4 exon III repeat region and ADHD. However, in the current study we fail to observe preferential transmission of the DRD4 exon III long 7 repeat allele, chi(2) = 0. 142, P < 0.1, df = 1. Nor was any preferential transmission observed when genotypes were compared, chi(2) = 0.180, P > 0.1, df = 1. Possible reasons are discussed, especially lack of sufficient power in analying more refined phenotypes, why the current results in contrast to previous findings fail to support a role for the long form of the DRD4 receptor as a putative risk factor for ADHD.     

Parenting in adults with attention-deficit/hyperactivity disorder (ADHD)

Although the validity of adult ADHD is well established and research has identified a variety of impairments associated with the condition in adults, study of how ADHD impacts an adult's ability to parent has been relatively neglected. Parenting is a particularly important domain of functioning given the familial nature of the disorder and emerging evidence that parenting behaviors play a role in the development or maintenance of child ADHD symptoms, comorbid psychopathologies, and other associated difficulties. In this paper, we focus on three broad categories of cognitive dysfunction proposed across models of ADHD - cognitive processes (e.g., working memory, planning, and inhibitory control), self-regulation deficits (e.g., self-monitoring of performance to detect errors or the need for regulation of behavior and/or emotions), and motivational or arousal difficulties (e.g., response to incentives, delay aversion). We consider how these deficits may lead to impairments in the parenting behaviors of effective behavioral control and emotional responsiveness, and review the available evidence regarding parenting in adults with ADHD symptoms. We conclude by noting the limitations in existing studies, and argue for further research that is theoretically grounded in how core deficits of ADHD may be related to dimensions of parenting. The implications of an improved understanding of how ADHD impacts parenting for the development of early intervention or prevention programs are outlined.     

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.     

Association of attention-deficit/hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects

Attention-deficit/hyperactivity disorder (ADHD) is an important public health problem. Although serotonin is believed to be an important neurotransmitter in the etiology of this disorder, it remains unclear which specific 5-HT receptors are involved in regulating the symptoms of ADHD. Previous studies have provided favorable evidence for the association of ADHD with both the serotonin transporter gene and serotonin 1B receptor gene. To further investigate the role of other genes of the serotonergic pathway in ADHD, the current study examined variants of the serotonin 4 receptor gene in a relatively large sample of ADHD nuclear families. The T allele of the 83097 C>T polymorphism of HTR4 showed a tendency of preferential transmission to probands with ADHD (chi(2)=2.699, P=0.100). When haplotype TDT analysis of HTR4 was performed, we further found that the C/G haplotype of the 83097 C>T and 83198 A>G polymorphisms (chi(2)=8.783, P=0.003) and the C/G/C haplotype of these and the -36 C>T polymorphism (chi(2)=5.762, P=0.016) were under-transmitted to probands with ADHD. These results suggest that the HTR4 gene may play a role in the genetic predisposition to ADHD.     

Actigraphy and parental ratings of sleep in children with attention-deficit/hyperactivity disorder (ADHD)

STUDY OBJECTIVES: To assess various sleep parameters in latency-aged children with ADHD and their normally developing peers through the use of multiple sleep measures. DESIGN: Six sleep parameters were evaluated for two groups of children, ADHD and normal comparison. Each group consisted of 25 children (20 males, 5 females) who ranged in age from 7 to 11 years. All children underwent rigorous diagnostic procedures and the ADHD subjects were selected only if they displayed pervasiveness in their symptomatology and were medication naive. Parents completed a retrospective questionnaire which evaluated sleep problems over the past six months. Additionally, each child wore an actigraph for seven consecutive nights, and the child's parents completed a sleep diary during this time period. SETTING: N/A. PATIENTS or PARTICIPANTS: N/A. INTERVENTIONS: N/A. RESULTS: Based on the findings from the questionnaire, parents of children with ADHD reported significantly more sleep problems than parents of normally developing children. However, the majority of these sleep differences were not verified through actigraphy or sleep diary data, with the exception of longer sleep duration for children with ADHD and parent reports that describe increased bedtime resistence. It was also found that child-parent interactions during bedtime routines were more challenging in the ADHD group. CONCLUSIONS: Despite the possibility of intrinsic sleep problems such as longer sleep duration, results indicate that many of the sleep problems of children with ADHD may be due to challenging behaviours during bedtime routines. The reason for discrepancies among sleep studies employing objective measures as well as between retrospective and prospective measures are discussed.     

Further evidence from haplotype analysis for linkage of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder

Several studies have suggested a possible association of a polymorphism at the dopamine D4 receptor gene and attention-deficit hyperactivity disorder [LaHoste et al., 1996; Rowe et al., 1998; Smalley et al., 1998; Sunohara et al., submitted; Swanson et al., 1998]. The allele reported to be associated with attention-deficit hyperactivity disorder (ADHD) is the allele with seven copies of the 48 bp repeat in the third exon. We extend our study of the dopamine D4 gene and ADHD by testing for linkage using two additional polymorphisms in the dopamine D4 receptor gene and a polymorphism in the closely linked gene, tyrosine hydroxylase. We also searched for two previously reported deletions, a 13 bp and a 21 bp deletion in the first exon. We examined the haplotypes of three polymorphisms of the D4 receptor gene and observed biased transmission of two of these haplotypes. Our findings further support the role of the dopamine D4 gene in ADHD.     

Improving antisaccade performance in adolescents with attention-deficit/hyperactivity disorder (ADHD)

The goal of the study was to examine the effects of task manipulations on antisaccade accuracy and response times (RTs) of adolescents with attention-deficit/hyperactivity disorder (ADHD), age-matched controls, 10-year-olds and young adults. Order effects were tested by administering the task at the beginning and end of the session. Other manipulations involved a visual landmark to reduce demands on working memory and internal generation of saccades; spatially specific and non-specific cues at three intervals; and central engagement of attention through perceptual and cognitive means at three intervals. As expected, adolescents with ADHD were impaired relative to age-matched controls in terms of accuracy and saccadic RT on the first administration of the task. Although their accuracy improved with most of the manipulations, it did not improve disproportionately compared to age-matched controls. Nevertheless, with most of the manipulations, they could achieve the same level of accuracy as unaided controls on the first administration of the task. In contrast, the saccadic RTs of the ADHD group came close to normal under several conditions, indicating that elevated antisaccade RTs in this disorder may be related to attentional factors. The ADHD group made more premature saccades and fewer corrective saccades than both the age-matched and younger groups, suggesting difficulties with impulsivity and goal neglect. The findings suggest that cognitive scaffolds can ameliorate at least some of the inhibition deficits in adolescents with ADHD.     

Attention-deficit disorder (attention-deficit/ hyperactivity disorder without hyperactivity): a neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity)

Most studies of attention-deficit/hyperactivity disorder (ADHD) have focused on the combined type and emphasized a core problem in response inhibition. It is proposed here that the core problem in the truly inattentive type of ADHD (not simply the subthreshold combined type) is in working memory. It is further proposed that laboratory measures, such as complex-span and dual-task dichotic listening tasks, can detect this. Children with the truly inattentive type of ADHD, rather than being distractible, may instead be easily bored, their problem being more in motivation (underarousal) than in inhibitory control. Much converging evidence points to a primary disturbance in the striatum (a frontal-striatal loop) in the combined type of ADHD. It is proposed here that the primary disturbance in truly inattentive-type ADHD (ADD) is in the cortex (a frontal-parietal loop). Finally, it is posited that these are not two different types of ADHD, but two different disorders with different cognitive and behavioral profiles, different patterns of comorbidities, different responses to medication, and different underlying neurobiologies.     

Cortical excitability in adult patients with attention-deficit/hyperactivity disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is more and more focused on, and the awareness of adult patients with ADHD increases. Deficits in inhibitory processes in cortical brain areas are discussed as possible causes for ADHD. An easy measurement of these processes is provided by transcranial magnetic stimulation (TMS). We applied single- and double-pulse TMS to the left motor cortex while an electromyogram (EMG) was taken at the abductor pollicis brevis muscle (APB) of the right hand. Intracortical inhibition (SICI) and facilitation (ICF) were measured in ten adult ADHD patients and ten healthy participants using inter-pulse intervals of 2 and 3ms (SICI), and 8 and 15ms (ICF). Furthermore, resting motor threshold (RMT) and latency of the motor evoked potential (MEP) following magnetic stimulation were compared. t-Tests were calculated for statistical analysis. TMS measurements resulted in impaired inhibition in ADHD patients, whereas there were no differences in facilitation, RMT and MEP-latency between groups. Large variability in the patient group was found. This study expands the findings of deficits in inhibition described in earlier studies in children to an adult population, which could be a hint for similar neurophysiological mechanisms underlying ADHD symptomatology in children and adults.     

Adult attention deficit hyperactivity disorder and the dopamine D4 receptor gene

Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 22-33% of patients continue to suffer from ADHD during late adolescence and adulthood. Convincing evidence supports the contribution of genetic factors in the etiology of ADHD, and the interaction of the psychostimulants with the dopamine system suggests that dopamine is involved in the pathophysiology. The 7-repeat allele of the 48 base pair repeat of the dopamine D4 receptor gene (DRD4) has been reported, with several replications, to be associated with ADHD in children. We tested for the presence of association between the DRD4 48 base repeat and adult ADHD in two independent samples: one comprised of cases and ethnically matched controls, and the second made up of nuclear families. Each case was assessed using a battery of adult ADHD assessment instruments. The analysis of the 66 cases and 66 controls showed a significantly higher presence of the 7-repeat in the adult ADHD patients vs. controls (chi(2) = 5.65; df = 1; P = 0.01). In the analysis of transmission of DRD4 alleles in 44 nuclear families with the transmission disequilibrium test, a trend was observed toward a increased transmission of the 7-repeat from the heterozygous parents to the affected offspring (chi(2) = 2.00; df = 1; P = 0.15). When the two samples were combined, the overall significance was stronger (N = 110; z = 2.68; P = 0.003). The results of our study suggest a role of the 7-repeat allele in adult subjects suffering from ADHD. This finding is an important continuation of the group of studies that together strongly suggest the involvement of DRD4 in ADHD.     

Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention-deficit hyperactivity disorder

Data from animal studies suggest that the dopamine D3 receptor gene may have a role in locomotion and behavioral regulation. Therefore, this gene has been suggested as a candidate for attention-deficit hyperactivity disorder (ADHD). The dopamine D3 receptor gene (DRD3) has two common polymorphisms, one in exon I that changes a Serine to Glycine (Ser9Gly) and alters the recognition site for the restriction enzyme MscI [Lannfelt et al., 1992]. The other common polymorphism is located in intron 5 and results in the change of a restriction site for MspI [Griffon et al., 1996]. We investigated the possibility of linkage of the dopamine D3 receptor gene in 100 small, nuclear families consisting of a proband with ADHD, their parents, and affected siblings. We examined the transmission of the alleles of each of these polymorphisms and the haplotypes of both polymorphisms using the transmission disequilibrium test [Spielman et al., 1993]. We did not observe biased transmission of the alleles at either polymorphism or any haplotype. Our findings using this particular sample do not support the role of the dopamine D3 gene in ADHD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:114-117, 2000.     

Lack of imprinting of the human dopamine D4 receptor (DRD4) gene

The term genomic imprinting has been used to refer to the differential expression of genetic material depending on whether it has come from the male or female parent. In humans, the chromosomal region 11p15.5 has been shown to contain 2 imprinted genes (H19 and IGF2). The gene for the dopamine D4 receptor (DRD4), which is of great interest for research into neuropsychiatric disorders and psychopharmacology, is also located in this area. In the present study, we have examined the imprinting status of the DRD4 gene in brain tissue of an epileptic patient who was heterozygous for a 12 bp repeat polymorphism in exon 1 of the DRD4 gene. We show that both alleles are expressed in equivalent amounts. We therefore conclude that the DRD4 gene is not imprinted in the human brain. © 1996 Wiley-Liss, Inc.