多巴胺D4受体基因与注意缺损多动障碍

为探讨注意缺损多动障碍（ADHD）与多巴胺D4受体基因（dopamine D4 receptor gene,DRD4)间的关系,采用Amp-FLP的方法检测了上海地区汉族人群中68例ADHD患及其父母DRD4的多态性,数据采用基于单体型的单体型相对风险（HHRR）及传递不平衡检验（TDT）进行遗传关联分析。结果表明HHRR分析和复等位基因的TDT检验,均未显示出与ADHD的遗传关联性（P＞0．05）。提示上海地区人群中DRD4基因与ADHD无显性关联。     

Polymorphisms and low plasma activity of dopamine-beta-hydroxylase in ADHD children

Attention-deficit Hyperactivity disorder (ADHD) is a multifactorial disorder clinically characterized by inattentiveness, impulsivity and hyperactivity. The occurrence of this disorder is between 3 and 6% of the children population, with boys predominating over girls at a ratio of 3:1 or more. The research of some candidate genes (DRD4, DAT, DRD5, DBH, 5HTT, HTR1B and SNAP25) brought consistent results confirming the heredity of ADHD syndromes. Dopamine-beta-hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into noradrenaline. Alteration of the dopamine/noradrenaline levels can result in hyperactivity. The DBH protein is released in response to stimulation. DBH activity, derived largely from sympathetic nerves, can be measured in human plasma. Patients with ADHD showed decreased activities of DBH in serum and urine. Low DBH levels correlate indirectly with the seriousness of the hyperkinetic syndrome in children [19,20]. In the DBH gene, the G444A, G910T, C1603T, C1912T, C-1021T, 5 -ins/del and TaqI polymorphisms occur frequently and may affect the function of gene products or modify gene expression and thus influence the progression of ADHD. This article reviews the DBH itself and polymorphisms in the DBH gene that influence the DBH activity in the serum and the CSF level of DBH. All those are evaluated in connection with ADHD.     

Role of Dopamine Receptors in ADHD: A Systematic Meta-analysis

The dopaminergic system plays a pivotal role in the central nervous system via its five diverse receptors (D1-D5). Dysfunction of dopaminergic system is implicated in many neuropsychological diseases, including attention deficit hyperactivity disorder (ADHD), a common mental disorder that prevalent in childhood. Understanding the relationship of five different dopamine (DA) receptors with ADHD will help us to elucidate different roles of these receptors and to develop therapeutic approaches of ADHD. This review summarized the ongoing research of DA receptor genes in ADHD pathogenesis and gathered the past published data with meta-analysis and revealed the high risk of DRD5, DRD2, and DRD4 polymorphisms in ADHD.     

Dopamine receptor genetic polymorphisms and body composition in undernourished pastoralists: An exploration of nutrition indices among nomadic and recently settled Ariaal men of northern Kenya

Background  

Minor alleles of the human dopamine receptor polymorphisms, DRD2/TaqI A and DRD4/48 bp, are related to decreased functioning and/or numbers of their respective receptors and have been shown to be correlated with body mass, height and food craving. In addition, the 7R minor allele of the DRD4 gene is at a higher frequency in nomadic compared to sedentary populations. Here we examine polymorphisms in the DRD2 and DRD4 genes with respect to body mass index (BMI) and height among men in two populations of Ariaal pastoralists, one recently settled (n = 87) and the other still nomadic (n = 65). The Ariaal live in northern Kenya, are chronically undernourished and are divided socially among age-sets.     

DRD4 and TH gene polymorphisms are associated with activity,impulsivity and inattention in Siberian Husky dogs

Both dopamine receptor D4 (DRD4) exon 3 and tyrosine hydroxylase (TH) intron 4 repeat polymorphisms have been linked to activity and impulsivity in German Shepherd dogs (GSDs). However, the results in GSDs may not be generalisable to other breeds, as allelic frequencies vary markedly among breeds. We selected the Siberian Husky for further study, because it is highly divergent from most dog breeds, including the GSD. The study sample consisted of 145 racing Siberian Huskies from Europe and North America. We found that this breed possesses seven DRD4 length variants, two to five more variants than found in other breeds. Among them was the longest known allele, previously described only in wolves. Short alleles of the DRD4 and TH repeat polymorphisms were associated with higher levels of activity, impulsivity and inattention. Siberian Huskies possessing at least one short allele of the DRD4 polymorphism displayed greater activity in a behavioural test battery than did those with two long alleles. However, the behavioural test was brief and may not have registered variation in behaviour across time and situations. Owners also completed the Dog‐Attention Deficit Hyperactivity Disorder Rating Scale (Dog‐ADHD RS), a more general measure of activity and attention. Siberian Huskies from Europe with two short alleles of the TH polymorphism received higher ratings of inattention on the Dog‐ADHD RS than did those with the long allele. Investigation of the joint effect of DRD4 and TH showed that dogs possessing long alleles at both sites were scored as less active–impulsive than were others. Our results are aligned with previous studies showing that DRD4 and TH polymorphisms are associated with activity–impulsivity related traits in dogs. However, the prevalence of variants of these genes differs across breeds, and the functional role of specific variants is unclear.     

Effect of EEG Biofeedback on Cognitive Flexibility in Children with Attention Deficit Hyperactivity Disorder With and Without Epilepsy

Attention deficit hyperactivity disorder (ADHD) is one of the most common developmental disorders in school-aged children. Symptoms consistent with ADHD have been observed in 8–77 % of children with epilepsy. Researchers have been motivated to search for alternative forms of treatment because 30 % of patients with ADHD cannot be treated by psychostimulants. Several studies support the use of a multimodal treatment approach that includes neurofeedback (NF) for the long-term management of ADHD. These studies have shown that NF provides a sustained effect, even without concurrent treatment with stimulants. We aimed to assess cognitive flexibility in ADHD children with and without temporal lobe epilepsy (TLE), and to evaluate the effects of NF on cognitive flexibility in these groups of children. We prospectively evaluated 69 patients with ADHD aged 9–12 years. The control group was 26 ADHD children without TLE who received no treatment. The first experimental group comprised 18 children with ADHD. The second experimental group comprised 25 age-matched ADHD children with TLE. This group was further divided in two subgroups. One subgroup comprised those with mesial temporal lobe epilepsy (16 patients, 9 with hippocampal sclerosis and 7 with hippocampal atrophy), and the other with lateral temporal lobe epilepsy (9 patients, 5 with temporal lobe dysplasia, 3 with temporal lobe cysts, and 1 with a temporal lobe cavernoma). We treated their ADHD by conducting 30 sessions of EEG NF. Reaction time and error rates on the Trail Making Test Part B were compared before and after treatment, and significant differences were found for all groups of patients except those who had mesial temporal lobe epilepsy with hippocampal atrophy. Our results demonstrate that in most cases, NF can be considered an alternative treatment option for ADHD children even if they have TLE. Additional studies are needed to confirm our results.     

Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs

A variable number of tandem repeats (VNTR) polymorphism in exon 3 of the human dopamine D4 receptor gene ( DRD4 ) has been associated with attention deficit hyperactivity disorder (ADHD). Rodents possess no analogous repeat sequence, whereas a similar tandem repeat polymorphism of the DRD4 gene was identified in dogs, horses and chimpanzees. Here, we present a genetic association study of the DRD4 VNTR and the activity-impulsivity dimension of the recently validated dog-ADHD Rating Scale. To avoid false positives arising from population stratification, a single breed of dogs (German shepherd) was studied. Two DRD4 alleles (referred to as 2 and 3a ) were detected in this breed, and genotype frequencies were in Hardy–Weinberg equilibrium. For modelling distinct environmental conditions, 'pet' and 'police' German shepherds were characterized. Police German shepherds possessing at least one 3a allele showed significantly higher scores in the activity-impulsivity dimension of the dog-ADHD Rating Scale than dogs without this allele ( P  = 0.0180). This difference was not significant in pet German shepherds. To the best of our knowledge, this is the first report of an association between a candidate gene and a behaviour trait in dogs, and it reinforces the functional role of DRD4 exon 3 polymorphism.     

Potential Contribution of Dopaminergic Gene Variants in ADHD Core Traits and Co-Morbidity: A Study on Eastern Indian Probands

Association of dopaminergic genes, mainly receptors and transporters, with Attention Deficit Hyperactivity Disorder (ADHD) has been investigated throughout the world due to the importance of dopamine (DA) in various physiological functions including attention, cognition and motor activity, traits. However, till date, etiology of ADHD remains unknown. We explored association of functional variants in the DA receptor 2 (rs1799732 and rs6278), receptor 4 (exon 3 VNTR and rs914655), and transporter (rs28363170 and rs3836790) with hyperactivity, cognitive deficit, and co-morbid disorders in eastern Indian probands. Diagnostic and Statistical Manual for Mental Disorders-IV was followed for recruitment of nuclear families with ADHD probands (N = 160) and ethnically matched controls (N = 160). Cognitive deficit and hyperactive traits were measured using Conner’s parents/teachers rating scale. Peripheral blood was collected after obtaining informed written consent and used for genomic DNA isolation. Genetic polymorphisms were analyzed by PCR-based methods followed by population- as well as family-based statistical analyses. Association between genotypes and cognitive/hyperactivity traits and co-morbidities was analyzed by the Multifactor dimensionality reduction (MDR) software. Case–control analysis showed statistically significant difference for rs6278 and rs28363170 (P = 0.004 and 1.332e?007 respectively) while family-based analysis exhibited preferential paternal transmission of rs28363170 ‘9R’ allele (P = 0.04). MDR analyses revealed independent effects of rs1799732, rs6278, rs914655, and rs3836790 in ADHD. Significant independent effects of different sites on cognitive/hyperactivity traits and co-morbid disorders were also noticed. It can be summarized from the present investigation that these gene variants may influence cognitive/hyperactive traits, thereby affecting the disease etiology and associated co-morbid features.     

Genetic Variation in the Human Brain Dopamine System Influences Motor Learning and Its Modulation by L-Dopa

Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson''s disease.     

Season of birth and dopamine receptor gene associations with impulsivity, sensation seeking and reproductive behaviors

Background

Season of birth (SOB) has been associated with many physiological and psychological traits including novelty seeking and sensation seeking. Similar traits have been associated with genetic polymorphisms in the dopamine system. SOB and dopamine receptor genetic polymorphisms may independently and interactively influence similar behaviors through their common effects on the dopaminergic system.

Methodology/Principal Findings

Based on a sample of 195 subjects, we examined whether SOB was associated with impulsivity, sensation seeking and reproductive behaviors. Additionally we examined potential interactions of dopamine receptor genes with SOB for the same set of traits. Phenotypes were evaluated using the Sociosexual Orientation Inventory, the Barratt Impulsivity Scale, the Eysenck Impulsivity Questionnaire, the Sensation Seeking Scale, and the Delay Discounting Task. Subjects were also asked about their age at first sex as well as their desired age at the birth of their first child. The dopamine gene polymorphisms examined were Dopamine Receptor D2 (DRD2) TaqI A and D4 (DRD4) 48 bp VNTR. Primary analyses included factorial gender×SOB ANOVAs or binary logistic regression models for each dependent trait. Secondary analysis extended the factorial models by also including DRD2 and DRD4 genotypes as independent variables. Winter-born males were more sensation seeking than non-winter born males. In factorial models including both genotype and season of birth as variables, two previously unobserved effects were discovered: (1) a SOB×DRD4 interaction effect on venturesomeness and (2) a DRD2×DRD4 interaction effect on sensation seeking.

Conclusion

These results are consistent with past findings that SOB is related to sensation seeking. Additionally, these results provide tentative support for the hypothesis that SOB modifies the behavioral expression of dopaminergic genetic polymorphism. These findings suggest that SOB should be included in future studies of risky behaviors and behavioral genetic studies of the dopamine system.     

No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample

Noradrenergic neurotransmission influences executive functions, attentional performance, and general alertness, involving neuronal networks affected in attention deficit/hyperactivity disorder (ADHD). The norepinephrine transporter facilitates the reuptake of norepinephrine and dopamine in the prefrontal cortex and represents the main target of atomoxetine, an effective drug in the treatment of ADHD. Due to its influence on catecholaminergic signaling, variants of the coding gene (SLC6A2) have been widely investigated in ADHD. Several previous studies report an association between single nucleotide polymorphisms located in SLC6A2 and ADHD; however, the findings are inconsistent. The variant A-3081T (rs28386840) has been shown to have major influence on the expression levels of SLC6A2 due to sequence alteration at a repressor binding site, with the T-allele being associated with ADHD. We tested this potential association of A-3081T in a German family-based ADHD sample of 235 children from 162 families, which has a power >99% based on the previously reported odds ratios. There was no evidence for an overtransmission of the risk allele T (transmission rate: 48.5%, P = 0.55). We conclude that A-3081T is not a major risk variant in our ADHD sample, though SLC6A2 remains an interesting candidate gene in ADHD, especially for the inattentive subtype.     

No evidence for strong recent positive selection favoring the 7 repeat allele of VNTR in the DRD4 gene

The human dopamine receptor D4 (DRD4) gene contains a 48-bp variable number of tandem repeat (VNTR) in exon 3, encoding the third intracellular loop of this dopamine receptor. The DRD4 7R allele, which seems to have a single origin, is commonly observed in various human populations and the nucleotide diversity of the DRD4 7R haplotype at the DRD4 locus is reduced compared to the most common DRD4 4R haplotype. Based on these observations, previous studies have hypothesized that positive selection has acted on the DRD4 7R allele. However, the degrees of linkage disequilibrium (LD) of the DRD4 7R allele with single nucleotide polymorphisms (SNPs) outside the DRD4 locus have not been evaluated. In this study, to re-examine the possibility of recent positive selection favoring the DRD4 7R allele, we genotyped HapMap subjects for DRD4 VNTR, and conducted several neutrality tests including long range haplotype test and iHS test based on the extended haplotype homozygosity. Our results indicated that LD of the DRD4 7R allele was not extended compared to SNP alleles with the similar frequency. Thus, we conclude that the DRD4 7R allele has not been subjected to strong recent positive selection.     

5' UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism

Multiple dopamine receptors in the dopaminergic system may be prime candidates for genetic influence on alcohol abuse and dependence due to their involvement in reward and reinforcing mechanisms. Genetic polymorphisms in dopamine receptor genes are believed to influence the development and/or severity of alcoholism. To examine the genetic effects of the Dopamine Receptor D1 (DRD) gene family (DRD1-DRD5) in the Korean population, 11 polymorphisms in the DRD gene family were genotyped and analyzed in 535 alcohol-dependent subjects and 273 population controls. Although none of the polymorphisms of DRD1-5 genes were found to be associated with the risk of alcoholism, one 5' UTR polymorphism in the DRD1 (DRD1-48A>G) gene was significantly associated with severity of alcohol-related problem, as measured by the Alcohol Use Disorders Identification Test (AUDIT) in a gene dose-dependent manner, i.e., 24.37 (+/-8.19) among patients with -48A/A genotype, 22.37 (+/-9.49) among those with -48A/G genotype, and 17.38 (+/-8.28) among those with -48G/G genotype (P=0.002). The genetic effects of DRD1-48A>G were further analyzed with other phenotypes among alcohol-dependent subjects. Interestingly, the DRD1-48A>A genotype was also found to be associated with novelty seeking (NC), harm avoidance (HA), and persistence (P) (P =0.01, 0.02, and 0.003, respectively). The information derived from this study could be valuable for understanding the genetic factors involved in alcoholic phenotypes and genetic distribution of the DRD gene family, and could facilitate further investigation in other ethnic groups.     

Association between the dopamine D4 receptor gene exon III variable number of tandem repeats and political attitudes in female Han Chinese

Twin and family studies suggest that political attitudes are partially determined by an individual''s genotype. The dopamine D4 receptor gene (DRD4) exon III repeat region that has been extensively studied in connection with human behaviour, is a plausible candidate to contribute to individual differences in political attitudes. A first United States study provisionally identified this gene with political attitude along a liberal–conservative axis albeit contingent upon number of friends. In a large sample of 1771 Han Chinese university students in Singapore, we observed a significant main effect of association between the DRD4 exon III variable number of tandem repeats and political attitude. Subjects with two copies of the 4-repeat allele (4R/4R) were significantly more conservative. Our results provided evidence for a role of the DRD4 gene variants in contributing to individual differences in political attitude particularly in females and more generally suggested that associations between individual genes, and neurochemical pathways, contributing to traits relevant to the social sciences can be provisionally identified.     

No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs

Attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.     

Genetic polymorphism in dopamine receptor D4 is associated with early body condition in a large population of greater flamingos, Phoenicopterus roseus

Body condition is an important determinant of fitness in many natural populations. However, as for many fitness traits, the underlying genes that regulate body condition remain elusive. The dopamine receptor D4 gene (DRD4) is a promising candidate as dopamine is known to play an important role in the regulation of food intake and the metabolism of both glucose and lipids in vertebrates. In this study, we take advantage of a large data set of greater flamingos, Phoenicopterus roseus, to test whether DRD4 polymorphism predicts early body condition (EBC) while controlling for whole-genome effects of inbreeding and outbreeding using microsatellite multilocus heterozygosity (MLH). We typed 670 of these individuals for exon 3 of the homologue of the human DRD4 gene and 10 microsatellite markers. When controlling for the effects of yearly environmental variations and differences between sexes, we found strong evidence of an association between exon 3 DRD4 polymorphisms and EBC, with 2.2-2.3% of the variation being explained by DRD4 polymorphism, whereas there was only weak evidence that MLH predicts EBC. Because EBC is most likely a polygenic trait, this is a considerable amount of variation explained by a single gene. This is to our knowledge, the first study to show an association between exon 3 DRD4 polymorphism and body condition in non-human animals. We anticipate that the DRD4 gene as well as other genes coding for neurotransmitters and their receptors may play an important role in explaining variation in traits that affect fitness.     

Role of brain dopamine in food reward and reinforcement

The ability of food to establish and maintain response habits and conditioned preferences depends largely on the function of brain dopamine systems. While dopaminergic transmission in the nucleus accumbens appears sufficient for some forms of reward, the role of dopamine in food reward does not appear to be restricted to this region. Dopamine plays an important role in both the ability to energize feeding and to reinforce food-seeking behaviour; the role in energizing feeding is secondary to the prerequisite role in reinforcement. Dopaminergic activation is triggered by the auditory and visual as well as the tactile, olfactory, and gustatory stimuli of foods. While dopamine plays a central role in the feeding and food-seeking of normal animals, some food rewarded learning can be seen in genetically engineered dopamine-deficient mice.