Dopamine D2 Receptor Gene Research Articles

The polymorphism of dopamine receptor D4 (DRD4) and dopamine transporter (DAT) genes in the men with antisocial behaviour and mixed martial arts fighters

Objectives: Variable-number tandem repeat (VNTR) polymorphisms of DRD4 and DAT genes were studied in the Russian and Chechen men convicted of crimes, and two control groups comprised of the MMA fighters and a sample of general population. A group of MMA fighters included only the subjects without history of antisocial behaviour.Methods: DNA was isolated by phenol–chloroform extraction from the blood. Genotyping VNTR polymorphisms of the DRD4 and DAT genes were performed by PCR on published methods.Results: Among those convicted of felonies and most grave crimes, carriers of DRD4 long alleles are found more frequently, similarly to the cohort of MMA fighters (lacking criminal record in both paternal lines). The 9/9 DAT genotype carriers are more frequently encountered among the habitual offenders. A frequency of the combination of the DRD4 genotype 4/7 and DAT genotype 10/10 is clearly higher among the convicts of violent crimes and the MMA fighters. One can speculate the presence of a ‘controlled aggression’ without a predisposition to pathological violence in the MMA fighters.Conclusions: Our study supports the hypothesis of genetic predisposition to different variants of extreme behaviour mediated by genetic determinants involved in the functioning of neuromediator systems including those controlling dopamine pathways.

Genetically-Driven Enhancement of Dopaminergic Transmission Affects Moral Acceptability in Females but Not in Males: A Pilot Study.

Moral behavior has been a key topic of debate for philosophy and psychology for a long time. In recent years, thanks to the development of novel methodologies in cognitive sciences, the question of how we make moral choices has expanded to the study of neurobiological correlates that subtend the mental processes involved in moral behavior. For instance, in vivo brain imaging studies have shown that distinct patterns of brain neural activity, associated with emotional response and cognitive processes, are involved in moral judgment. Moreover, while it is well-known that responses to the same moral dilemmas differ across individuals, to what extent this variability may be rooted in genetics still remains to be understood. As dopamine is a key modulator of neural processes underlying executive functions, we questioned whether genetic polymorphisms associated with decision-making and dopaminergic neurotransmission modulation would contribute to the observed variability in moral judgment. To this aim, we genotyped five genetic variants of the dopaminergic pathway [rs1800955 in the dopamine receptor D4 (DRD4) gene, DRD4 48 bp variable number of tandem repeat (VNTR), solute carrier family 6 member 3 (SLC6A3) 40 bp VNTR, rs4680 in the catechol-O-methyl transferase (COMT) gene, and rs1800497 in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene] in 200 subjects, who were requested to answer 56 moral dilemmas. As these variants are all located in genes belonging to the dopaminergic pathway, they were combined in multilocus genetic profiles for the association analysis. While no individual variant showed any significant effects on moral dilemma responses, the multilocus genetic profile analysis revealed a significant gender-specific influence on human moral acceptability. Specifically, those genotype combinations that improve dopaminergic signaling selectively increased moral acceptability in females, by making their responses to moral dilemmas more similar to those provided by males. As females usually give more emotionally-based answers and engage the “emotional brain” more than males, our results, though preliminary and therefore in need of replication in independent samples, suggest that this increase in dopamine availability enhances the cognitive and reduces the emotional components of moral decision-making in females, thus favoring a more rationally-driven decision process.

P363 Neurophysiologic alterations and effects of DRD2 gene polymorphism in burning mouth syndrome

Background and aims Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of dopamine D2 receptor (DRD2) gene may contribute to pain perception. We investigated whether the neurophysiologic findings differ in BMS patients compared with healthy controls, and whether 957C > T polymorphism of the DRD2 gene influences perception or interference of pain in daily life in BMS. Methods 45 BMS patients (43 women, mean age 62.5 years) and 32 healthy controls (30 women, mean age 64.8 years) participated. Patients estimated pain intensity, suffering, quality of life (QoL) and sleep with NRS. Blink reflex (BR) of the supraorbital (SON), mental (MN) and lingual (LN) nerves and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C > T polymorphism was determined in 31 patients and its effects on neurophysiologic and clinical variables analysed. Results Cool ( p = 0.0090) and warm detection thresholds ( p = 0.0229) were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls ( p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls ( p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest ( p p = 0.0254–0.0352). Conclusions Thepatients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy in BMS. The DRD2 957 C > T genotype may influence perception and interference of pain in BMS.

Interaction effects of GIT1 and DRD4 gene variants on continuous performance test variables in patients with ADHD.

IntroductionThe G protein‐coupled receptor kinase interacting protein 1 gene (GIT1) has been proposed to be a risk gene for attention deficit hyperactivity disorder (ADHD), and it regulates the endocytosis of G protein‐coupled receptors like dopamine receptors. The purpose of this study was to investigate the interaction effects of GIT1 and dopamine receptor D4 (DRD4) gene variants on variables of the continuous performance test (CPT).MethodsThis study recruited 255 ADHD patients and 98 healthy controls (HC) who underwent CPT and genetic analyses. The genotypes were classified into two groups (the C/C and C/T genotype groups for GIT1, 4R homozygotes and others for DRD4) and the genotype × genotype effects were examined using hierarchical multivariable linear regression analyses.ResultsThere were significant GIT1 × DRD4 effects for commission errors on the CPT in the ADHD group (p = .006). In contrast, there were no significant GIT1 × DRD4 effects on any CPT variables in the HC.ConclusionsThe present findings demonstrated that there were significant interaction effects of the GIT1 and DRD4 gene variants on impulsivity in ADHD. Replication studies with larger sample sizes that include patients from various ethnic backgrounds are warranted to confirm these findings.

Association of Dopamine D1 and D3 Receptor Gene Polymorphisms with Essential Hypertension in 3 Ethnic Groups in China.

BackgroundEssential hypertension (EH) is one of the major cardiovascular diseases. Recent studies demonstrated that dopamine D1 and D3 receptor gene polymorphisms (DRD1 and DRD3) play an important role in EH.Material/MethodsTo investigate whether DRD1 and DRD3 polymorphisms are associated with EH, 3 single-nucleotide polymorphisms (SNPs) of the DRD1 and 6 SNPs of DRD3 gene were analyzed in 3 ethnic groups. SNPStats was used to obtain odds ratios (ORs), 95% confidence intervals (CIs), and P values. Multiple logistic regression models (co-dominant, dominant, recessive, over-dominant, and log-additive) and chi-squared test were conducted to analyze the genetic data by chi-squared test.ResultsSynonymous SNPs (rs1799914 and rs4867798) of the DRD1 gene and SNPs (rs9880168) of the DRD3 were associated with EH in Hani nationality (OR 3.77, 0.63, 1.43, 5.00, respectively; 95% CI 1.05–13.54, p=0.024; 0.44–0.90, p=0.0121; 1.06–1.94, p=0.019; 1.08–23.10, p=0.017, respectively; Recessive, over-dominant model, respectively). However, none SNPs of DRD1 and DRD3 of best models showed association with EH in Han and Yi nationality.ConclusionThese results suggest that SNPs of DRD1 and DRD3 may be contributed to essential hypertension in Hani nationality of China.

DRD4 Gene Polymorphisms as a Risk Factor for Children with Attention Deficit Hyperactivity Disorder in Iranian Population.

Background and Objective Dopamine dysfunction is known to be associated with attention deficit hyperactivity disorder (ADHD). Dopamine D4 receptor gene (DRD4) is one of the important genes in this pathway. This study intended to investigate the variable number of tandem repeats (VNTR) in exon 3 of the DRD4 gene in Iranian children and adolescents. Materials and Methods In this study, 130 children with ADHD, aged 6–14 years, and 130 healthy children, within the same age range, were enrolled. All children were selected from northwest of Iran which have Caucasian ethnic background and are of a Turkic ethnic group. VNTR polymorphisms of the DRD4 gene were evaluated by PCR using exon 3-specific primers followed by agarose gel electrophoresis. Findings The Hardy-Weinberg principle and Chi-square test showed a significant difference in 4-repetition (4R) alleles between the ADHD (76.2%) and control (53.8%) groups (p = 0.004; X2 = 17.39; df = 5). The least percentage of repetition alleles in both groups was 2R. Conclusion There is a significant correlation between the 4R alleles of DRD4 and ADHD in the northwest of Iran.

Association of polymorphic variants in MSTN, PRL, and DRD2 genes with intensity of young animal growth in Pushkin breed chickens

Polymorphic variants in the myostatin, prolactin, and D2 dopamine receptor genes were analyzed in Pushkin breed chickens (n = 231). The rs313744840 single nucleotide polymorphism was studied in the myostatin gene by means of the PCR–RFLP method. The cocks with different genotypes did not differ from each other by the live weight. Chickens with AA genotype were found to be significantly larger than their coevals with AG and GG genotypes at the age of 49 days (P < 0.01). Polymorphism based on the insertion–deletion of a small gene region (indel-polymorphism) was considered in the prolactin and D2 dopamine receptor genes. Differences by the prolactin gene were observed at 7 days of age. The cocks homozygous by the DD deletion were significantly larger than heterozygous ID coevals (P < 0.05). The II cocks significantly differed by the D2 dopamine receptor gene from heterozygous ID coevals by the live weight at 49 and 110 days. In chickens, II homozygotes by the mutation in the D2 dopamine receptor gene were larger than coevals at 7 days, while they had a lower live weight at 110 days (P < 0.05).

Relationship of the functional polymorphism of dopamine D4 receptor gene with behavioral problems in school-age twins

Objective To investigate the correlation and characteristic of the functional polymorphism of the dopamine D4 receptor gene on the behavioral problems in school-age twins. Method The behavioral problems were assessed among a total of 147 twin pairs aged 6-12 years with the Achenbach Child Behavior Checklist (CBCL). The DRD4 gene polymorphism was applied for different types with polymerase chain reaction. The generalized estimating equations model was used to analyze the effect of DRD4 gene polymorphism and the interaction of DRD4 gene polymorphism with children age, gender, monozygotic/dizygotic on twins’ behavioral problems. Results (1) School-age children’s anxiety/depression, withdrawn, thought problems, attention problems, social problems, delinquent problems, aggressive behavior and total variance mainly were correlated with DRD4 gene polymorphism (P<0.05), and physical discomfort might be related with DRD4 gene polymorphism (P=0.067). Except social problems, the detection rate of behavioral problems of the twins with 4/6 genotype (Gene type carrying 5 or more repeated sequences) of DRD4 gene (6.25%-21.25%)was higher than those with other genotypes (0-14.74%). (2) Withdrawal was related to children age (χ2=4.348, P<0.05), and twins aged 6-10 might lead to withdrawal. (3) The interaction of DRD4 gene polymorphism and children age had a significant effect on withdrawal (χ2=4.348, P<0.05) and physical discomfort(χ2 =5.189, P<0.05), and the elder age (11-12 years) children had a certainly protective effect on the withdrawal and physical discomfort with 4/6 genotype in twins.The detection rates were 3.54% and 2.65% in the younger-age (6-10 years) twins, while all 0 in the elder-age (11-12 years) for the withdrawal and the physical discomfort respectively. Conclusions The DRD4 gene polymorphism may be correlated with behavioral problems in school-age twins. The interaction of DRD4 polymorphism and children age had a significantly effect on withdrawal and physical discomfort. Key words: DRD4 gene; School-age children; Twins; Behavioral problems

Associations Between Dopamine D2 Receptor (DRD2) Gene, Maternal Positive Parenting and Trajectories of Depressive Symptoms from Early to Mid-Adolescence.

Using data from the Longitudinal Study of Chinese Children and Adolescents (LSCCA), this study is the first to examine the roles of the dopamine D2 receptor (DRD2) gene polymorphisms (i.e., TaqIA and A241G) and maternal positive parenting at ages 10 and 11years in the trajectories of depressive symptoms from early to mid-adolescence (ages 11 to 16years). In a sample of 1090 Chinese adolescents (50% girls), three trajectories of depressive symptoms were identified: (i) low-stable (36.1%), (ii) moderate-increasing (44.5%), and (iii) high-increasing (19.4%). A241G AA homozygotes and youth exposed to lower levels of maternal positive parenting were both at increased odds to follow the high-increasing vs. low-stable trajectory. Moreover, the A241G polymorphism interacted with maternal positive parenting to distinguish the moderate-increasing trajectory from the high-increasing and the low-stable trajectories. For A241G G-allele carriers, but not AA homozygotes, exposure to high quality of maternal parenting decreased the odds to follow the high-increasing vs. moderate-increasing trajectory of depressive symptoms. For AA homozygotes, but not G-allele carriers, high quality of maternal parenting increased the odds to follow the low-stable vs. moderate-increasing trajectory. The DRD2 TaqIA polymorphism had neither a direct nor an interactive effect with maternal positive parenting on trajectory membership. The current findings highlight the importance of investigating gene-by-environment interactions (G×E) in trajectories of depressive symptoms over adolescence, and support a developmental versus static nature of G×E effects.

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.

A dopamine receptor genetic variant enhances perceptual speed in cognitive healthy subjects

IntroductionCognition is under strong genetic control, yet the specific genes are unknown. MethodsOne hundred and fifty-three cognitive healthy European subjects from the Reference Abilities Study (RANN) were genotyped for 1,160 variants within 446 neuropsychiatric genes. Adjusted linear regression models evaluated the association between the genetic variants and four reference abilities (Vocabulary, Episodic Memory, Perceptual Speed, and Reasoning). ResultsOne hundred and fifty-nine variants nominally were found significant in the RANN cohort and re-evaluated in an independent cohort of 868 cognitive healthy subjects from the Religious Orders Study and Rush Memory Aging Project. Meta-analysis yielded a Bonferroni adjusted statistically significant association between perceptual speed and a variant located in the promoter of the dopamine receptor D4 gene, rs3756450 (β = 0.23, standard error = 0.05, Pmeta = 2.3 × 10−5). DiscussionOur data suggest that genetic variation in a dopamine pathway gene influences perceptual speed performance in cognitively healthy individuals.

Variation on the dopamine D2 receptor gene (DRD2) is associated with basal ganglia-to-frontal structural connectivity

Dopaminergic neurotransmission in the mesocortical system is crucial for higher order cognition. Common variation on the dopamine D2 receptor (DRD2) gene has been linked to individual differences in dopaminergic signaling and was also repeatedly associated to cognitive markers. The relationship between dopaminergic genetic variants and neurostructural properties of the mesocortical system, however, has received little attention so far. Recently, the direction of a dopaminergic manipulation was predicted from the integrity of fiber tracts between subcortical areas and the frontal lobes. Fiber tract integrity was therefore proposed as an indicator of baseline dopamine activity. This raises the question whether DRD2 variants that relate to dopamine turnaround are also linked to fiber tract integrity. In the present study we assessed associations between the DRD2 rs6277 polymorphism and subcortical connections from connectome maps derived from diffusion weighted imaging in n=105 healthy volunteers (43 males and 62 females). Carriers of the CC genotype who are characterized by elevated striatal dopamine turnaround showed higher integrity in terms of fractional anisotropy on fiber tracts between the basal ganglia and frontal regions compared to carriers of the CT and TT variant. Our results indicate that structural connectivity could serve as a conceptual link between genetically determined individual differences in dopaminergic activity and effects of dopamine challenges on executive functioning.

Association of Dopamine D2 Receptor Gene with Creative Ideation

Although several studies suggest that dopamine D2 receptor (DRD2) gene may contribute to creativity, the relationship between DRD2 and creativity still needs to be further validated. To further test the relevance of DRD2 and creativity, this study explored the association between DRD2 and creative ideation in 483 unrelated healthy Chinese undergraduate students. A total of 15 single nucleotide polymorphisms (SNPs) covering the DRD2 were genotyped, and creative ideation was assessed by the Runco Ideational Behavior Scale (RIBS). Single SNP analysis showed that 2 SNPs (rs4648317 and rs4938019) were nominally associated with fluency, 4 SNPs (rs4648317, rs4938019, rs4648319, and rs1800497) were nominally associated with flexibility, and 1 SNP (rs4648317) was nominally associated with originality. Haplotype analysis showed several haplotypes were nominally associated with various creative ideation indexes. However, none of these nominal associations survived correction for multiple testing. Overall, this study provides suggestive evidence for the genetic impact of DRD2 on creative ideation and supports the assumption that the genotype variations in DRD2 contribute to creativity.

The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum

Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BPND), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BPND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BPND of the high-affinity D2 receptor tracer 18F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BPND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BPND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.

Association of methylation status of CpG islands in DAT1 and DRD4 genes with attention deficit hyperactivity disorder

Objective To explore the difference of methylation status of CpG island in promoter region of DAT1 and DRD4 genes between children with attention deficit hyperactivity disorder (ADHD) and normal controls, and further understand the pathogenesis of ADHD from a epigenetics point of view. Methods 111 ADHD patients and 118 normal controls were enrolled in the present study. The demographic data and peripheral venous blood were collected from both groups. Bisulfite genomic sequencing (BGS) was used to confirm the methylation status of every CpG site in promoter region of DAT1 and DRD4 genes. Results No significant differences were found between ADHD patients and normal controls on percentage of methylated CpG sites in total CpG islands for both DAT1 and DRD4 (P>0.05). However, the percentage of methylation in No. 17 CpG site for DAT1 and No. 8 CpG site for DRD4 was higher in ADHD patients (23.42% and 64.86% respectively)compared with that in normal controls(11.86% and 47.46% respectively)(P<0.05). In all samples, the percentage of methylated CpG site in total CpG island for DAT1 was higher in males compared with that in females(P<0.05), whereas that for DRD4 was higher in females compared with that in males (P<0.05); the same gender difference on methylation level for DAT1 was also found in ADHD patients and for DRD4 in normal controls(P<0.05). In all samples and in ADHD patients, percentage of methylated CpG site in total CpG island for DAT1 was higher in individuals over 7 years old compared with that in individuals younger than or equal to 7 years old(P<0.05). Conclusions Methylation status of CpG island in DAT1 and DRD4 genes promoter region might correlate with ADHD susceptibility.Methylation status of CpG island in DAT1 and DRD4 genes show differences in different age span and sex. Key words: Attention deficit hyperactivity disorder; Epigenetics; DNA methylation; Dopamine transporter gene (DAT1/SLC6A3); Dopamine receptor D4 gene (DRD4)

Family-based association study of DRD4 gene in methylphenidate-responded Attention Deficit/Hyperactivity Disorder.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD. Use of a multiplex family design (i.e., samples of families that included multiple affected members) may facilitate identification of additional gene variants of interest and advance understanding of gene-environment interplay in regard to parenting. Thirty multiplex families consisting of 114 individuals (66 youth, 48 parents) completed a multi-stage, multi-informant diagnostic and neurocognitive assessment, measures of parenting, and provided saliva samples for DNA analyses. Sanger sequencing of the DRD4 gene yielded 16 rare variants; a polygenic risk score was computed for both parents and youth. Generalized estimating equations (GEE) examined the predictive effects of parental ADHD symptoms, parental neurocognitive functioning, and poor parenting dimensions on youth ADHD as well as moderation of these effects by parental and youth DRD4 variants. Findings indicated that parental DRD4 variants moderated the impact of parental ADHD and neurocognitive functioning on youth ADHD symptoms. Youth DRD4 variants moderated the impact of parental inconsistent discipline on child ADHD. In all cases, stronger associations were observed for those individuals with more risk variants. These exploratory findings highlight the potential utility of a multiplex family design for examining the interplay between parent and child characteristics in predicting youth outcomes.

Key role of the dopamine D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission.

Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4 receptor, the expanded intracellular domain of the humanized D4 receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.