Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.
Attention Deficit Disorder with Hyperactivity ; diagnostic imaging ; genetics ; pathology ; Brain ; diagnostic imaging ; Cerebellum ; diagnostic imaging ; Child ; Corpus Striatum ; diagnostic imaging ; Female ; Frontal Lobe ; diagnostic imaging ; Genotype ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Minisatellite Repeats ; genetics ; Neural Pathways ; diagnostic imaging ; Oxygen ; blood ; Receptors, Dopamine D4 ; genetics ; metabolism ; Rest

OBJECTIVETo assess the association of cognitive functions with gender, age, education and polymorphism of dopamine receptor D4 (DRD4) gene in healthy adults.

METHODSFour hundred and fifty-five healthy participants have completed 3 cognitive function tests including Tower of Hanoi (TOH), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Peripheral blood samples were collected from all participants, and genomic DNA was extracted according to a standard phenol-chloroform procedure. Rs3758653 in the promoter region of the DRD4 gene was genotyped using Illumina GoldenGate genotyping assay.

RESULTSMales have performed better than females in terms of TOH executive time and TOH total score, but did worse in TOH planning time. Most of the measured cognitive domains were affected by age and education. Cognitive ability has decreased along with increased age and decline of educational years. The polymorphism of rs3758653 has mainly correlated with the TOH executive time. Compared with A allele carriers, G allele carriers did worse in TOH executive time.

CONCLUSIONGender, age, education and the rs3758653 polymorphism of the DRD4 gene play an important role in cognitive functions in healthy adults.

Adolescent ; Adult ; Age Factors ; Cognition ; Education ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Polymorphism, Single Nucleotide ; Receptors, Dopamine D4 ; genetics ; Sex Factors ; Young Adult

OBJECTIVETo investigate the relationship between 5-HTTLPR and/or DRD4 gene polymorphisms and the accident tendentiousness of drivers.

METHODSA case-control study, including 42 patients and 46 controls, were performed using type-A behavior questionnaire and EPQ scale. 5-HTTLPR and DRD4 gene -521 C/T were detected by the PCR-RFLP technique.

RESULTSThe scores of type-A behavior questionnaires, such as TH and TH + CH in exposure group were significantly higher than those in control group (P < 0.05). P and N scores of EPQ questionnaires in exposure group were significantly higher than those in control group, and L score in exposure group was significantly lower than that in control group (P < 0.05 or P < 0.01). There were significant differences in the frequencies of the genotypes and alleles of 5-HTTLPR gene between the cases and the controls (P < 0.05), but there were no significant differences in the frequencies of the genotypes and alleles of DRD4 gene between the two groups (P > 0.05). In the drivers with the accident tendentiousness, P scores in the cases with homozygous genotypes of the S/S in 5-HTTLPR gene were significantly higher than those in the cases with the genotypes of S/L and L/L in 5-HTTLPR gene (P > 0.05). E scores in subjects with homozygous genotypes of the T/T in DRD4 gene were significantly higher than those in subjects with genotypes of the T/C+C/C in DRD4 gene (P > 0.05).

CONCLUSIONThe driver accident tendentiousness may be associated with 5-HTTLPR gene, but not associated with DRD4 gene. The two genes are associated with the type-A behavior and personality characteristics of drivers with accident tendentiousness. However, 5-HTTLPR and DRD4 gene may not have synergism in these behaviors and personality.

Accidents, Traffic ; statistics & numerical data ; Adult ; Automobile Driving ; Case-Control Studies ; Genotype ; Humans ; Male ; Personality ; genetics ; Polymorphism, Genetic ; Receptors, Dopamine D4 ; genetics ; Serotonin Plasma Membrane Transport Proteins ; genetics

BACKGROUND: Recent research demonstrates a strong association between smoking-related behaviors and genetic variation. We investigated the clinical features and genetic effects of dopamine receptors and a serotonin transporter on smoking cessation in Koreans. METHODS: Smokers (n=51) wanting to quit smoking were included as the study population. They were genotyped for polymorphisms in dopamine D2 receptor (DRD2) (TaqI and -141C), dopamine D4 receptor (DRD4), and a serotonin transporter (5-HTT). We defined abstinence as stopping smoking at six months after enrollment. RESULTS: Eighteen patients (35.3%) stopped smoking at six months. The abstinence group had a higher rate of alcohol use whereas the non-abstinence group had more coughing. However, there were no significant differences in average smoking rate, starting age of smoking, gender, nicotine dependence, and forced expiratory volume in one second between the two groups. As for the genes in the dopamine pathway, the polymorphisms of DRD2 TaqI (A1 allele) and DRD2 -141C (Ins C allele) were not genotypically different between the two groups (P=0.245 and 0.409, respectively). The genetic variation in the DRD4 variable number of tandem repeats (VNTR) also showed a similar distribution in the two groups. Regarding the polymorphisms of 5-HTT, there was no difference in the long allele between the two groups (P=0.852). CONCLUSIONS: This study suggests that the genetic variations of DRD2 TaqI, DRD2 -141C, DRD4 VNTR, and 5-HTT might have little influence on smoking cessation in Korean smokers.
Alleles ; Cough ; DNA ; Dopamine ; Forced Expiratory Volume ; Genetic Variation ; Humans ; Minisatellite Repeats ; Polymorphism, Genetic ; Receptors, Dopamine ; Receptors, Dopamine D2 ; Receptors, Dopamine D4 ; Serotonin Plasma Membrane Transport Proteins ; Smoke ; Smoking ; Smoking Cessation ; Tobacco Use Disorder

OBJECTIVES: The aim of this study is to explore the association among DRD4 polymorphism, temperament and alcohol drinking behavior of Koreans in their early adulthood. METHOD: Participants were 172 healthy Korean adults (mean age 28.1 +/- 0.8). Their temperament was assessed with the Temperament and Character Inventory (TCI) and their alcohol drinking behavior were evaluated with a self-reported questionnaire including the CAGE and the Korean version of Alcohol Use Disorder Identification Test (AUDIT-K). DRD4 exon III 48 base pair variable number of tandem repeats (VNTR) was genotyped by PCR. RESULTS: No significant association was found between DRD4 polymorphism and TCI temperament dimension (novelty seeking, harm avoidance, reward dependence, and persistence) as well as alcohol drinking behavior scales. However, novelty seeking was significantly associated with alcohol drinking behavior. The higher level of novelty seeking was associated with the higher severity index of drinking (B = -0.225, p < 0.001) and problematic alcohol use on the CAGE and AUDIT-K [Odds Ratio (OR) = 1.111, 95% Confidence Interval (CI) 1.021-1.209, p = 0.015, OR = 1.087, 95% CI 1.009-1.170, p = 0.028]. CONCLUSION: In our study, while there is no significant association of DRD4 polymorphism with temperament and alcohol drinking behavior, novelty seeking affects problematic alcohol use. Results suggest that novelty seeking may play an important role in problematic alcohol use in young Korean adults.
Adult ; Alcohol Drinking ; Base Pairing ; Dopamine ; Drinking ; Exons ; Humans ; Minisatellite Repeats ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Receptors, Dopamine D4 ; Reward ; Temperament ; Weights and Measures ; Surveys and Questionnaires

We investigated the possible association between genetic polymorphisms in the dopamine receptor and serotonin transporter genes and the responses of schizophrenic patients treated with either risperidone or perospirone. The subjects comprised 27 patients with schizophrenia who were clinically evaluated both before and after treatment. The genotyping of the polymorphisms of the dopamine D2 receptor gene (DRD2) (rs1801028 and rs6277), the dopamine D4 receptor gene (DRD4) (120-bp tandem repeats and rs1800955), and serotonin transporter gene (5HTT)(variable number of tandem repeats; VNTR) were performed using the real-time polymerase chain reaction and sequencing. In DRD2 and 5HTT-VNTR, there were no significant correlations between clinical response and polymorphism in the case of risperidone, and for perospirone treatment it was impossible to analyze the clinical evaluation due to the absence of genotype information. On the other hand, in DRD4 there were significant correlations in the two-factor interaction effect on the Positive and Negative Syndrome Scale (PANSS) between the two drugs [120-bp tandem repeat, p=0.003; rs1800955, p=0.043]. Although the small sample represents a serious limitation, these results suggest that variants in DRD4 are a predictor of whether treatment will be more effective with risperidone or with perospirone in individual patients.
Genotype ; Hand ; Humans ; Isoindoles ; Polymorphism, Genetic ; Real-Time Polymerase Chain Reaction ; Receptors, Dopamine ; Receptors, Dopamine D2 ; Receptors, Dopamine D4 ; Risperidone ; Schizophrenia ; Serotonin Plasma Membrane Transport Proteins ; Tandem Repeat Sequences ; Thiazoles

OBJECTIVE: The aim of this study was to evaluate the association between a variable number of tandem repeats polymorphism at the dopamine D4 receptor gene (DRD4) and the performance of children with attention deficit hyperactivity disorder (ADHD) in a continuous performance test (CPT). METHODS: This study included 72 ADHD children (mean age=9.39+/-2.05 years) who were recruited from one child psychiatric clinic. The omission errors, commission errors, reaction time and reaction standardization in the CPT were computed. The number of 48-base pairs tandem repeats in the exon III of DRD4 was analyzed in a blind manner. RESULTS: The homozygosity of the 4-repeat allele at DRD4 was significantly associated with fewer commission errors (t=2.364, df=28.685, p=0.025) and standard deviation of reaction time (t=2.351, df=24.648, p=0.027) even after adjusting for age. The results of analyses of CPT measured values among three groups showed that the group with higher frequency of the 4-repeat allele showed a lower mean score of commission errors (F=4.268, df=2, p=0.018). CONCLUSION: These results suggest a protective role of 4-repeat allele of the DRD4 polymorphisms on commission errors in the CPT in children with ADHD.
Alleles ; Attention Deficit Disorder with Hyperactivity ; Child ; Dopamine ; Exons ; Humans ; Minisatellite Repeats ; Reaction Time ; Receptors, Dopamine D4 ; Tandem Repeat Sequences

OBJECTIVEAttention deficit hyperactivity disorder (ADHD) is one of the most common behavior disorders in childhood and adolescent. The etiology of ADHD is unknown. The aim of this study was to investigate the relationship between each of the 14 polymorphisms in the five candidate genes and ADHD, and between the combination of some polymorphisms in those genes and ADHD, in attempting to examine whether combinations of genotypes would confer a significant susceptibility to ADHD.

METHODSOne hundred and thirty-nine children with ADHD and one hundred and nineteen normal children were enrolled. Eight single nucleotide polymorphisms (SNP) of three candidate genes were examined with PCR and RFLP techniques. 48 bp VNTR in DRD4 gene was examined with PCR, nondenaturing polyacrylamide gel electrophoresis and silver staining. Five microsatellites (MS) of three candidate genes were examined with genotyping. The relationship between the combinations of 12 polymorphisms and ADHD was examined with logistic regression analysis.

RESULTS1.The frequency of 1065T/1065T genotype and the 1065T allele were significantly higher in ADHD children than that in normal controls (P<0.05). The frequency of -48G/-48G genotype of the A-48G polymorphism of DRD1 gene was significantly lower in ADHD children than that in normal controls (P<0.05). 2. A specific combination of three polymorphisms in the two genes showing an association with ADHD gave a prediction level of 77.5%.

CONCLUSIONSThe T1065G polymorphism in the SNAP-25 may be associated with ADHD. The 1065T/1065T genotype and the 1065T allele may be a risk factor for ADHD. The A-48G polymorphism of DRDI may be associated with ADHD. The -48G/-48G genotype may be a protective factor for ADHD. The specific combination of three sites of SNP in SNAP-25 gene and DRDI gene is found and shows an association with ADHD in 12 polymorphisms of the five candidate genes on glutamatergic/dopaminergic pathway.

Adolescent ; Attention Deficit Disorder with Hyperactivity ; genetics ; Child ; Female ; Humans ; Logistic Models ; Male ; Minisatellite Repeats ; Polymorphism, Single Nucleotide ; Receptors, Dopamine D3 ; genetics ; Receptors, Dopamine D4 ; genetics ; Receptors, Dopamine D5 ; genetics ; Receptors, N-Methyl-D-Aspartate ; genetics ; Synaptosomal-Associated Protein 25 ; genetics

OBJECTIVETo study polymorphisms of dopamine D4 receptor (DRD4) in children with primary nocturnal enuresis (PNE) and explore the relationship between DRD4 gene polymorphisms and PNE.

METHODSGenomic DNA was isolated from leukocytes in 86 unrelated children with PNE and in 100 healthy unrelated children (controls). Polymorphisms of DRD4-1240L/S, -616C/G and -521C/T were genotyped by allele-specific primer PCR.

RESULTSThere were significant differences in allele frequencies (x2=8.13, P<0.05) and genotypes frequencies (x2=6.23, P<0.05) of DRD4-616C/G between PNE patients and healthy controls. The frequency of haplotype LCT consisting of 3 function polymorphic sites DRD4-1240L/S, -616C/G and -521C/T in PNE patients was statistically higher than that in healthy controls (x2=5.88, P<0.05).

CONCLUSIONSThe change of C to G of DRD4-616 may affect the induction and transcription of DRD4 gene. The haplotype LCT consisting of 3 function polymorphic sites DRD4-1240L/S, -616C/G and -521C/T may synergistically inhibit the transcription activity of DRD4 gene. This might lead to a reduction of DRD4 protein expression and cause nocturnal enuresis.

Adolescent ; Child ; Female ; Genotype ; Haplotypes ; Humans ; Male ; Nocturnal Enuresis ; genetics ; Polymorphism, Genetic ; Receptors, Dopamine D4 ; genetics

OBJECTIVES: The studies on the genetic risk factors of the children of alcoholics (COAs) are still in an early stage. The A 1 allele of the dopamine receptor 2 gene (DRD2) may be associated with the negative affect and positive alcohol expectancy of the COAs. In addition, several researchers reported that COAs might be associated with the GABAA receptor beta subunit gene (GABRB3) and serotonin transporter gene (5-HTTLPR). In this study, we investigated the association of polymorphism of the DRD2, Dopamine D4 receptor gene (DRD4), GABRB3, 5-HTTLPR with COAs to examine the genetic risk factors of COAs. METHODS: Twenty-two COAs and 23 control children (children of non-Alcoholics ; Non-COAs) were included for the genetic study. All COAs aged 6 to 18 were recruited and selected from families of alcoholic patients in alcohol clinics of three university and mental hospital. Alcoholism of parents was classified as type I (non-antisocial, late onset) and type II (antisocial, early onset) by Cloninger's classification. The genotyping of the DRD2, DRD4, GABRB3, 5-HTTLPR was carried out. Chi-square method was used for evaluating the associations between genetic polymorphism and the COAs. RESULTS: The frequency of A1+ allele of DRD2 in COAs were significantly higher than Non-COAs (Chi-square=4.45, df=1, p=0.035). Significant association between the genotype of DRD4 and COAs was found (Chi-square=8.32, df=1, p=0.004). G1- alleles of GABRB3 in COAs were significantly higher than in Non-COAs (Chi-square=6.622, df=1, p=0.022). We found no association of the polymorphic alleles of 5-HTTLPR with the COAs (Chi-square=0.021, df=1, p=0.884). There were significant associations between the type of parental alcoholism and depression of COAs. CONCLUSION: We found that the children of alcoholics had significantly increased genetic risk of alcohol drinking expectancy. This study provides some preliminary information on the risk and protective factors associated with the COAs, which can be used as a foundation for prevention and intervention of future psychopathology.
Alcohol Drinking ; Alcoholics* ; Alcoholism ; Alleles ; Child* ; Classification ; Depression ; Dopamine* ; Genotype ; Hospitals, Psychiatric ; Humans ; Korea* ; Parents ; Polymorphism, Genetic ; Psychopathology ; Receptors, Dopamine ; Receptors, Dopamine D4 ; Receptors, GABA-A* ; Risk Factors ; Serotonin Plasma Membrane Transport Proteins* ; Serotonin*