DRD4 genotyping may differentiate symptoms of attention-deficit/hyperactivity disorder and sluggish cognitive tempo

Objective: Studies to reduce the heterogeneity of attention-deficit/hyperactivity disorder (ADHD) have increased interest in the concept of sluggish cognitive tempo (SCT). The aim of this study was to investigate if the prevalence of two variable-number tandem repeats (VNTRs) located within the 3′-untranslated region of the DAT1 gene and in exon 3 of the dopamine D4 receptor (DRD4) gene differ among four groups (31 subjects with SCT but no ADHD, 146 individuals with ADHD but no SCT, 67 subjects with SCT + ADHD, and 92 healthy controls). Methods: We compared the sociodemographic profiles, neurocognitive domains, and prevalence of two VNTRs in SCT and ADHD subjects versus typically developing (TD) controls. Results: The SCT without ADHD group had a higher proportion of females and lower parental educational attainment. Subjects in this group performed worse on neuropsychological tests, except for psychomotor speed and commission errors, compared to controls. However, the ADHD without SCT group performed significantly worse on all neuropsychological domains than controls. We found that 4R homozygosity for the DRD4 gene was most prevalent in the ADHD without SCT group. The SCT without ADHD group had the highest 7R allele frequency, differing significantly from the ADHD without SCT group. Conclusion: The 7R allele of DRD4 gene was found to be significantly more prevalent in SCT cases than in ADHD cases. No substantial neuropsychological differences were found between SCT and ADHD subjects.

Association between methylation status of CpG island in DAT1 and DRD4 genes and clinical symptoms of ADHD / 中国神经精神疾病杂志

Objective To investigate the correlation of methylation status in DA T1 and DRD4 genes and severity of clinical manifestations in ADHD patients.Methods One hundrd eleven DSM-Ⅳ defined ADHD patients were enrolled in this study and the demographic data were collected.Clinical symptoms were also assessed by Attention Deficit Hyperactivity Disorder Rating Scale-Ⅳ Home Version (ADHD-RS-Ⅳ) and self-developed Oppositional Defiant Disorder (ODD) rating scale.Bisulfite genomic sequencing (BGS) was used to detect the methylation status of every CpG site in DA T1 and DRD4 promoter CpG island in peripheral venous blood.Results The DNA methylation level in total CpG island for DA T1 was higher in individuals without depression,anxiety or ADHD family history compared to individuals with above family histories (P＜0.05).The differences on methylation levels for DA T1 and DRD4 were not significant between high and low ADHD-RS-Ⅳ total score (≤30 vs.＞30),ADHD-RS-Ⅳ inattention score (≤ 17 vs.＞17),and ADHD-RS-Ⅳ hyperactivity/impulsivity score (≤13 vs.＞13) subgroups (all P＜0.05).The methylation levels in total CpG island in DA T1 was higher in individuals whose ODD score were ＜9 compared to those whose ODD score were ≥9 (P＜0.05).Conclusions Methylation status of CpG island in DAT1 may influence the severity of oppositional defiant symptom in ADHD patients,which is correlated with depression,anxiety and ADHD family histories.

DRD4/DAT1 mRNA expression in attention deficit hyperactivity disorder children before and after methylphenidate treatment / 中华行为医学与脑科学杂志

Objective To investigate mRNA expression level changes of dopamine transporter gene (DAT1) and dopamine receptor gene(DRD4) in attention deficit hyperactivity disorder(ADHD) children's peripheral blood before and after methylphenidate treatment,and to explore associations between the mRNA expression level and symptom severity,as well as methylphenidate response.Methods Forty five ADHD children by DSM-Ⅳ diagnostic criteria,aged six to fifteen years old participated in a six-week drug titration treatment of metbylphenidate.ADHD-RS-Ⅳ Home Version, WCST and VCPT were used to evaluate the ADHD clinical symptoms and cognitive functions.RNA Simple Total RNA Kit was used to extract the total RNA.After reverse transcription, the obtained c-DNA was used in the following qRT-PCR to evaluate relative mRNA expression of the candidate genges before and after medication.Results The DRD4 mRNA relative expression level after taking methylphenidate was significantly higher than that before methylphenidate treatment (0.23 ± 0.23 vs 0.16± 0.18, P =0.041).There was no significant difference between DAT1 mRNA relative expression level before (0.43 ± 0.40) and after (0.43±0.40) methylphenidate treatment.No significant difference was found on eitber basal DAT1/DRD4 mRNA expression or fold change of DAT1/DRD4 mRNA expression before and after medication between methylphenidate treatment responders and non-responders groups.There was a positively significant correlation between baseline DRD4 mRNA relative expression level and erroneous T score of CPT(r=0.424, P=0.025) , however, no other statistically significant correlation was found between basal DRD4 mRNA relative expression level and ADHD-RS-Ⅳ total score,WCST conceptual level, CPT missing T score, and CPT reaction T sco~ (all P＞0.05).There was also no statistical significant correlation between basal DAT1 mRNA relative expression level and ADHD-RS-Ⅳ total score,WCST conceptual level,and CPT T scores(all P＞0.05).Conclusion DRD4 gene function may be increased after methylphenidate treatment and play an important role in impulsivity behavior of ADHD.Therefore, DRD4 mRNA expression level might be a biomarker for ADHD diagnosis and a predicting indicator of drug efficacy.

Lack of association between the G-660C polymorphism in the dopamine transporter gene (SLC6A3) and schizophrenia in the Iranian population.

Background: Dopaminergenic system plays an essential role in the plasticity of the human brain. The dopamine transporter gene (SLC6A3) mediates active reuptake of dopamine from synapsis, terminates dopamine signals, and therefore, is implicated in a number of dopamine-related disorders like psychosis. Variations in the form of single nucleotide polymorphisms in the core promoter of the SLC6A3 gene are reported to be involved in the pathogenesis of schizophrenia. In this study, we also attempted to establish the possible role of the polymorphism G-660C in the SLC6A3 gene promoter in schizophrenia in a case-control study. Materials and Methods: The allele and genotype frequency were analyzed in an Iranian cohort of 200 unrelated patients and 200 controls using polymerase chain reaction and restriction fragment length polymorphism. Results: The genotype frequency for case and control groups was GG 100%, GC 0%, CC 0%, and GG 100%, GC 0%, CC 0%, respectively. The C allele was failed in both groups. Conclusion: Our data suggest clearly that there is no association between the -660G/C polymorphism and outcome of schizophrenia in the Iranian population.

Dopamine Transporter Gene and Dopamine D2, D3, D4 Receptor Gene Polymorphisms in Attention Deficit Hyperactivity Disorder

OBJECTIVES: The aim of this study was to examine the association of attention-deficit hyperactivity disorder (ADHD) in Korean populations with functional polymorphisms of six genes dopamine receptors (Ser311/Cys311 polymorphism, Taq1 A polymorphism, and Taq1 B polymorphism in DRD2, BalI polymorphism in DRD3, and promoter -521 C/T polymorphism and exon III 48 bp repeat polymorphism in DRD4) and one gene in dopamine transporter (DAT1). METHODS: Participants were 58 children with ADHD and 110 control children. The genotypes were determined by PCR. RESULTS: There was a statistically significant difference in genotype frequency of -521 C/T polymorphism within the promoter region of the DRD4 between two groups. Furthermore, in the male group, both genotype and allele frequencies showed statistically significant differences. CONCLUSION: Findings of the study indicate that -521 C/T polymorphism in promoter region of DRD4 appears to be a possible candidate gene for ADHD in Korean population.

Association Study Between Dopamine Transporter Gene 40 bp VNTR and Antipsychotics-Induced Restless Legs Syndrome / 수면정신생리

OBJECTIVES: The pathophysiology of restless legs syndrome (RLS) is not obvious, but many promising theories involve dopaminergic deficiency and genetic causes. The RLS is presumed to occur more frequently among schizophrenic patients who take antipsychotics, most of which blocks the dopamine receptors. This study aimed to investigate whether dopamine transporter gene (DAT1) 40 base pair (bp) variable number of tandem repeat (VNTR) polymorphism is associated with the antipsychotic-induced RLS in schizophrenia. METHODS: We determined the diagnosis of RLS among the 190 Korean schizophrenic patients by the diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG). Genotyping was performed for the 40bp VNTR in DAT1 gene using polymerase chain reaction. RESULTS: We separated the schizophrenic patients into 44 patients with RLS and 146 patients without RLS. The genotype and allele frequencies did not differ significantly between two groups. CONCLUSIONS: These results suggest that DAT1 gene 40bp VNTR is not associated with the antipsychotic-induced RLS in schizophrenia. To confirm these results, larger-scale association study is needed in the future.

Association between Panic Disorder and Dopamine Transporter Gene(DAT1) Polymorphism

OBJECTIVES: There have been many association studies of panic disorder. However, studies about the do-paminergic function in panic disorder have been few. This study was aimed to examine the possible as-sociation of dopamine transporter gene(DAT1) polymorphism and panic disorder in Korean population. METHODS: Ninety-eight patients with panic disorder(43 male(46.9%), mean age 42.13+/-10.88 years) and one hundred and thirteen comparison subjects(67 male(40.7%), mean age 33.14+/-8.55 years) were tested for DAT1 polymorphism. Genotypes of DAT1 with variable number of tandem repeats(VNTR) were determined using polymerase chain reaction. The differences of allelic frequency and genotype frequency distribution between patient and the control group were tested with Fisher-Freeman-Halton test. RESULTS: There was association between DAT1 polymorphism and panic disorder(allele : p<0.03, genotype : p<0.05). The frequency of 10/10 homozygotes of DAT1 was significantly higher in control group(chi2=4.452, df=1, p=0.035). CONCLUSION: These results in our Korean samples suggest that DAT1 polymorphism might be associated with the vulnerability of panic disorder. Possible association of dopaminergic genes and panic disorder should be investigated with future studies using larger and different population.

Lack of Association between Polymorphisms of the Dopamine Receptor D4 and Dopamine Transporter Genes and Personality Traits in a Korean Population

Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.

Polymorphism of Dopamine Transporter Gene(DAT1) in Korean Social Phobia Patients: Preliminary Study

OBJECTIVE: Although polymorphism of dopamine transporter gene(DAT1) has been considered to be implicated in the pathogenesis of social phobia, previous investigations have been inconsistent and controversial. The authors investigated the relationship between DAT1 polymorphism and social phobia in Koreans. METHODS: DAT1 and alleles of fifty subjects who met DSM-IV criterion of social phobia, and those of age- & sex- matched fifty normal controls in Korea were compared. Additionally, patients were grouped into generalized(33) and nongeneralized(17) types and DAT1 polymorphism was compared with that of age- & sex- matched controls. DAT1 with variable number of tandem repeats(VNTR) were determined by using polymerase chain reaction. To compare the distribution of the DAT1 polymorphism between different groups, Fisher`s exact test was used. RESULTS: There were no significant differences in either genotypic(p=0.451) or allelic(p=0.452) distributions between the social phobia patients and the controls. There also were no differences in genotypic distribution between subtypes of social phobia patients and the controls. CONCLUSION: We couldn't find any association between DAT1 polymorphism and social phobia. Further studies including larger number of samples and diverse clinical variables should be conducted to elucidate the present findings.

Effect of Homozygosity for 10-Repeat Allele at Dopamine Transporter Gene and Dopamine Transporter Density Assessed with 123IIPT SPECT on Response to Methylphenidate Treatment in Attention Deficit Hyperactivity Disorder / 신경정신의학

OBJECTIVES: The symptoms of attention-deficit/hyperactivity disorder (ADHD) can be treated with methylphenidate, a potent blocker of the dopamine transporter (DAT). The homozygosity of the 10-repeat allele at dopamine transporter gene (DAT1) seems to be associated with a poor response to methylphenidate (MPH) in children with ADHD. In present study, we investigated association between DAT density using I-123N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane ([123I]IPT SPECT) and the homozygosity for 10-repeat allele at DAT1, and response to MPH in children with ADHD. METHODS: Eleven drug-naive children with ADHD were included in the study and treated with MPH for about 8 weeks. After the genotyping and SPECT were performed, we compared DAT density between ADHD children with and without the homozygosity for the 10-repeat allele at DAT1 and investigated correlation between the homozygosity for the 10-repeat allele and response to MPH. RESULTS: ADHD children with 10/10 genotype (n=7) had a significantly higher DAT density in basal ganglia than the children without 10/10 genotype (n=4)(Right: z=-2.65, p=0.008; Left: z=-2.65, p=0.008). We found that while only 28.6% (2/7) of the subject with 10/10 genotype showed good response (> or =50% improvement) to MPH treatment, 100% (4/4) of the subjects without 10/10 genotype showed good response to MPH treatment (chi2 test: F=5.238, df=1, p=0.022). CONCLUSION: Our findings support an association between homozygosity for the 10-repeat allele at DAT1 and the DAT density assessed in vivo and correlation between the homozygosity for the 10-repeat allele and poor response to MPH.

Prolactin Response to Antipsychotic Drug and Dopamine Transporter Gene Polymorphisms

OBJECT: We investigated the relationship between prolactin response to antipsychotics and clinical courses of psychotic symptoms and DAT gene polymorphisms. METHOD: Twenty-four acute psychotic inpatients completed the 12-week trial of risperidone. Serum prolactin, BPRS, ESRS and hyperprolactinemia-related symptoms were measured at baseline, 2, 4, 8 and 12 weeks after medication. The DAT gene polymorphisms were analyzed. RESULTS: The serum prolactin was significantly increased over time. According to the prolactin level at 2-week, the subjects were divided into the severe group(serum prolactin>60ng/mL, N=15) and the mild group (serum prolactin<60ng/mL, N=9). The prolactin levels of the mild group didn't increase beyond 60ng/mL throughout 12 weeks. Severe group had slower decrement of BPRS scores than those of mild group. Six females in severe group complained of irregular menstruations, but no female in mild group. Most patients had 10 allele of DAT gene. CONCLUSION: This study suggests that the magnitude of prolactin elevation at the 2-week of risperidone medication is correlated with severity of hyperprolactinemia throughout treatments. Our results did not show the relationship between prolactin responses and DAT gene polymorphisms.

Dopamine Transporter Gene Polymorphism Association between ADHD Patients and the Parents Group / 대한정신약물학회지

OBJECTIVES: Attention deficity hyperactive disorder is known to be a disease with a high genetic trait. Recently the relationship between alleles frequency distribution and ADHD has been actively researched. In Korea, the relationship between the genetic type and alleles for dopamine transporter gene has been studied in ADHD patients. METHODS: Thirty five patients diagnosed with ADHD according to the DSM-IV diagnostic criteria were selected for study. The diagnosis and clinical features were confirmed by korean version Child behavior check list, korean version Conner's parent rating scale, Attention deficit Diagnostic System, korean version Spielberger state-trait anxiety scale etc. For the control group, the parents of patients were chosen. Blood samples were taken from the 105 subjects. DNA was extracted from blood lymphocytes, PCR was performed for dopamine transporter gene. RESULTS AND CONCLUSION: In comparing the ADHD transmitted group and the not transmitted group, significant difference was seen between the DAT1 genetic type and alleles distribution. As a result, it is viewed that there is relationship between ADHD and the dopamine transporter gene. Follow up studies with larger patient or pure subgroups are expected.

Association between Attention Deficit Hyperactivity Disorder and Dopamine Transporter Gene(DAT1) Polymorphism in Korean / 신경정신의학

OBJECTIVES: Study results of association between dopamine transporter gene(DAT1) and attention deficit hyperactivity disorder(ADHD) were not conclusive. Distribution of DAT1 polymorphism is variable according to ethnicity. Ethnic differences in the distribution of DAT1 can be an impediment to apply previous findings to Korean ADHD. This study was to examine the association between DAT1 and ADHD, and the risk allele of ADHD among DAT1 polymorphism in Korean. METHODS: DNA extracted from blood of 100 normal controls and 44 ADHD patients. DAT1 with variable number of tandem repeats(VNTR) were determined using polymerase chain reaction. The differences of allelic frequency distribution and genotype frequency distribution between patient group and control group were tested with Fisher's exact test. The pairs of allele and of genotype with difference between the two groups were selected by Fisher's excat test adjusting p-values with permutation method. Odds ratios of two alleles and of two genotypes between the two groups were computed. RESULTS: There was association between DAT1 and ADHD(genotype: p<0.05, allele: p<0.05. Patients with ADHD were more likely to have 440 base pairs than 480 base pairs comparing to controls (OR=4.46, 95% CI: 1.44-13.75). Patients with ADHD were more likely to have 9/10 genotype than 10/10 genotype comparing to controls(Odd Ration=3.74, 95% Confidence Interval: 1.11-12.61). CONCLUSIONS: We found the association between DAT1 and ADHD, and possible risk allele of Korean ADHD. Replication of the results in larger sample is needed.