The influence on the schizophrenic symptoms by the DRD2Ser/Cys311 and -141C Ins/Del polymorphisms

The hyperactivity of dopaminergic systems is one of the major etiological hypotheses of schizophrenia. The major support for this hypothesis is that effective antipsychotic drugs bind to dopamine receptors and improve acute schizophrenic symptoms. For this reason, we investigated the allelic association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. The subjects were 190 schizophrenics (120 males and 70 females) and 103 normal controls (53 males and 50 females). There were no significant differences between the patients and controls in the allele frequencies and the frequencies of the genotypes. We found no statistical association between schizophrenia and polymorphisms of the DRD2 genes for the Ser/Cys311 and -141C Ins/Del. These results indicate that the DRD2 gene may not develop schizophrenia. Next, we examined whether the genotypes influence the symptoms of schizophrenia the using Positive and Negative Symptom Scale scores. The Ser/Cys patients exhibited significantly lower positive and negative symptom scores than Ser/Ser patients. Patients with Del/Del, Ins/Del, or Ins/Ins showed higher positive symptom scores in descending order. This result suggested that the Del allele worsens the positive symptoms. We concluded that the DRD2 receptor gene may not influence the onset of schizophrenia, but there is a strong possibility that the Cys311 and -141C Del have a significant influence on the symptoms of schizophrenia.     

Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia

The D2 subtype of dopamine receptor has been widely implicated in the pathogenesis of schizophrenia. Early evidence supporting an association between the Cys311Ser polymorphism of the D2 receptor gene (DRD2) and schizophrenia was subsequently refuted and, eventually, dismissed. From all 24 published case-control studies, we calculated a pooled estimate of this association. The pooled odds ratio was 1.3 for the Cys allele, which was highly significant (P=0.007). The odds ratio derived from each study was unrelated to the ethnicity or gender composition of the sample, or the age of the control group. There was no evidence of publication bias or excessive influence attributable to any given study. Although more family-based studies are needed to confirm this relation, our results provide strong evidence that DRD2 influences susceptibility to schizophrenia.     

Effects of DRD2/ANKK1 gene variations and clinical factors on aripiprazole efficacy in schizophrenic patients

OBJECTIVES: Aripiprazole, a novel antipsychotic agent, acts as a partial agonist at dopamine D2 receptors (DRD2). We investigate whether its efficacy is predictable by DRD2/ANKK1 gene polymorphisms and clinical factors in Han Chinese hospitalized patients with acutely exacerbated schizophrenia. METHOD: After hospitalization, the patients (n=128) were given aripiprazole for up to 4 weeks. They were genotyped for four functional DRD2/ANKK1 polymorphisms: -141 Ins/Del, Ser311Cys, C957T, and TaqIA. Clinical factors such as gender, age, illness duration, education level, diagnostic subtype, and medication dosage were also recorded. Psychopathology was measured biweekly with the positive and negative syndrome scale (PANSS). The effects of genetic and clinical factors on PANSS performance upon aripiprazole treatment were analyzed by a mixed modeling approach (SAS Proc MIXED). RESULTS: Compared to the patients with TaqI A2/A2 genotype, A1 carriers are associated with superior therapeutic response on positive symptoms after 4-week aripiprazole treatment. Regarding the C957T polymorphism, patients with C/C genotype were associated with poor aripiprazole response for excitement symptoms when compared with T/T patients. The other two polymorphisms, -141 Ins/Del, and Ser311Cys, have no significant effects on PANSS performance. The clinical factors including medication dosage, illness duration, and diagnostic subtype could influence PANSS performance upon aripiprazole treatment. CONCLUSION: This study suggests that DRD2/ANKK1 gene variations and some clinical factors may predict individual response to aripiprazole.     

The dopamine D2 receptor gene is a susceptibility locus for Parkinson's disease.

The dopamine D2 receptor (DRD2) gene has been proposed as a candidate gene underlying several psychiatric and neurologic disorders. The aim of the present study was to examine if selected polymorphisms in the DRD2 gene are associated with Parkinson's disease (PD). We determined the allelic frequencies for four polymorphisms located in the DRD2 gene in a sample of 135 patients with PD and 202 normal control subjects. No significant difference was observed in the allelic frequencies between patients with PD and control subjects with regard to the -141C Ins/Del and the Ser311/Cys311 variants. On the contrary, the A1 allele of the TaqIA polymorphism and the B1 allele of the TaqIB polymorphism were more frequent in patients with PD than in control subjects (control subjects: TaqIA A1 = 14.6%, TaqIB B1 = 10.6%; patients with PD: TaqIA A1 = 20.7%, TaqIB B1 = 17.4%). Patients carrying the A1 allele or the B allele had an increased risk of developing PD (TaqIA, odds ratio: 1.71, 95% confidence intervals: 1.08-2.73; TaqIB, odds ratio: 1.83, 95% confidence intervals: 1.12-3.02). The TaqIA and TaqIB polymorphisms were in strong linkage disequilibrium, suggesting that these two polymorphisms convey the same information about the risk of presenting with PD. Genetic variation in the DRD2 gene may influence the risk of developing PD, thus confirming that the DRD2 gene is a susceptibility locus for PD.     

No Evidence for an Association between Dopamine D2 Receptor Polymorphisms and Tardive Dyskinesia in Korean Schizophrenia Patients

Objective

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic. Dopaminergic activity in the nigrostriatal system have been proposed to be involved in development of TD and dopamine D2 receptors (DRD2) has been regarded as a candidate gene for TD because the antipsychotics have potent antagonism DRD2. This study was aimed to find the relationship between DRD2 gene and antipsychotic-induced TD.

Methods

We evaluated whether 5 DRD2 single nucleotide polymorphisms (-141Cins>del/TaqID/NcoI/Ser311Cys/TaqIA) are associated with antipsychotic-induced TD in 263 Korean schizophrenia patients with (n=100) and without TD (n=163) who were matched for antipsychotic drug exposure and other relevant variables. Haplotype analyses were also performed.

Results

None of 5 polymorphisms were found to be significantly associated with TD and with TD severity as measured by Abnormal Involuntary Movement Scale. Overall haplotype (-141Cins>del/TaqID/NcoI/Ser311Cys/TaqIA) frequency was also not significantly different between TD and non-TD groups, although one rare haplotype (I-D1-T-G-A1) showed significantly different frequency between TD and non-TD groups (2.7% vs. 8.5%, respectively, p=0.031).

Conclusion

The present study does not support that DRD2 gene may be involved in TD in the Korean population, although further studies are warranted.     

The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.     

Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population

Polymorphisms in the dopamine D2 receptor gene (DRD2) have repeatedly been associated with schizophrenia. Recently, the C957T polymorphism (rs6277), which alters mRNA stability and dopamine-induced upregulation of DRD2 expression in cell cultures and DRD2 mRNA translation in vitro, was tested for an association with the disease. Frequency of the C allele, corresponding to a normal wild-type level of expression, was higher in patients compared to controls, and that of the T allele was lower. To replicate and extend previous findings, we conducted an association study of the C957T polymorphism and two additional SNPs (C939T and TaqIA) in 311 patients with a DSM-IV diagnosis of schizophrenia and 364 mentally healthy people from the Russian population as controls. The results of our study confirmed the association between the C957T polymorphism and schizophrenia. Consistent with previous findings, frequency of the C allele and the CC genotype were higher in patients compared to the control group (p = 0.002). Meta-analysis of total 5 samples also suggests significant allelic association. The distribution of C939T genotypes in the case sample was significantly different from that of the controls: in the case sample, the TT genotype frequency was higher compared to the combined frequency of CT and CC genotypes (p = 0.002). Though no association was found between the TaqIA polymorphism and schizophrenia, a haplotype-wise analysis revealed a lower frequency of the T–C (C957T–TaqIA) haplotype in patients (p = 0.02). In conclusion, our findings provide additional evidence for an association between the C957T polymorphism and schizophrenia.     

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case-control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.     

多巴胺D2、D3受体基因多态性与汉族人精神分裂症相关研究

目的探索多巴胺D2受体(Dopamine D2receptor,DRD2)基因第8外显子Taq I A位点多态和多巴胺D3受体(Dopamine D3receptor,DRD3)基因第5内含子Msp I位点多态与汉族人群精神分裂症是否关联及其在不同性别是否存有差异。方法使用聚合酶链反应-限制性片段长度多态性(Polymerase chain reaction-re-striction fragment length polymorphism,PCR-RFLP)及DNA测序技术,对317例精神分裂症患者及310名对照DRD2Taq I A基因多态性和DRD3Msp I位点基因多态性进行检测。结果患者组与对照组间DRD2 Taq I A位点等位基因分布差异显著(P<0.01)、两两基因型对比(A1/A2与A1/A1相比:P<0.05;A2/A2与A1/A1相比:P<0.01)及两基因型联合对比(A1/A2+A2/A2与A1/A1:P<0.01)组间差异也显著。性别分层研究DRD2Taq I A位点女性组间差异显著(P<0.01),男性组间差异无意义(P>0.05)。DRD3Msp I位点的基因型频率、等位基因分布及性别分层分析等所有数据均显示患者组与对照组之间差异无统计学意义(P>0.05)。风险因子趋势检验结果DRD2Taq I A位点等位基因A2:P<0.01;DRD3Msp I位点等位基因2:P>0.05。结论所得数据支持DRD2Taq I A位点等位基因A2可能为精神分裂发生的风险因子,特别对女性而言。数据分析不支持DRD3Msp I位点基因与精神分裂发生有关。此结果需更进一步研究证实。     

The 3' region of the DRD2 gene is involved in genetic susceptibility to schizophrenia

The gene coding for the D2 dopamine receptor (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene yielded conflicting results, for example because of differences in methodology (linkage versus association studies) and variability in the loci analyzed (the DRD2 gene having many polymorphic sites). We used a progressive strategy with two different approaches (case-control and transmission disequilibrium test) and investigated six genetic polymorphisms spanning the DRD2 gene in 103 patients with DSM-IV criteria of schizophrenia, their 206 parents and 83 matched healthy control subjects. We found a significant excess of the A2 allele in subject with schizophrenia compared to unaffected controls. An excess of transmission of the A2 allele (and haplotypes containing this marker) from the parents to the affected children was also observed. Interestingly, the TaqI A1/A2 polymorphism, located 9.5 kb downstream from the DRD2 gene, maps in a novel gene, untitled "X-kinase", and leads to a 713Glu-->Lys substitution in exon 8. As the analysis of the other markers within the DRD2 gene does not improve the strength of the association, our data are in favor of a specific role of the 3' chromosomic region of the DRD2 gene in the vulnerability to schizophrenia.     

Genotypic association between the dopamine D3 receptor and tardive dyskinesia in chronic schizophrenia.

Dopamine receptor antagonism is a common mechanism underlying the therapeutic efficacy of all classical antipsychotic drugs. It is also thought to underlie the propensity of these agents to induce the movement disorder, tardive dyskinesia (TD), in one fifth of chronically exposed schizophrenia patients. We examined the polymorphic serine to glycine substitution in the first exon of the gene encoding the dopamine D3 receptor (DRD3) inn 53 schizophrenia patients with TD, 63 matched patients with similar antipsychotic exposure but no TD and 117 normal controls. There was a difference in allele frequency that was of borderline significance (P = 0.055), due to an excess of the DRD3gly allele (allele 2) in the schizophrenia patients with TD. The difference in genotype distribution among the groups was highly significant (chi2 = 19.1, d.f. 4, P = 0.0008) due to an excess of the DRD3ser-gly genotype in the schizophrenia patients with TD. The difference between the schizophrenia patients with TD and the controls was highly significant (chi2 = 19.0, d.f. 2, P = 0.00007), even after correction for multiple testing, as was the difference between the combined group of schizophrenia patients and the controls (chi2 = 12.2, d.f. 2, P = 0.002). Comparing the schizophrenia patients with and without TD, genotypes containing the gly allele (DRD3ser-gly and DRD3gly-gly genotypes combined) were significantly associated with dyskinesia (OR = 2.62, 95% CI 1.18-5.59, P = 0.02). DRD3 genotype and age at first antipsychotic treatment contributed significantly to total score on the Abnormal Involuntary Movements Scale (AIMS). The contribution of DRD3 to the variance in AIMS total was 5.2% and the total proportion of the variance accounted for by these two variables together was 11.9%. These results support and extend the report by Steen et al (1997) of an association between DRD3 and TD in schizophrenia patients.     

Association in Japanese patients between neuroleptic malignant syndrome and functional polymorphisms of the dopamine D(2) receptor gene

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D(2) receptor (DRD(2)) gene: TaqI A, -141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the -141C Ins/Del polymorphism between patients with and without NMS. The -141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of -141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the -141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.     

Allelic variation in the human prodynorphin gene promoter and schizophrenia

Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in schizophrenia. In particular, the prodynorphin (PDYN), the precursor of the dynorphin opioid peptides, has been shown to play an important role in several aspects of human mental diseases. Recently, a functional polymorphism in the promoter of PDYN gene has been described. We studied the possible relationship between this polymorphism and schizophrenia and we found no significant difference in allelic and genotype distributions between schizophrenic patients and control subjects. However, we observed a significant interactive effect with the receptor 3 of dopamine gene (DRD3); in particular, the frequency of subjects carrying PDYN allele 3 being also homozygotes for DRD3 Gly allele (of Ser9Gly polymorphism) was significantly greater in patients than controls. We conclude that PDYN gene polymorphism alone does not alter the risk for schizophrenia but, by an epistatic interaction with the Gly allele of DRD3 gene, may contribute to the susceptibility to this disorder.     

Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression

Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of dopamine receptor D3 (DRD3) and dopamine receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder. One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon Gly/Ser variants and DRD2 codon 311 Ser/Cys variants using polymerase chain reaction techniques. DRD3 and DRD2 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. The tested gene variants are not a main factor influencing TSD outcome in bipolar disorder.     

Gene polymorphism influencing treatment response in psychotic patients in a naturalistic setting

RATIONALE: Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins. OBJECTIVES: To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6). MATERIAL AND METHODS: Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in J?nk?ping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236C>T, 2677G>T/A, 3435C>T and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects. RESULTS: Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs. CONCLUSION: If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.     

DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability

The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia. Since DRD2 in mice and the COMT gene in humans modulate working memory, we examined the relationship and possible interaction of both polymorphisms to working memory performance in 188 healthy adults. Subjects having the DRD2 C/C allele showed the poorest performance in a word serial position test. Moreover, the effect of the C957T genotype was strengthened when interaction with the COMT Val158Met polymorphism was included in the analysis. We propose that an interaction of the DRD2 C957T and COMT Val158Met may be involved in the generation of some working memory deficits in schizophrenia.     

Association of dopamine receptor polymorphisms with schizophrenia and antipsychotic response in a South Indian population

Background  

Alterations in the dopamine transmission and receptor density are hypothesized in the pathophysiology of schizophrenia but ethnic disparities are reported to exist in disease association and therapeutic response to psychotropic medication. Antipsychotics have higher binding affinity to D2 subtype of dopamine receptor. DRD2 Cys311, TaqIB1 and TaqIA1 variants are considered to have either reduced affinity for dopamine and hypo-dopaminergic activity.     

多巴胺D2受体基因Taq1A多态性与利培酮、帕利哌酮所致高泌乳素血症的关系

目的:探讨多巴胺2(D2)受体基因Taq1A多态性与利培酮、帕利哌酮所致高泌乳素血症(HPRL)的关联性。方法:92例女性精神分裂症患者给予利培酮或帕利哌酮治疗4周,于治疗前后测定血清PRL水平及治疗后的9-羟利培酮血药浓度;并检测所有受试者的D2受体基因Taq1A多态性。结果:HPRL组(治疗后PRL水平≥3 500 m IU/L者,n=30例)与LPRL组(治疗后PRL水平3 500m IU/L者,n=37例)Taq1A基因型等位基因频率组间差异无统计学意义(χ~2=1.73,P=0.42);Taq1A 3种基因型(A1/A1,A1/A2及A2/A2)患者血清PRL水平治疗后均明显增高,但治疗前后差值比较,组间差异无统计学意义(F=1.40,P=0.26)。结论:未发现D2受体基因Taq1A多态性与利培酮、帕利哌酮所致HPRL存在关联。     

Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population

Dysregulation of dopaminergic neurotransmission has been implicated in the etiology of major psychoses. The dopamine D(1) receptor (DRD1) plays a role in some brain functions and mechanisms of psychotropic drugs. Therefore, the DRD1 gene makes a good candidate gene for molecular genetic studies in schizophrenia and bipolar affective disorder. In the present study, the -48A/G polymorphism of the DRD1 gene was estimated in patients with schizophrenia (n=407) or bipolar affective disorder (n=380), and in healthy controls (n=399). No association was found between the polymorphism studied and schizophrenia, either in the whole group of patients or in subgroups divided by gender, age at onset or predominance of positive or negative symptoms. A statistical trend was obtained for an association between this polymorphism and bipolar affective disorder (p=0.059 for genotypes, p=0.073 for alleles). The G/G genotype and G allele were significantly more frequent in patients with bipolar disorder, type II (p=0.016 for genotypes, p=0.008 for alleles), especially in the women subgroup (p=0.054 for genotypes, p=0.024 for alleles). An association between the G/G genotype and bipolar affective disorder with disease onset after 18 years of age was also found (p=0.022). These data suggest that the -48A/G polymorphism of the DRD1 gene may be involved in the etiology of bipolar disorder in a Polish population.