Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of the present study was to use a meta-analysis on previous studies plus our own unpublished data to confirm and extend findings which indicate that the variation in the dopamine D4 receptor (DRD4) gene is best represented by a mixture of two different ethnic groups. The genotype distribution was divided into either a long or short form using a mixture analysis of normal controls of different ethnic origins under the assumption that there is a single major gene. The meta-analysis was based on the data from 19 independent samples, 18 association studies, and from our own unpublished data, including a total of 1431 schizophrenic patients (sporadic cases 1309, familial cases 122) and 1439 controls. No significant genotype differences were noted between patients and controls for the whole sample. However, reorganization of the studies into different groups by the geographical origin of samples revealed significant ethnic heterogeneity. In addition, there was a significant association between the long form of DRD4 gene and schizophrenia in Caucasians, especially those with familial schizophrenia.
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PMID:Ethnic heterogeneity in allele variation in the DRD4 gene in schizophrenia. 1222 55

The dopamine D4 receptor (D4) is a target for most common neuroleptic medications. After its initial discovery, it was found to possess the highest affinity of all dopamine receptor subtypes for the archetypical, atypical, antipsychotic clozapine. Nevertheless, initial clinical trials have not provided evidence that this receptor is a primary target for antipsychotic drugs. Considering the accumulated in vivo evidence that at least a subgroup of psychotic patients have altered dopamine signaling, all dopamine receptor subtypes likely contribute to the phenotypic expression of schizophrenia. New insights into the function of this receptor and its role in the modulation of excitatory signaling support the view that this dopamine receptor may affect attention and cognition. In this review, the authors outline some recent developments that provide insight into D4 receptor physiology, function and its possible relationship to schizophrenia treatment.
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PMID:The dopamine D4 receptors and mechanisms of antipsychotic atypicality. 1464 69

Alterations in dopaminergic system have been implicated in the pathophysiology of this disease for many years, and this study was performed to assess the possible involvement of the dopamine D4 receptor (DRD4) gene polymorphisms either in the 5' upstream or in the coding regions, in the etiology of schizophrenia. The approach included an association study with 90 Portuguese trios by doing the analysis of the individual alleles and the haplotypes. For the polymorphisms in the 5' upstream region (-C616G and -C521T) and in the coding region (48 bp repeat) of the DRD4 gene, negative results were obtained with both haplotype relative risk (HRR) and transmission disequilibrium test (TDT), as well as transmit. These data suggest that polymorphisms (-C616G, -C521T, and 48 bp repeat) at the DRD4 gene do not have a minor effect in the susceptibility to schizophrenia in our sample.
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PMID:No evidence of association or linkage disequilibrium between polymorphisms in the 5' upstream and coding regions of the dopamine D4 receptor gene and schizophrenia in a Portuguese population. 1475 38

Recently, an interaction between season of birth and the expression of candidate genes has been suggested. Season of birth variations in tryptophan hydroxylase (TPH), the serotonin transporter (5-HTTLPR) and the dopamine D4 receptor (DRD4) gene polymorphisms are different for affective disorders and schizophrenia. The DRD4 gene has been postulated as a candidate gene for attention-deficit-hyperactivity disorder (ADHD), equivalent to hyperkinetic disorder (HD). The seven-repeat long variant of this gene (DRD4*7) in comparison to the short repeat variants of the DRD4 gene polymorphism, has been found to be associated with ADHD. A seasonal pattern of birth has also been proposed for different subtypes of ADHD. Therefore, in a subgroup of children with HD and conduct disorder (CD) and in healthy controls, we investigated a possible association between the DRD4*7 allele and HD + CD in association with the season of birth. Supporting this hypothesis, we found an interaction between the seasons of birth and the expression of the DRD4 candidate gene in children with HD + CD as well as in controls, which differ significantly from each other. Depending on the season of birth, children carrying the DRD4*7R allele showed different relative risks for developing HD + CD.
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PMID:Gene-environment interaction in hyperkinetic conduct disorder (HD + CD) as indicated by season of birth variations in dopamine receptor (DRD4) gene polymorphism. 1528 35

The dopamine D4 receptor (DRD4) is the most important gene in psychiatric genetics since its involvement in the physiology of behavior, pharmacology response and psychopathology. DRD4's sequence gene present some polymorphism such as in the exon 3 constituted from 2 to 10 copies of repetitive sequences of 48 base pair (bp), from class variable number tandem repeats (VNTR). An additional genetic variant in the exon 1 presents polymorphisms to 12 bp VNTR, and the variation -521 C by T of the promoter region. The -521 T allele can reduce the efficiency of the gene expression in comparison with the C allele. The DRD4 gene codes a protein transmembranal of 7 domains, distributed in front cortex, striatum, hypothalamus and hippocampus. This review discusses the biological significance of DRD4 gene and its perspective with emphasis on the impact of association studies in some illness mental and behavioral traits. The DRD4 polymorphism has been studied in association with illnesses like schizophrenia, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive with tics, bipolar manic-depressive disorder, in addition behavioral traits such as novelty seeking. The DRD4 gene is a genetic marker that could play a role in etiology of different mental illness, and behavioral traits, and its polymorphism can be used in association studies, epigenetic and pharmacogenomic analysis for help to understand the genetics basis of both mental disorders and traits.
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PMID:[DRD4 polymorphism and the association with mental disorders]. 1598 60

To investigate the relationship between 48 bp variant number tandem repeat polymorphism in dopamine D4 receptor gene and response to clozapine in schizophrenic patients, the authors included 81 inpatients with a DSM-IV diagnosis of schizophrenia and patients meeting criteria for refractory to treatment were excluded. This study found that the frequencies of five 48 bp repeats homozygous genotype and five 48 bp repeats allele were significantly less in the responders than the nonresponders, which divided by improving total schizophrenic symptom. The results of this study suggest that inherited variants of D4 may explain some of the interindividual variation seen in patient response to clozapine.
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PMID:Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to clozapine. 1622

The changes of P300 parameters (lower amplitude and increased latency) are thought to be the most prominent phenomena of schizophrenia. A role of gene polymorphism in P300 generation was supported by several associative studies in psychiatrically well subjects and patients with mental disorders. We studied P300 parameters and the following polymorphisms: T102C for the serotonin receptor type 2A (5-HTR2A) gene, the 5-HTTLPR for the serotonin transporter gene, -809G/A, -616G/C N -52C/T SNPs in the promoter region of the dopamine D4 receptor (DRD4) gene and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) in 74 patients with schizophrenia and spectrum disorders and 71 their first-degree relatives. No association was found between serotonergic system genes and P300. The -809G/A DRD4 gene polymorphism was related to amplitude in all frontal leads (p=0,01) in patients. In relatives, an association was observed between -521C/T DRD4 variants and latency (p=0,005) as well as between the COMT gene polymorphism and P300 amplitude (p=0,004) at the central lead. Thus, the genes involved in dopaminergic system play a role in P300 generation both in patients with schizophrenia and spectrum disorders and their relatives.
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PMID:[A study of some genes related to serotoninergic and dopaminergic systems and auditory evoked-potentials (P300) in patients with schizophrenia and spectrum disorders and their first-degree relatives]. 1628 77

The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D4 receptor antagonist A-381393 blocked both c-Fos expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D4 receptor and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D4 receptor activation. Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D4 antagonist A-381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity.
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PMID:Dopamine D4 receptor signaling in the rat paraventricular hypothalamic nucleus: Evidence of natural coupling involving immediate early gene induction and mitogen activated protein kinase phosphorylation. 1632 24

Recent association studies suggest that polymorphisms in the promoter and exon 1 upstream region of the dopamine D4 receptor (DRD4) gene play a functional role in the development of common psychiatric illnesses, although there are also conflicting results. In this study, we re-sequenced this region to identify all genomic variants, and tested them for association with schizophrenia. A total of 570 Japanese schizophrenic cases with matched controls were studied by genotyping all identified/validated common polymorphisms (-1106T>C, -906T>C, -809G>A, -616G>C, -521T>C, -376C>T, -291C>T and 12-bp repeat) and a known microsatellite (120-bp tandem duplication) in the upstream region. A single nucleotide polymorphism (SNP) -809G>A in the promoter region was found to be significantly associated with disease (P=0.018 and 0.032 for allelic and genotypic comparisons, respectively), although not surviving after Bonferroni correction. Logistic regression analysis showed that a combination of the four polymorphisms, -809G>A, -616G>C, -291C>T and the 12-bp repeat, conferred a susceptibility to schizophrenia. These results suggest that the upstream variants have a primary functional effect in the etiology of schizophrenia in the Japanese population.
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PMID:Association and synergistic interaction between promoter variants of the DRD4 gene in Japanese schizophrenics. 1708 69

In this study, we investigated whether polymorphisms of the dopamine D4 receptor (DRD4) gene were associated with psychotic symptomatology rather than with a unique diagnosis such as schizophrenia. A number of association studies between the DRD4 gene 48 bp-VNTR polymorphism at exon 3 and psychotic disorders have been reported, but the results have been controversial. Both 48 bp-VNTR and the 12 bp-VNTR (at exon 1) polymorphisms of this gene were analyzed in a group of 149 unrelated Mexican subjects with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, major depression and bipolar disorder, both with psychotic symptoms, brief psychotic disorder, delusional disorder and non-specific psychotic disorder, and in 169 individuals free of psychiatric illnesses. There were no differences in allele or genotype frequencies between groups for the 12 bp-VNTR polymorphisms. However, a significant excess of "rare" alleles (3-, 5-, 6- and 8-48 bp repeats alleles) was found in the group of psychotics. Moreover, haplotypes 3-A1, 5-A1, 6-A1 and 8-A1 were significantly more frequently associated with cases. This positive association supports a role of this molecule as a genetic risk factor in psychotic disorders.
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PMID:Association analysis of exon III and exon I polymorphisms of the dopamine D4 receptor locus in Mexican psychotic patients. 1782 80


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