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)

A vast body of associative studies reported a role of highly polymorphic dopamine receptor DRD4 gene in regulation of emotional processes and development of mental disorders. The present study addresses allele, genotype and haplotype distribution of 3 polymorphic DRD4 markers (-809G/A, -616G/C N -521C/T) in Russian patients with schizophrenia spectrum disorders and their relation to the disease and personality traits. A sample included 151 patients with iCD-10 diagnosis of schizophrenia, schizoaffective psychosis and schizotypal personality disorders, 89 their first-degree non-psychotic relatives and 131 mentally healthy individuals. No differences in allele and genotype frequency was found between the patients and the controls. Transmission disiquilibrium test (TDT) did not reveal a preferential transmission of either allele from parents to proband. The 521C/T N -616G/C markers were linked to the disease when the EH program has been used in the analysis. Patients with the GG (-809G/A) and GG (-616G/C) genotypes had higher scores on the Hypomania scale (MMPI) comparing to the GA(-809G/A)+AA(-809G/A) and GC(-616G/C)+CC(-616G/C) genotypes but the association did not reach a level of significance (p = 0.06). The results confirmed the literature reports on the relation of the DRD4 gene to schizophrenia and personality traits related to social activity.
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PMID:[Dopamine receptor DRD4 gene polymorphism and its association with schizophrenia spectrum disorders and personality traits of patients]. 1625 86

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

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

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.
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PMID:Schizotypy, attention deficit hyperactivity disorder, and dopamine genes. 1710 13

The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.
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PMID:Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. 1719 67

Linkage between the DRD4 and COMT genes and cognitive measures characterizing verbal memory, executive functions, and associative processes was studied in 150 patients with schizophrenia, 83 of their relatives, and 118 mentally healthy subjects without any family history of psychoses, with the aim of detecting the main effects of the polymorphic markers -809G/A and -521C/T (DRD4) and Val158Met (COMT) when present individually and together. The group of patients showed a main effect for polymorphism -521C/T on verbal fluency and an effect of the interaction of this polymorphism and the COMT gene on this cognitive trait. The highest level of verbal fluency was seen among carriers of the Val/Val+CC and Met/Met+TT genotypes. In the combined group of unaffected individuals, the interaction of the COMT and DRD4 -521C/TT genotypes had an effect on the standardness of speech associations due to a decrease in the standardness of associations in carriers of the Met/Met+CC genotype. Finally, both patients and unaffected individuals showed an effect for the interaction between the COMT and DRD4 -809G/A genotypes on working memory. Patients and healthy subjects showed similar features: the highest values were seen in subjects homozygous for the Val and G alleles, while the lowest values were seen in homozygotes for the Met and A alleles. These data provide evidence for a relationship between the DRD4 and COMT genes and different aspects of executive functions and the absence of such a relationship in relation to verbal memory.
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PMID:Interaction of dopamine system genes and cognitive functions in patients with schizophrenia and their relatives and in healthy subjects from the general population. 1776 83

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

Dynamic adaptations of one's behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMT Val allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.
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PMID:The impact of catechol-O-methyltransferase and dopamine D4 receptor genotypes on neurophysiological markers of performance monitoring. 1809 58

To better understand the effect of the dopamine D4 receptor (DRD4) on glutamate (Glu) neurotransmission in the brain, we utilized transgenic mice with partial or complete removal of functional DRD4 plasma membrane expression (DRD4+/- and DRD4-/-, respectively). We measured resting extracellular Glu levels, Glu clearance kinetics, and KCl-evoked release of Glu in the striatum and nucleus accumbens core of these mice using in vivo amperometry coupled to a novel microelectrode array configured for sub-second detection of Glu. Recordings from DRD4-/- and DRD4+/- mice were compared with their wild-type littermates (DRD4+/+). Resting extracellular levels of Glu were increased in the striatum of DRD4-/- mice (p<0.01). Glu clearance kinetics were significantly decreased in the dorsal striatum of DRD4-/- mice (p<0.05). KCl-evoked overflow of Glu was reliably measured but unchanged in the striatum of the three groups. By contrast, no changes in resting Glu, Glu uptake kinetics, or KCl-evoked release of Glu were observed in the nucleus accumbens core among the three genotypes. These data indicate that the DRD4 receptor is involved in modulation of Glu neurotransmission, primarily in the striatum. A better understanding of Glu control by the DRD4 may improve our understanding of the physiological role of the DRD4 in disorders such as attention-deficit/hyperactivity disorder and schizophrenia.
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PMID:Decreased dopamine D4 receptor expression increases extracellular glutamate and alters its regulation in mouse striatum. 1853 4

In an effort to pinpoint potential genetic risk factors for schizophrenia, research groups worldwide have published over 1,000 genetic association studies with largely inconsistent results. To facilitate the interpretation of these findings, we have created a regularly updated online database of all published genetic association studies for schizophrenia ('SzGene'). For all polymorphisms having genotype data available in at least four independent case-control samples, we systematically carried out random-effects meta-analyses using allelic contrasts. Across 118 meta-analyses, a total of 24 genetic variants in 16 different genes (APOE, COMT, DAO, DRD1, DRD2, DRD4, DTNBP1, GABRB2, GRIN2B, HP, IL1B, MTHFR, PLXNA2, SLC6A4, TP53 and TPH1) showed nominally significant effects with average summary odds ratios of approximately 1.23. Seven of these variants had not been previously meta-analyzed. According to recently proposed criteria for the assessment of cumulative evidence in genetic association studies, four of the significant results can be characterized as showing 'strong' epidemiological credibility. Our project represents the first comprehensive online resource for systematically synthesized and graded evidence of genetic association studies in schizophrenia. As such, it could serve as a model for field synopses of genetic associations in other common and genetically complex disorders.
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PMID:Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. 1858 79


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