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

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.
 ...
PMID:Allelic variation in the human prodynorphin gene promoter and schizophrenia. 1220 42

There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.
 ...
PMID:Pharmacogenomics in schizophrenia: the quest for individualized therapy. 1235 88

The putative role of dopamine in the pathophysiology of tardive dyskinesia (TD) makes the genes coding for dopamine receptors the appropriate candidates for study. We investigate the association of the polymorphism of the Ser311Cys and Ser9Gly of the dopamine D2 (DRD2) and D3 receptor (DRD3) genes respectively with TD in Chinese patients with schizophrenia. In a case-control study, 117 Chinese patients with TD were compared to 200 patients without TD. Patients were diagnosed to have schizophrenia according to DSM-IV criteria. Dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS), whereas extrapyramidal side-effects (EPSE) were assessed by the Simpson-Angus Rating Scale. Genotype groups were comparable in age, gender, duration of illness, daily neuroleptic and benzodiazepine dose as well as the mean scores for EPSE. We failed to find an association between the polymorphism of the DRD2 gene with TD but found an increased risk of developing TD among those with D3 serine/serine genotype. Our results did not indicate that the D2 genotype has a role in the pathophysiology of TD in Chinese patients with schizophrenia. The association of TD with the serine/serine genotype of the DRD3 may be an epiphenomenon of patients with a subtype of schizophrenia who had more exposure to neuroleptics.
 ...
PMID:Polymorphisms of dopamine receptors and tardive dyskinesia among Chinese patients with schizophrenia. 1249 14

The major targets of current drugs used in mental health, such as neurotransmitter receptors and transporters, are based on serendipitous findings from several decades ago, and there is currently a severe drought of new drug targets. There is a pressing need for novel drugs, and much hope has been placed on the use of molecular genetics to help define them. However, despite evidence for a genetic basis to schizophrenia stretching back for over a century, and a heritability of about 80%, the identification of susceptibility genes has been an uphill struggle. Candidate gene studies, which have generally focussed on obvious candidates from the dopamine and serotonin systems, as well as genes involved in brain development, have not generally been successful, although meta-analysis indicates that the dopamine D3 receptor gene (DRD3) and the serotonin receptor gene type 2A (HTR2A) may have a very small influence on risk. Linkage analysis has provided robust evidence of genetic loci, for example, on chromosomes 8p, 13q and 22q, and also implies shared genetic aetiology with bipolar disorder. The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin. Interestingly, these genes point more towards a role for the glutamate pathway rather than the dopamine pathway in schizophrenia. We have attempted to replicate some of these findings in schizophrenic patients from SW China, and we find significant association with a novel neuregulin 1 haplotype, with proline dehydrogenase polymorphisms, but not with catechol-O-methyltransferase (COMT). The replication of neuregulin 1 association on chromosome 8p by several investigators is the most convincing to date, and the presence of a syndrome similar to dementia praecox of 8p linked families, and the lack of linkage of bipolar disorder to this region is a testament to the ideas of Kraepelin more than 100 years ago.
 ...
PMID:The genetics of schizophrenia: glutamate not dopamine? 1462 61

Molecular components of the dopaminergic system may play an important role in the pathophysiology of schizophrenia. In this study, we investigated the relationship of the Ser9Gly (S/G) polymorphism of the dopamine D3 receptor (DRD3) and the variable number of tandem repeats (VNTR) polymorphism of the dopamine transporter (DAT) with therapeutic response to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) and cognitive functions. No associations were found between the DRD3 and DAT polymorphisms and schizophrenia. The S/S genotype and the S allele were more frequent in the non-responder patients (n = 28) than in the group of responders (n = 47) (cut-off: >20-point improvement in Global Assessment of Functioning (GAF) scale). The patients with S/S genotype completed fewer categories and had more perseverative errors in the Wisconsin Card Sorting Test (WCST) compared with the S/G patients. The S/S and S/G patients did not differ in positive and negative symptoms, GAF scores, WCST failure to maintain set, and verbal learning. No differences in symptoms or WCST measures were observed in the patients with different DAT genotypes. These results suggest that the S/S genotype of the DRD3 is associated with worse therapeutic response and more severe executive dysfunctions in patients with schizophrenia.
 ...
PMID:Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. 1468 4

Schizophrenia is a highly heritable condition, as demonstrated in family, twin and adoption studies. Candidate genes from the dopaminergic system have long been hypothesized to be involved in the etiology of this disorder. In the present study, we investigated the genetic association between polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3) genes and schizophrenia. We examined 90 trios from Portugal, and negative results were obtained from association studies with both Haplotype Relative Risk (HRR) and Transmission Disequilibrium Test (TDT), as well as TRANSMIT. Therefore, we conclude that neither the DRD2 nor the DRD3 gene polymorphisms investigated are associated with schizophrenia in our sample.
 ...
PMID:Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a Portuguese population. 1505 Nov 79

Schizophrenia is a severe and common psychiatric disorder afflicting 1% of the world population. A role of many neurotransmitter receptors in schizophrenia was suggested by an association with several polymorphisms located in their coding regions. In this study we examined the contribution of the T-102C and A-206G transitions in the 5-HTR2a and DRD3 receptor genes respectively to genetic susceptibility and phenotypic expression of schizophrenia disorder within the Greek population. We determined by PCR and RFLP analysis the genotype for the above polymorphisms in 114 schizophrenic hospitalized individuals and 192 control samples. In contrast to previous reports from large European multicentre studies, which indicate significant correlation between schizophrenia and C-102 allele of the T-102C polymorphism, in this study we observed a statistically significant overall association between the disorder and allele T-102 (P<0.0001, odds ratio (OR)=2.11, 95% CI=1.48-3.02). We also found a highly significant excess of the T-102/C-102 and C-102/C-102 genotypes in the normal group (P<0.001). Comparison of the patients with the controls for the DRD3 polymorphism (A-206G transition) showed marginally nonsignificant differences in the genotypic (P=0.054) and no significance in the allelic (P=0.163) frequencies. However, the A-206/A-206 genotype seems to positively contribute to the disorder appearance, when compared to A-206/G-206 as genotype base line risk (P=0.016, OR=1.88, 95% CI=1.09-3.26). In conclusion, from genetic association analysis of this schizophrenic population, a significant association is clearly determined between the HTR2 genetic polymorphism and the presence of schizophrenic disorder, manifested as increased risk of schizophrenia for carriers of the T-102 allele.
 ...
PMID:Association between schizophrenia and DRD3 or HTR2 receptor gene variants. 1508 67

It has been suggested that genetic influences unmasked during neurodevelopment to produce schizophrenia may appear throughout neurodegeneration to produce AD plus psychosis. Risk of schizophrenia and psychosis in Alzheimer's disease (AD) has been linked to polymorphic variation at the dopamine receptor DRD3 gene implying similar causative mechanisms. We tested this association in a large cohort of Alzheimer's disease patients with a diagnosis of probable AD of 3 years or more duration from the relatively genetically homogenous Northern Irish population. We assessed relationships between genotypes/alleles of the DRD3 BalI polymorphism and the presence or absence of psychotic symptoms (delusions, hallucinations) in AD patients during the month prior to interview and at any stage during the dementia. No significant associations were found when delusions and hallucinations were cross-tabulated against S and G alleles and SS, SG and GG genotypes. Logistic regression failed to detect any influence of APOE, gender, family history or prior psychiatric history. In conclusion, we were unable to confirm previously reported associations between the DRD3 BalI polymorphism and psychotic symptoms in AD.
 ...
PMID:Psychotic symptoms in Alzheimer's disease are not influenced by polymorphic variation at the dopamine receptor DRD3 gene. 1534 29

Previous studies found an elevation of the dopamine D3 receptor (DRD3) mRNA as determined in peripheral lymphocytes in schizophrenic patients. The aim of this study was to test the hypothesis of elevated DRD3 mRNA in schizophrenia compared to bipolar disorder. Twenty-four patients, 13 schizophrenic and 11 bipolar, were included according to DSM-IV criteria. Psychometric measures were conducted using the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Brief Psychiatric Rating Scale, Montgomery-Asberg Depression Rating Scale and Young Mania Rating Scale. mRNA was isolated from lymphocytes of venous blood samples and DRD3 mRNA was quantified using real-time reverse transcription PCR. We found a decrease in DRD3 mRNA in 13 schizophrenic (p = 0.009) and 11 bipolar (p = 0.023) patients as compared to controls. Medication history and severity of positive symptoms did not significantly influence DRD3 expression. Higher levels of DRD3 mRNA were correlated with negative schizophrenic symptoms. Interestingly, after treatment of patients with antipsychotics, DRD3 mRNA levels increased to similar levels as those of healthy controls. Bipolar patients, however, showed a slower increase in DRD3 mRNA levels after 3 weeks of therapy. Our findings suggest that the expression of DRD3 mRNA is reduced in schizophrenia and bipolar disorder, supporting the hypothesis of distorted homeostasis of dopamine receptor subtypes in psychotic disorder. The observed diminution was not specific for schizophrenia but also for bipolar disorder requiring further analysis of the regulatory factors involved in dopamine receptor subtype expression.
 ...
PMID:Decreased levels of dopamine D3 receptor mRNA in schizophrenic and bipolar patients. 1553 62

Polymorphic marker Ser9Gly of dopamine receptor D3 gene is considered perspective for associative studies of schizophrenia. Allele and genotype frequency of this polymorphism were studied in different ethnic groups of schizophrenic patients as well as the attempts have been made to reveal an association with clinical presentations of the disease. However, the results are inconsistent. The present study aimed at investigating Ser9Gly DRD3 gene polymorphism in Russian sample of schizophrenic patients. One hundred and fifty patients with ICD-10 diagnosis of schizophrenia (broad definition), 69 male and 81 female, aged 34.8+/-13.87 years, age at disease onset 24.3+/-9 years, have been examined. Control group consisted of 150 healthy subjects without family history of schizophrenia, 60 male and 90 female, aged 32.7+/-13.5 years. No between-group differences have been found for Ser9Gly DRD3 allele and genotype frequencies. However, a frequency of homozygous genotype Gly/Gly was significantly higher in female patients, comparing to female controls (p=0.038 Yate's corrected, OR 9. CI 0.95% 1.0-79.5). A role of sex-dependent association between Ser9Gly DRD3 polymorphism and schizophrenia is discussed.
 ...
PMID:[D3 dopamine receptor gene Ser9Gly polymorphism in Russian patients with schizophrenia]. 1555 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>