| 1 | Am. J. Med. Genet. 2001 Mar 105: 152-8 |
|---|---|
| PMID | 11304828 |
| Title | Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. |
| Abstract | Following the description of linkage of markers at chromosome 4p16 to bipolar disorder in several families [Blackwood et al., 1996], and the association of the alleles of a polymorphism closely linked to D5 dopamine receptor gene with schizophrenia [Williams et al., 1997], we have looked for linkage disequilibrium between a series of microsatellite markers from this region and major psychoses including schizophrenia, bipolar disorder, and unipolar major depressive disorder. A significant increase in the frequency of the 148 bp allele of DRD5 (P = 0.024) and the 244 bp allele of D4S615 (P = 0.001) was found in patients with schizophrenia (n = 158 DRD5; n = 133 D4S615), compared with patients with bipolar disorder (n = 270 DRD5; n = 107 D4S615), or controls without psychiatric illness (n = 437 DRD5; n = 309 D4S615). The frequency of the 148 bp allele of DRD5 was also increased in schizophrenia over unipolar major depressive disorder (n = 65). D4S615 was not typed in unipolar disorder. The estimated odds ratios confirmed that the 148 bp allele of DRD5 and the 244 bp allele of D4S615 conferred increased risk of schizophrenia. Estimated Haplotype (EH) analysis of 174 controls and 128 patients with schizophrenia who were typed for both markers confirmed the strong associations with these alleles but did not show evidence that the markers were in linkage disequilibrium with each other even though they lie approximately 150 kb apart. The data are consistent with an association between markers close to the D5 dopamine receptor and schizophrenia, but not bipolar disorder or unipolar major depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 2 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Feb 125B: 38-42 |
| PMID | 14755441 |
| Title | Polymorphisms in the dopamine D5 receptor (DRD5) gene and ADHD. |
| Abstract | There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A microsatellite located near the dopamine D5 receptor (DRD5) gene has been associated with ADHD in a number of studies, but other polymorphisms within the vicinity of this gene have not been examined. In this study we genotyped three microsatellites spanning the DRD5 region in a large clinical sample. Overall, we found little evidence to support a role for DRD5 in ADHD. We found no evidence of association with either the previously associated DRD5 marker, or a repeat in the promoter region of the gene. We did, however, find significant association for an allele of D4S615, a dinucleotide repeat located 131 kb 3' of DRD5 that has been previously associated with schizophrenia. A global test incorporating all alleles of this marker, however, was not significant and thus this finding needs replication before any conclusions can be made. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 3 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 6-9 |
| PMID | 15635698 |
| Title | No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample. |
| Abstract | It has been suggested that genes involved in dopamine neurotransmission contribute to the pathogenesis of schizophrenia. However, reported associations of the disorder with genetic markers in dopaminergic genes have yielded inconsistent results. Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, and the use of small sample sizes. Here, we present a two-stage analysis of 12 dopaminergic genes in a large sample of Dutch schizophrenic patients. To reduce genetic heterogeneity, only patients with at least three Caucasian grandparents of Dutch ancestry were ascertained. An efficient genotyping strategy was used, in which polymorphic microsatellite markers were first screened for association in DNA pools. Promising results were followed up by individual genotyping in an extended sample. The pooled samples consisted of 208 schizophrenic patients and 288 unmatched control individuals. For each of the genes, more than one microsatellite marker was selected where possible, either intragenic or close to the gene. After correcting for multiple testing, significantly different allele frequencies were detected for DRD5 marker D4S615. Subsequently, we individually genotyped this particular marker and another DRD5 marker, as well as a DRD3 marker that could not be analyzed using the pooling strategy. This was done in an extended sample of 282 schizophrenic patients and a control sample of 585 individuals. In this second stage of the study, we found no association between these three markers and schizophrenia. The results of our comprehensive analysis provide no evidence for association between schizophrenia and 12 dopaminergic genes in a large Dutch sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 4 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Apr 134B: 6-9 |
| PMID | 15635698 |
| Title | No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample. |
| Abstract | It has been suggested that genes involved in dopamine neurotransmission contribute to the pathogenesis of schizophrenia. However, reported associations of the disorder with genetic markers in dopaminergic genes have yielded inconsistent results. Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, and the use of small sample sizes. Here, we present a two-stage analysis of 12 dopaminergic genes in a large sample of Dutch schizophrenic patients. To reduce genetic heterogeneity, only patients with at least three Caucasian grandparents of Dutch ancestry were ascertained. An efficient genotyping strategy was used, in which polymorphic microsatellite markers were first screened for association in DNA pools. Promising results were followed up by individual genotyping in an extended sample. The pooled samples consisted of 208 schizophrenic patients and 288 unmatched control individuals. For each of the genes, more than one microsatellite marker was selected where possible, either intragenic or close to the gene. After correcting for multiple testing, significantly different allele frequencies were detected for DRD5 marker D4S615. Subsequently, we individually genotyped this particular marker and another DRD5 marker, as well as a DRD3 marker that could not be analyzed using the pooling strategy. This was done in an extended sample of 282 schizophrenic patients and a control sample of 585 individuals. In this second stage of the study, we found no association between these three markers and schizophrenia. The results of our comprehensive analysis provide no evidence for association between schizophrenia and 12 dopaminergic genes in a large Dutch sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 5 | Neurotox Res 2006 Dec 10: 167-79 |
| PMID | 17197367 |
| Title | Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 6 | Neurotox Res 2006 Dec 10: 167-79 |
| PMID | 17197367 |
| Title | Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 7 | Pharmacogenomics 2008 Oct 9: 1437-43 |
| PMID | 18855532 |
| Title | Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. |
| Abstract | Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics. We conducted a pharmacogenetic study to evaluate whether variants in dopamine-related genes (DRD1-DRD5, AKT1 and GSK3beta) and serotonin receptor genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR6 and HTR7) can be used to predict the efficacy of risperidone treatment for schizophrenia. A total of 120 first-episode neuroleptic-naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale. Among the 30 variants that we examined, two SNPs in DRD2 (-241A>G [rs1799978] and TaqIA [rs1800497]) and two SNPs in AKT1 (AKT1-SNP1 [rs3803300] and AKT1-SNP5 [rs2494732]) were significant predictors of treatment response to risperidone. These data suggest that the SNPs in DRD2 and AKT1 may influence the treatment response to risperidone in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 8 | Bull. Exp. Biol. Med. 2008 Jan 145: 65-7 |
| PMID | 19024005 |
| Title | Association of dopamine receptor D5 gene polymorphism with peculiarities of voluntary attention in schizophrenic patients and their relatives. |
| Abstract | We studied the relationship between DRD5 gene polymorphism presented by microsatellites with cognitive signs in 152 schizophrenic patients, 81 mentally healthy relatives, and 125 mentally healthy control individuals. An association was found between DRD5 polymorphism with efficiency of visual voluntary attention in patients (p = 0.02) and their relatives (p = 0.006). Carriers of two copies of the 148-b.p. allele were characterized by low efficiency of attention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 9 | Croat. Med. J. 2009 Aug 50: 361-9 |
| PMID | 19673036 |
| Title | Association of tagging single nucleotide polymorphisms on 8 candidate genes in dopaminergic pathway with schizophrenia in Croatian population. |
| Abstract | To perform a comprehensive evaluation of association of common genetic variants in candidate genes in the dopaminergic pathway with schizophrenia in a sample from Croatian population. A case-control association study was performed on 104 unrelated patients with schizophrenia recruited from a psychiatric hospital in Zagreb and 131 phenotypically normal Croatian subjects. Forty-nine tagging single nucleotide polymorphisms (tagSNPs) in 8 candidate genes in the dopaminergic pathway were identified from the HapMap database and tested for association. Genotyping was performed using the SNPlex platform. Statistical analysis was conducted to assess allelic and genotypic associations between cases and controls using a goodness of fit chi(2) test and trend test, respectively; adjustment for multiple testing was done by permutation based analysis. Significant allele frequency differences between schizophrenia cases and controls were observed at 4 tagSNPs located in the genes DRD5, HTR1B1, DBH, and TH1 (P<0.005). A trend test also confirmed the genotypic association (P<0.001) of these 4 tagSNPs. Additionally, moderate association (P<0.05) was observed with 8 tagSNPs on SLC6A3, DBH, DRD4, SLC6A4, and COMT. Common genetic variants in genes involved in the dopaminergic pathway are associated with schizophrenia in the populations of Caucasian descent. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 10 | Schizophr. Res. 2009 Oct 114: 33-8 |
| PMID | 19682861 |
| Title | Association study of the gamma-aminobutyric acid type a receptor gamma2 subunit gene with schizophrenia. |
| Abstract | schizophrenia (SCZ) is a severe neuropsychiatric disorder with a strong genetic basis. We analyzed eight GABRG2 and one DRD5 tag single-nucleotide polymorphisms for association with SCZ in 109 small nuclear families and 229 independent SCZ case-control pairs. The marker rs183294 in the 5' region of GABRG2 was found to be associated with SCZ in both samples with the C allele over-represented in SCZ cases and over-transmitted in SCZ families (combined z=9.18; p<1 x 10(-3)). Taken together, the results of the present study suggest that GABRG2 may be involved in SCZ susceptibility, but further studies are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 11 | Neuropathol. Appl. Neurobiol. 2011 Feb 37: 206-19 |
| PMID | 20874815 |
| Title | Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. |
| Abstract | signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. using a yeast two-hybrid approach, we previously identified 11 novel dopamine receptor-interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1-DRD5) and DARPP-32] by real-time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. the expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP-32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease-related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 12 | Neuropathol. Appl. Neurobiol. 2011 Feb 37: 206-19 |
| PMID | 20874815 |
| Title | Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder. |
| Abstract | signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. using a yeast two-hybrid approach, we previously identified 11 novel dopamine receptor-interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1-DRD5) and DARPP-32] by real-time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. the expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP-32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP-32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease-related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 13 | Mol. Biol. Rep. 2011 Apr 38: 2569-72 |
| PMID | 21110120 |
| Title | Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia? |
| Abstract | schizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 14 | Mol. Biol. Rep. 2011 Apr 38: 2569-72 |
| PMID | 21110120 |
| Title | Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia? |
| Abstract | schizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 15 | Mol. Biol. Rep. 2011 Apr 38: 2569-72 |
| PMID | 21110120 |
| Title | Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia? |
| Abstract | schizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 16 | Pharmacogenomics J. 2012 Apr 12: 156-64 |
| PMID | 20714340 |
| Title | Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. |
| Abstract | Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with most antipsychotics. We have conducted the first in-depth examination of dopamine receptor genes in antipsychotic-induced weight gain. A total of 206 patients (139 of European descent and 56 African Americans) who underwent treatment for chronic schizophrenia or schizoaffective disorder were evaluated after on average over 6 weeks of treatment. Thirty-six tag single nucleotide polymorphisms (SNPs) and one variable-number tandem repeat, spanning the five dopamine receptor genes (DRD1-DRD5) were analyzed. In the total sample, we found a nominally significant association between the DRD2 rs1079598 marker and weight change using a cutoff of 7% gain (P=0.03). When stratifying the sample according to ethnicity and antipsychotics with highest risk for weight gain, we found significant associations in three DRD2 SNPs: rs6277 (C957T), rs1079598 and rs1800497 (TaqIA). The other genes were primarily negative. We provide evidence that dopamine receptor DRD2 gene variants might be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 17 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Apr 37: 62-75 |
| PMID | 22203087 |
| Title | Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: replication and exploration. |
| Abstract | This study aimed to: 1) replicate previously reported associations between dopamine D4 receptor gene (DRD4) polymorphisms and antipsychotic (AP) response in a clozapine (CLZ) response sample; and 2) explore possible associations of polymorphisms across dopamine D5 receptor gene (DRD5) as well as other DRD4 regions. DRD4 exon III 48-bp, intron I (G)(n), and 120-bp repeat polymorphisms, and three DRD4 single nucleotide polymorphisms (SNPs); and DRD5 (CA/CT/GT)(n) microsatellite and four DRD5 SNPs were assessed using standard genotyping and statistical procedures. We report evidence, which does not survive correction for multiple testing, supporting previous DRD4 findings. Findings of interest include the 120-bp 1-copy allele, intron I (G)(n) 142-bp/140-bp genotype, and exon III 4R allele with CLZ response. All DRD5 tests were negative. Overall, these results suggest a possible minor contribution of DRD4 variants, but not DRD5 variants, towards the AP/CLZ response phenotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 18 | Psychiatr. Genet. 2013 Oct 23: 183-7 |
| PMID | 23851595 |
| Title | Analysis of association between dopamine receptor genes' methylation and their expression profile with the risk of schizophrenia. |
| Abstract | schizophrenia (SCZ) is a type of psychotic disorder that affects ~1% of the population. Dopamine is one of the major neurotransmitters in the brain and its receptors are associated with a number of psychotic disorders, including SCZ. The aims of the present study were to analyze methylation and the expression profile of dopamine receptor DRD1, DRD2, DRD4, and DRD5 genes in patients with SCZ. Promoter methylation of DRD1, DRD2, DRD4, and DRD5 genes was assayed by a methylation-specific PCR in blood samples obtained from 80 SCZ cases and 71 healthy controls. Also, we investigated DRD1, DRD2, DRD4, and DRD5 mRNA levels using real-time reverse transcription PCR in 34 blood samples of healthy controls and cases. Promoter methylation of DRD4, DRD5, and DRD2 genes was statistically different in cases compared with healthy controls. The mRNA expression level results also showed statistically significant differences (P<0.0001) between cases and healthy controls for the DRD2, DRD4, and DRD5 genes, but not for DRD1. Analyses of DRD genes' methylation have highlighted the fact that the DRD gene network, overall, is actively involved in the increased risk of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 19 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Apr 162B: 273-82 |
| PMID | 23505263 |
| Title | Identification of rare copy number variants in high burden schizophrenia families. |
| Abstract | Over the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 20 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 21 | Eur. Psychiatry 2014 Jun 29: 304-6 |
| PMID | 24630741 |
| Title | Psychosis-proneness correlates with expression levels of dopaminergic genes. |
| Abstract | Psychosis-proneness or schizotypy is a personality organisation mirroring individual risk for schizophrenia-development. Believed to be a fully dimensional construct sharing considerable geno- and phenotypal variance with clinical schizophrenia, it has become an increasingly promising tool for basic psychosis-research. Although many studies show genetic commonalities between schizotypy and schizophrenia, changes in regulation of gene expression have never been examined in schizotypy before. We therefore extracted RNA from the blood, a valid surrogate for brain tissue, of a large sample of 67 healthy male volunteers and correlated the activities of all genes relevant for dopaminergic neurotransmission with the positive schizotypy-scale of the O-LIFE. We found significant negative correlations regarding the expression of the genes COMT, MAOB, DRD4, DRD5 and FOS, indicating that increased schizotypy coincides with higher levels of dopaminergic dysregulation on the mRNA-level. Considering the advantages of this method, we suggest that it be applied more often in fundamental psychosis-research. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 22 | Genet. Mol. Res. 2014 -1 13: 1609-18 |
| PMID | 24668635 |
| Title | Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese. |
| Abstract | Dopamine (DA) has been implicated in the pathophysiol-ogy of several psychiatric disorders, including schizophrenia. Thus, genes related to the dopaminergic (DAergic) system are good candidate genes for schizophrenia. One of receptors of the DA receptor system is dopa-mine receptor 5 (DRD5). Single nucleotide polymorphisms (SNPs) in the regulatory regions of DRD5 gene may affect gene expression, influence biosynthesis of DA and underlie various neuropsychiatric disorders re-lated to DA dysfunction. The present study explored the association of SNPs within the DRD5 gene with paranoid schizophrenia in Han Chinese. A total of 176 patients with schizophrenia and 206 healthy controls were genotyped for four DRD5 SNPs (rs77434921, rs2076907, rs6283, and rs1800762). Significant group differences were observed in the allele and genotype frequencies of rs77434921 and rs1800762 and in the frequen-cies of GC haplotypes corresponding to rs77434921-rs1800762. Our find-ings suggest that common genetic variations of DRD5 are likely to con-tribute to genetic susceptibility to paranoid schizophrenia in Han Chinese. Further studies in larger samples are needed to replicate this association. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |
| 23 | Neurosci. Lett. 2016 Apr 619: 126-30 |
| PMID | 26957229 |
| Title | Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis. |
| Abstract | Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizotypy |