| 1 | Hum. Mol. Genet. 2002 Oct 11: 2517-30 |
|---|---|
| PMID | 12351588 |
| Title | Pharmacogenomics in schizophrenia: the quest for individualized therapy. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2003 Jan 8: 109-13 |
| PMID | 12556915 |
| Title | D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine. |
| Abstract | A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P < 0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT(2A), and 5HT(2C) polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P < 0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Am J Pharmacogenomics 2005 -1 5: 149-60 |
| PMID | 15952869 |
| Title | Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. |
| Abstract | No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | J Neural Transm (Vienna) 2005 Nov 112: 1575-82 |
| PMID | 15785860 |
| Title | An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | J Neural Transm (Vienna) 2005 Nov 112: 1575-82 |
| PMID | 15785860 |
| Title | An association study of dopamine receptors polymorphisms and the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | Dopamine (DA), an important neurotransmitter in prefrontal cortex (PFC), is involved in the pathogenesis of schizophrenia. The aim of the study was to test an association between common polymorphism of genes for DA receptors DRD1, DRD2, DRD3, DRD4, and performance on the Wisconsin Card Sorting Test (WCST), measuring various functions of PFC, in 138 schizophrenic patients. Patients with G/G genotype of DRD1 tended to obtain worse results in all domains of WCST compared to patients with remaining genotypes, particularly for number of completed corrected categories, and trials to set the first category. A relationship was also found in female patients between DRD2 polymorphism and number of perseverative errors, while no association between WCST results and DRD3 or DRD4 polymorphism was observed in patients studied. The results may suggest an association between DRD1 gene polymorphism and performance on PFC test in schizophrenia. Also, the gender-dependent role of DRD2 in this process may be presumed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | Hum. Mol. Genet. 2006 Nov 15: 3132-45 |
| PMID | 16984965 |
| Title | Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. |
| Abstract | The variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | Neuropsychobiology 2006 -1 53: 46-50 |
| PMID | 16397404 |
| Title | Dopamine receptor D1 gene -48A/G polymorphism is associated with bipolar illness but not with schizophrenia in a Polish population. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | J. Alzheimers Dis. 2007 Aug 12: 73-92 |
| PMID | 17851196 |
| Title | Genetics of Alzheimer's disease. A rapidly evolving field. |
| Abstract | Genetic factors have a variable impact on Alzheimer's Disease (AD), ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD, where a polygenic component is present. Most genes conferring susceptibility to AD are related to amyloid-beta deposition (APP; PS1; PS2; APOE; Cystatin-C; ubiquilin-1), oxidative stress (NOS2; NOS3) and inflammatory response (IL-1 alpha; IL-1 beta; IL-6; TNF-alpha). Genome-wide analyses, transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability. Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes (COMT), transporters (5-HTTLPR) and receptors (DRD1; DRD3). Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia, while it is generally not recommended as a predictive testing for AD in asymptomatic individuals. Drugs currently in use to treat AD are effective in only 20% of patients; their therapeutic effect is predominantly under genetic control (CYP26 gene; APOE). Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression, schizophrenia and ADHD. The study of gene-environment interactions in AD, that are still poorly understood, is essential to predict disease-risk in asymptomatic individuals. Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Psychiatry Clin. Neurosci. 2007 Feb 61: 3-19 |
| PMID | 17239033 |
| Title | Molecular genetics of bipolar disorder and depression. |
| Abstract | In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Sep 144B: 809-15 |
| PMID | 17455212 |
| Title | Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. |
| Abstract | DRD(1) and DRD(2) receptor gene variants have been associated with clinical aspects of schizophrenia; however only specific features were analyzed in different samples. To assess the complex interaction between genetic and clinical factors, we studied the possible cross-interactions between DRD1 and DRD2 dopamine receptor gene polymorphisms, symptomatology of schizophrenia and schizoaffective disorders, and the occurrence of treatment induced side effects taking into consideration possible clinical confounding variables. One hundred thirty one outpatients in stable remission meeting the DSMIV criteria for schizophrenia spectrum disorders and receiving long-term maintenance therapy with haloperidol, fluphenazine, zuclopenthixole, or risperidone were genotyped for DRD1 A-48G, DRD2 Ins-141CDel, and DRD2 Ser311Cys polymorphisms. Psychopathological symptoms were assessed with the positive and negative syndrome scale for schizophrenia (PANSS). Extrapyramidal side effects were assessed with the Simpson-Angus extrapyramidal side effects scale (EPS), the Barnes Akathisia scale (BARS), and the abnormal involuntary movement scale (AIMS). Drug dosage was included as covariant because it was associated with the severity of symptomatology, akathisia, and parkinsonism. No association was observed for DRD1 and DRD2 polymorphisms and extrapyramidal side effects, or with the other clinical variables considered. Our study suggests that DRD1 and DRD2 variants are not liability factors for tardive dyskinesia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | J. Psychopharmacol. (Oxford) 2007 Sep 21: 718-27 |
| PMID | 17092969 |
| Title | Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. |
| Abstract | Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | J. Psychopharmacol. (Oxford) 2007 Sep 21: 718-27 |
| PMID | 17092969 |
| Title | Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. |
| Abstract | Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | 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 |
| 16 | Nat. Genet. 2008 Jul 40: 827-34 |
| PMID | 18583979 |
| Title | Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Methods Mol. Biol. 2008 -1 448: 187-212 |
| PMID | 18370235 |
| Title | Epigenetic alterations of the dopaminergic system in major psychiatric disorders. |
| Abstract | Although there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as membrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Neuroreport 2008 Apr 19: 603-7 |
| PMID | 18382271 |
| Title | Multivariate analyses suggest genetic impacts on neurocircuitry in schizophrenia. |
| Abstract | We investigated the relationship of functional neurocircuitries and dopamine receptor D1 (DRD1) polymorphisms in schizophrenics during a working memory task. Participants performed the Serial Item Recognition Paradigm memory task during functional magnetic resonance imaging acquisition. We performed a data-driven multivariate analysis (partial least squares) to characterize brain network (covariance) patterns. Genetic testing identified two main genotypes. Accuracy did not differ between the groups. Covariance patterns of different areas (including the dorsolateral prefrontal cortex and the inferior parietal lobule) were inversely related between the two genotypes. Two groups of schizophrenic patients with similar symptomatology and performance on a working memory task, but with distinct dopamine receptor genotypes, may use distinct neural systems to retrieve information. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Neuroreport 2008 Apr 19: 603-7 |
| PMID | 18382271 |
| Title | Multivariate analyses suggest genetic impacts on neurocircuitry in schizophrenia. |
| Abstract | We investigated the relationship of functional neurocircuitries and dopamine receptor D1 (DRD1) polymorphisms in schizophrenics during a working memory task. Participants performed the Serial Item Recognition Paradigm memory task during functional magnetic resonance imaging acquisition. We performed a data-driven multivariate analysis (partial least squares) to characterize brain network (covariance) patterns. Genetic testing identified two main genotypes. Accuracy did not differ between the groups. Covariance patterns of different areas (including the dorsolateral prefrontal cortex and the inferior parietal lobule) were inversely related between the two genotypes. Two groups of schizophrenic patients with similar symptomatology and performance on a working memory task, but with distinct dopamine receptor genotypes, may use distinct neural systems to retrieve information. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | Neuroreport 2008 Apr 19: 603-7 |
| PMID | 18382271 |
| Title | Multivariate analyses suggest genetic impacts on neurocircuitry in schizophrenia. |
| Abstract | We investigated the relationship of functional neurocircuitries and dopamine receptor D1 (DRD1) polymorphisms in schizophrenics during a working memory task. Participants performed the Serial Item Recognition Paradigm memory task during functional magnetic resonance imaging acquisition. We performed a data-driven multivariate analysis (partial least squares) to characterize brain network (covariance) patterns. Genetic testing identified two main genotypes. Accuracy did not differ between the groups. Covariance patterns of different areas (including the dorsolateral prefrontal cortex and the inferior parietal lobule) were inversely related between the two genotypes. Two groups of schizophrenic patients with similar symptomatology and performance on a working memory task, but with distinct dopamine receptor genotypes, may use distinct neural systems to retrieve information. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Neuropsychobiology 2008 -1 57: 49-54 |
| PMID | 18451638 |
| Title | Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia. |
| Abstract | The cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia. We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions. We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05). These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Neuropsychobiology 2008 -1 57: 49-54 |
| PMID | 18451638 |
| Title | Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia. |
| Abstract | The cause of restless legs syndrome (RLS) is not yet clear, but more promising theories involve dopaminergic deficiency and genetic causes. This study investigated whether single-nucleotide polymorphisms in the genes of dopamine receptors DRD1, DRD2, DRD3 and DRD4 are associated with antipsychotics-induced RLS in schizophrenia. We evaluated 190 Korean schizophrenic patients using the diagnostic criteria of the International Restless Legs Syndrome Study Group and its rating scale for RLS. Genotyping was performed for the DRD1 gene -48A/G, DRD2 gene TaqI A, DRD3 gene Ser9Gly and DRD4 gene -521C/T single-nucleotide polymorphisms. The method of multifactor dimensionality reduction was used to analyze gene-gene interactions. We classified the schizophrenic patients into 96 with and 94 without RLS symptoms. The genotype frequencies of all polymorphisms investigated did not differ significantly between these 2 groups. MDR analysis did not show a significant effect of the 4 dopamine receptor gene variants on susceptibility to antipsychotic-induced RLS symptoms (p > 0.05). These genetics data suggest that the analyzed polymorphisms of the dopamine genes may not be associated with RLS symptoms in schizophrenia. Confirming the results reported here requires a larger-scale study involving patients taking specific antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | Ann. Hum. Genet. 2010 Jul 74: 291-8 |
| PMID | 20456319 |
| Title | Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia. |
| Abstract | Emerging evidence indicates that the DRD1-BDNF-DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Acta Neurobiol Exp (Wars) 2010 -1 70: 86-94 |
| PMID | 20407490 |
| Title | Influence of dopaminergic and serotoninergic genes on working memory in healthy subjects. |
| Abstract | Working memory is an ability to keep information in short-term memory and manipulate them 'on line'. Working memory is also involved in complex frontal executive functions. The role of dopaminergic system in modulating working memory processes in prefrontal cortex is well established. Also the role of serotoninergic receptors is postulated. The purpose of this study was to assess the association between the polymorphisms of dopaminergic (DRD1, DRD3, DRD4, COMT) and serotoninergic (SERT--serotonin transporter, 5HT2A, 5HT2C) genes' polymorphisms and performance on WCST in 200 volunteers from the Polish population. We found the association between DRD1, DRD4, COMT and SERT genes polymorphisms and the performance on WCST. The results obtained in the study indicate that dopaminergic and serotoninergic genes may play a role in modulating the executive function and working memory processes in healthy subjects. The pattern of this influence may be different in males and females. Moreover, the relationship between the efficacy of prefrontal cognitive function and genes polymorphisms may differ between healthy subjects and schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Zhonghua Yi Xue Za Zhi 2010 Nov 90: 3059-62 |
| PMID | 21211326 |
| Title | [Gene-gene interaction between DNMT3B and DRD1 in schizophrenia]. |
| Abstract | to identify the impact of gene-gene interaction between DNMT3B and DRD1 on the risk of schizophrenia. two SNPs (rs2424908 and rs6119954) within DNMT3B and five SNPs (rs4532, rs5326, rs2168631, rs6882300 and rs267418) within DRD1 were genotyped in 365 schizophrenic patients and 365 healthy controls. The gene-gene interaction between DNMT3B and DRD1 was analyzed by Multifactor Dimensionality Reduction (MDR) software. the frequency of genotypes of rs6119954 within DNMT3B was significantly higher in patients than that in controls (?(2) = 8.06, P = 0.018). MDR revealed that the significance were shown in patterns with 2 SNPs (rs6119954-rs267418) (OR = 1.79, 95%CI: 1.29 - 2.47; ?(2) = 12.51, P = 0.0004), 3 SNPs (rs6119954-rs5326-rs267418) (OR = 2.36, 95%CI: 1.73 - 3.22; ?(2) = 29.33, P < 0.0001) and 4 SNPs (rs2424908-rs6119954-rs5326-rs267418) (OR = 3.08, 95%CI: 2.24 - 4.24;?(2) = 48.88, P < 0.0001). the gene-gene interaction between DNMT3B and DRD1 may exist and increase the risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Zhonghua Yi Xue Za Zhi 2010 Nov 90: 3059-62 |
| PMID | 21211326 |
| Title | [Gene-gene interaction between DNMT3B and DRD1 in schizophrenia]. |
| Abstract | to identify the impact of gene-gene interaction between DNMT3B and DRD1 on the risk of schizophrenia. two SNPs (rs2424908 and rs6119954) within DNMT3B and five SNPs (rs4532, rs5326, rs2168631, rs6882300 and rs267418) within DRD1 were genotyped in 365 schizophrenic patients and 365 healthy controls. The gene-gene interaction between DNMT3B and DRD1 was analyzed by Multifactor Dimensionality Reduction (MDR) software. the frequency of genotypes of rs6119954 within DNMT3B was significantly higher in patients than that in controls (?(2) = 8.06, P = 0.018). MDR revealed that the significance were shown in patterns with 2 SNPs (rs6119954-rs267418) (OR = 1.79, 95%CI: 1.29 - 2.47; ?(2) = 12.51, P = 0.0004), 3 SNPs (rs6119954-rs5326-rs267418) (OR = 2.36, 95%CI: 1.73 - 3.22; ?(2) = 29.33, P < 0.0001) and 4 SNPs (rs2424908-rs6119954-rs5326-rs267418) (OR = 3.08, 95%CI: 2.24 - 4.24;?(2) = 48.88, P < 0.0001). the gene-gene interaction between DNMT3B and DRD1 may exist and increase the risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jun 153B: 948-54 |
| PMID | 20127886 |
| Title | Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia. |
| Abstract | Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jun 153B: 948-54 |
| PMID | 20127886 |
| Title | Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia. |
| Abstract | Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Psychiatry Res 2010 May 177: 350-3 |
| PMID | 20382433 |
| Title | No genetic association between dopamine D1 receptor gene and [early onset] schizophrenia. |
| Abstract | Decreased dopaminergic activity in the prefrontal cortex (PFC) has been consistently reported in schizophrenia patients. The dopamine D1 receptor (DRD1) plays an important role in mediating dopaminergic transmission in the PFC. Controversy about this topic still exists despite ample evidence suggesting that the DRD1 gene is associated with performance on neuropsychological tests probing the function of the PFC in schizophrenia, as well as positive and negative symptoms and therapeutic response to antipsychotics. To determine whether this gene is involved in the etiology of schizophrenia, we undertook a case-control study to look for an association. We genotyped five single nucleotide polymorphisms (SNPs) rs4532, rs5326, rs2168631, rs6882300 and rs267418 within the DRD1 involving 373 schizophrenia patients with early age of onset and 379 healthy subjects. No significant differences of genotype, allele or haplotype distribution were identified between patients and controls. Our results do not preclude a possible role of DRD1 in the etiology of schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes. Further relevant studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Transl Psychiatry 2011 -1 1: e9 |
| PMID | 22832404 |
| Title | Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms. |
| Abstract | Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | J Clin Psychiatry 2011 Apr 72: 458-63 |
| PMID | 20868635 |
| Title | Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. |
| Abstract | Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA). Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls). Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not. A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175% higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | AMIA Annu Symp Proc 2011 -1 2011: 1127-33 |
| PMID | 22195173 |
| Title | Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling. |
| Abstract | In this study, we retrieved 39 schizophrenia-related antipsychotic drugs from the DrugBank database. These drugs had interactions with 142 targets, whose corresponding genes were defined as drug targeted genes. To explore the complexity between these drugs and their related genes in schizophrenia, we constructed a drug-target gene network. These genes were overrepresented in several pathways including: neuroactive ligand-receptor pathways, glutamate metabolism, and glycine metabolism. Through integrating the pathway information into a drug-gene network, we revealed a few bridge genes connected the sub-networks of the drug-gene network: GRIN2A, GRIN3B, GRIN2C, GRIN2B, DRD1, and DRD2. These genes encode ionotropic glutamate receptors belonging to the NMDA receptor family and dopamine receptors. Haloperidol was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug-gene interaction level during the treatment of schizophrenia. This study represents the first systematic investigation of drug-gene interactions in psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Zhonghua Yi Xue Za Zhi 2011 Aug 91: 2019-22 |
| PMID | 22093926 |
| Title | [Association analysis between dopamine D1 receptor gene and symptom quantitative trait of schizophrenia]. |
| Abstract | To explore the relationship between dopamine D1 receptor gene (DRD1) and symptom quantitative trait of schizophrenia. Peripheral blood samples were collected from 211 schizophrenics and 247 healthy controls at our center. Five tag SNPs (single nucleotide polymorphisms) (rs4532, rs5326, rs2168631, rs6882300 & rs267418) within DRD1 gene were genotyped by TaqMan SNP genotyping assay. The positive and negative syndrome scale (PANSS) was used to quantify the phenotypes of schizophrenia. No significant differences existed in the frequencies of genotypes and alleles of DRD1 gene between the schizophrenics and normal controls (Ps > 0.05); strong linkage disequilibrium was observed between rs4532 and rs5326 (D' = 0.84); no significant difference of haplotypic distribution was identified between the patients and controls (Ps > 0.05); the patients with rs4532G allele had a higher negative subscale score than those without G allele (20.3 ± 3.3 vs 18.2 ± 3.9, P < 0.01). The rs4532 within DRD1 gene may be associated with negative symptom quantitative trait in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Zhonghua Yi Xue Za Zhi 2011 Aug 91: 2019-22 |
| PMID | 22093926 |
| Title | [Association analysis between dopamine D1 receptor gene and symptom quantitative trait of schizophrenia]. |
| Abstract | To explore the relationship between dopamine D1 receptor gene (DRD1) and symptom quantitative trait of schizophrenia. Peripheral blood samples were collected from 211 schizophrenics and 247 healthy controls at our center. Five tag SNPs (single nucleotide polymorphisms) (rs4532, rs5326, rs2168631, rs6882300 & rs267418) within DRD1 gene were genotyped by TaqMan SNP genotyping assay. The positive and negative syndrome scale (PANSS) was used to quantify the phenotypes of schizophrenia. No significant differences existed in the frequencies of genotypes and alleles of DRD1 gene between the schizophrenics and normal controls (Ps > 0.05); strong linkage disequilibrium was observed between rs4532 and rs5326 (D' = 0.84); no significant difference of haplotypic distribution was identified between the patients and controls (Ps > 0.05); the patients with rs4532G allele had a higher negative subscale score than those without G allele (20.3 ± 3.3 vs 18.2 ± 3.9, P < 0.01). The rs4532 within DRD1 gene may be associated with negative symptom quantitative trait in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Brain Res. 2011 Oct 1420: 106-13 |
| PMID | 21955727 |
| Title | An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. |
| Abstract | Deficits in dopamine transmission at D1 receptors in the PFC are implicated in schizophrenia. Genetic polymorphisms in functional regions of DRD1 have a plausible role in modulating the risk of schizophrenia. In order to evaluate the role of DRD1 polymorphisms as a risk factor for schizophrenia, we performed a detailed analysis of possible functional single nucleotide polymorphisms (SNPs) in regulatory and coding regions of DRD1. Nine SNPs were identified by DNA sequencing in 20 patients with schizophrenia. Then 385 cases and 350 healthy control subjects were genotyped using the nine SNPs (rs4867798, rs686, rs1799914, rs4532 rs5326, rs265981, rs10078714, rs10063995, rs10078866). Statistically significant differences were observed in the allelic or genotypic frequencies of the rs686 and rs10063995 polymorphism in the DRD1 gene. A significantly lower risk of schizophrenia was associated with the G allele and AG+GG genotype of rs686 (OR (G allele)=0.632, 95%CI (G allele): 0.470-0.849; OR (AG+GG genotype)=0.578, 95%CI (AG+GG genotype): 0.416-0.803) compared with the A allele and AA genotype, respectively. And a significantly increased risk of schizophrenia was associated with the T allele of rs10063995 (OR=1.446, 95%CI: 1.125-1.859) compared with the G allele. The haplotype analysis indicated the G-T variant containing the T allele of rs10063995 is a risk for schizophrenia (P=0.005, OR=1.467, 95%CI: 1.123-1.917). These data suggest that DRD1 gene polymorphisms confer susceptibility to schizophrenia, and also support the notion that dysfunction of DRD1 is involved in the pathophysiological process of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | J. Neurosci. 2011 May 31: 7349-56 |
| PMID | 21593319 |
| Title | Contrasting roles for dopamine D1 and D2 receptor subtypes in the dorsomedial striatum but not the nucleus accumbens core during behavioral inhibition in the stop-signal task in rats. |
| Abstract | Dopamine and dopamine-receptor function are often implicated in behavioral inhibition, and deficiencies within behavioral inhibition processes linked to attention deficit/hyperactivity disorder (ADHD), schizophrenia, obsessive-compulsive disorder, and drug addiction. In the stop-signal task, which measures the speed of the process of inhibition [stop-signal reaction time (SSRT)], psychostimulant-related improvement of SSRT in ADHD is linked with dopamine function. However, the precise nature of dopaminergic control over SSRT remains unclear. This study examined region- and receptor-specific modulation of SSRT in the rat using direct infusions of the dopamine D1 receptor (DRD1) antagonist SCH 23390 or dopamine D2 receptor (DRD2) antagonist sulpiride into the dorsomedial striatum (DMStr) or nucleus accumbens core (NAcbC). DRD1 and DRD2 antagonists had contrasting effects on SSRT that were specific to the DMStr. SCH 23390 decreased SSRT with little effect on the go response. Conversely, sulpiride increased SSRT but also increased go-trial reaction time and reduced trial completion at the highest doses. These results suggest that DRD1 and DRD2 function within the DMStr, but not the NAcbC, may act to balance behavioral inhibition in a manner that is independent of behavioral activation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Neuropsychopharmacology 2011 Jun 36: 1385-96 |
| PMID | 21412225 |
| Title | Dopamine receptor mediation of the exploratory/hyperactivity effects of modafinil. |
| Abstract | Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine DRD1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the DRD1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male DRD1 KOs, rearing in female DRD1 KOs, or reducing spatial d in all DRD1 KOs, but produced similar effects in DRD1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the DRD1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine DRD1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine drd4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine DRD1 and drd4 receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Eur. J. Clin. Pharmacol. 2011 Apr 67: 383-8 |
| PMID | 21181138 |
| Title | Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia. |
| Abstract | Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS?=0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Eur. J. Clin. Pharmacol. 2011 Apr 67: 383-8 |
| PMID | 21181138 |
| Title | Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia. |
| Abstract | Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS?=0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | Exp. Mol. Med. 2011 Jan 43: 44-52 |
| PMID | 21178390 |
| Title | Associations between DRDs and schizophrenia in a Korean population: multi-stage association analyses. |
| Abstract | The dysregulation of the dopaminergic system has been implicated in the pathophysiology of major psychosis, including schizophrenia, with dopamine receptor genes (DRDs) presently targeted as the most promising candidate genes. We investigated DRD1-5 for association with schizophrenia using a multi-stage approach in a Korean sample. One hundred forty-two SNPs in DRD1-5 were selected from the dbSNP, and the associations of each SNP were then screened and typed by MALDI-TOF mass spectrometry using pooled DNA samples from 150 patients with major psychosis and 150 controls. Each of the suggested SNPs was then genotyped and tested for an association within the individual samples comprising each pool. Finally, the positively associated SNPs were genotyped in an extended sample of 270 patients with schizophrenia and 350 controls. Among the 142 SNPs, 88 (62%) SNPs in our Korean population were polymorphic. At the pooling stage, 10 SNPs (DRD1: 2, DRD2: 3, and DRD4: 5) were identified (P<0.05). SNPs rs1799914 of DRD1 (P=0.046) and rs752306 of DRD4 (P=0.017) had significantly different allele frequencies in the individually genotyped samples comprising the pool. In the final stage, with the extended sample, the suggestive association of DRD4 with rs752306 was lost, but the association of DRD1 with rs1799914 gained greater significance (P=0.017). In these large-scale multi-stage analyses, we were able to find a possible association between DRD1 and schizophrenia. These findings suggested the potential contribution of a multi-step strategy for finding genes related to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | 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 |
| 42 | 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 |
| 43 | Schizophr. Res. 2012 Dec 142: 206-8 |
| PMID | 23036699 |
| Title | DRD1 rs4532 polymorphism: a potential pharmacogenomic marker for treatment response to antipsychotic drugs. |
| Abstract | We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with antipsychotic treatment response in schizophrenia. We have analyzed 124 patients with schizophrenia, consisting of 59 treatment resistant (TR) and 65 non-TR. We found an association between G-allele and TR schizophrenia (p=0.001; adjusted OR=2.71). Setting the common AA-genotype as reference, the GG-homozygous presented a five-fold risk compared to AA-homozygous (p=0.010; OR=5.56) with an intermediate result for AG-genotype (p=0.030; adjusted OR=2.64). The DRD1 rs4532 polymorphism showed a dose-response gradient with increased risk for treatment resistance and may be a potential pharmacogenetic marker for antipsychotic drug treatment response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | 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 |
| 45 | Psychiatry Res 2013 Jan 205: 7-12 |
| PMID | 22940547 |
| Title | Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A, DRD3 and SNAP-25 Genes. |
| Abstract | The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine ?-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Schizophr Bull 2013 Jul 39: 848-56 |
| PMID | 22532702 |
| Title | Intermediate phenotype analysis of patients, unaffected siblings, and healthy controls identifies VMAT2 as a candidate gene for psychotic disorder and neurocognition. |
| Abstract | Psychotic disorders are associated with neurocognitive alterations that aggregate in unaffected family members, suggesting that genetic vulnerability to psychotic disorder impacts neurocognition. The aim of the present study was to investigate whether selected schizophrenia candidate single nucleotide polymorphisms (SNPs) are associated with (1) neurocognitive functioning across populations at different genetic risk for psychosis (2) and psychotic disorder. The association between 152 SNPs in 43 candidate genes and a composite measure of neurocognitive functioning was examined in 718 patients with psychotic disorder. Follow-up analyses were carried out in 750 unaffected siblings and 389 healthy comparison subjects. In the patients, 13 associations between SNPs and cognitive functioning were significant at P < .05, situated in DRD1, DRD3, SLC6A3, BDNF, FGF2, SLC18A2, FKBP5, and DNMT3B. Follow-up of these SNPs revealed a significant and directionally similar association for SLC18A2 (alternatively VMAT2) rs363227 in siblings (B = -0.13, P = .04) and a trend association in control subjects (B = -0.10, P = .12). This association was accompanied by a significantly increased risk for psychotic disorder associated with the T allele (linear OR = 1.51, 95% CI 1.10-2.07, P = .01), which was reduced when covarying for cognitive performance (OR = 1.29, 95% CI 0.92-1.81, P = .14), suggesting mediation. Genetic variation in VMAT2 may be linked to alterations in cognitive functioning underlying psychotic disorder, possibly through altered transport of monoamines into synaptic vesicles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | 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 |
| 48 | Front Neurosci 2013 -1 7: 103 |
| PMID | 23785309 |
| Title | Reward learning as a potential target for pharmacological augmentation of cognitive remediation for schizophrenia: a roadmap for preclinical development. |
| Abstract | Impaired cognitive abilities are a key characteristic of schizophrenia. Although currently approved pharmacological treatments have demonstrated efficacy for positive symptoms, to date no pharmacological treatments successfully reverse cognitive dysfunction in these patients. Cognitively-based interventions such as cognitive remediation (CR) and other psychosocial interventions however, may improve some of the cognitive and functional deficits of schizophrenia. Given that these treatments are time-consuming and labor-intensive, maximizing their effectiveness is a priority. Augmenting psychosocial interventions with pharmacological treatments may be a viable strategy for reducing the impact of cognitive deficits in patients with schizophrenia. We propose a strategy to develop pharmacological treatments that can enhance the reward-related learning processes underlying successful skill-learning in psychosocial interventions. Specifically, we review clinical and preclinical evidence and paradigms that can be utilized to develop these pharmacological augmentation strategies. Prototypes for this approach include dopamine D1 receptor and ?7 nicotinic acetylcholine receptor agonists as attractive targets to specifically enhance reward-related learning during CR. The approach outlined here could be used broadly to develop pharmacological augmentation strategies across a number of cognitive domains underlying successful psychosocial treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Neuropsychopharmacology 2013 Jul 38: 1512-20 |
| PMID | 23422792 |
| Title | D-amphetamine and antipsychotic drug effects on latent inhibition in mice lacking dopamine D2 receptors. |
| Abstract | Drugs that induce psychosis, such as D-amphetamine (AMP), and those that alleviate it, such as antipsychotics, are suggested to exert behavioral effects via dopamine receptor D2 (D2). All antipsychotic drugs are D2 antagonists, but D2 antagonism underlies the severe and debilitating side effects of these drugs; it is therefore important to know whether D2 is necessary for their behavioral effects. Using D2-null mice (Drd2-/-), we first investigated whether D2 is required for AMP disruption of latent inhibition (LI). LI is a process of learning to ignore irrelevant stimuli. Disruption of LI by AMP models impaired attention and abnormal salience allocation consequent to dysregulated dopamine relevant to schizophrenia. AMP disruption of LI was seen in both wild-type (WT) and Drd2-/-. This was in contrast to AMP-induced locomotor hyperactivity, which was reduced in Drd2-/-. AMP disruption of LI was attenuated in mice lacking dopamine receptor D1 (DRD1-/-), suggesting that D1 may play a role in AMP disruption of LI. Further supporting this possibility, we found that D1 antagonist SKF83566 attenuated AMP disruption of LI in WT. Remarkably, both haloperidol and clozapine attenuated AMP disruption of LI in Drd2-/-. This demonstrates that antipsychotic drugs can attenuate AMP disruption of learning to ignore irrelevant stimuli in the absence of D2 receptors. Data suggest that D2 is not essential either for AMP to disrupt or for antipsychotic drugs to reverse AMP disruption of learning to ignore irrelevant stimuli and further that D1 merits investigation in the mediation of AMP disruption of these processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Neuropsychiatr Dis Treat 2014 -1 10: 1133-9 |
| PMID | 25018632 |
| Title | Association of dopamine D1 receptor gene polymorphism with schizophrenia: a meta-analysis. |
| Abstract | To date, the role of dopamine D1 receptor (DRD1) polymorphism in schizophrenia remains controversial. We carried out a meta-analysis to determine whether DRD1 polymorphism influences the risk of schizophrenia. We examined whether rs4532 and rs5326 genetic variants are related to the etiology of schizophrenia, using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria. A total of ten studies were identified and included in our meta-analysis, nine for rs4532, with 1,941 cases and 2,480 controls, and four for rs5326, with 1,285 cases and 1,195 controls. No significant association was found between the rs4532 locus and schizophrenia. For the rs5326 locus, the guanine-adenine (GA) genotype was associated with schizophrenia as a risk factor (for GA vs guanine-guanine [GG], odds ratio [OR] =1.36, 95% confidence interval [CI]: 1.15-1.61, P<0.001). The GA genotype of rs5326 increased the risk of schizophrenia, but there was no association between rs4532 and schizophrenia. These data may provide references for case-control studies in schizophrenia in future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Neuropsychiatr Dis Treat 2014 -1 10: 645-52 |
| PMID | 24790447 |
| Title | Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population. |
| Abstract | Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Neuropsychiatr Dis Treat 2014 -1 10: 645-52 |
| PMID | 24790447 |
| Title | Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population. |
| Abstract | Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | PLoS ONE 2014 -1 9: e91151 |
| PMID | 24618531 |
| Title | Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway. |
| Abstract | Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17?-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Mol. Psychiatry 2014 Dec 19: 1258-66 |
| PMID | 24322206 |
| Title | Contrasting changes in DRD1 and DRD2 splice variant expression in schizophrenia and affective disorders, and associations with SNPs in postmortem brain. |
| Abstract | Dopamine 2 receptor (DRD2) is of major interest to the pathophysiology of schizophrenia (SCZ) both as a target for antipsychotic drug action as well as a SCZ-associated risk gene. The dopamine 1 receptor (DRD1) is thought to mediate some of the cognitive deficits in SCZ, including impairment of working memory that relies on normal dorsolateral prefrontal cortex (DLPFC) function. To better understand the association of dopamine receptors with SCZ, we studied the expression of three DRD2 splice variants and the DRD1 transcript in DLPFC, hippocampus and caudate nucleus in a large cohort of subjects (~700), including patients with SCZ, affective disorders and nonpsychiatric controls (from 14th gestational week to 85 years of age), and examined genotype-expression associations of 278 single-nucleotide polymorphisms (SNPs) located in or near DRD2 and DRD1 genes. Expression of D2S mRNA and D2S/D2-long (D2L) ratio were significantly increased in DLPFC of patients with SCZ relative to controls (P<0.0001 and P<0.0001, respectively), whereas D2L, D2Longer and DRD1 were decreased (P<0.0001). Patients with affective disorders showed an opposite pattern: reduced expression of D2S (major depressive disorder, P<0.0001) and increased expression of D2L and DRD1 (bipolar disorder, P<0.0001). Moreover, SCZ-associated risk alleles at rs1079727, rs1076560 and rs2283265 predicted increased D2S/D2L expression ratio (P<0.05) in control individuals. Our data suggest that altered splicing of DRD2 and expression of DRD1 may constitute a pathophysiological mechanism in risk for SCZ and affective disorders. The association between SCZ risk-associated polymorphism and the ratio of D2S/D2L is consistent with this possibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | Neurosci. Lett. 2015 Nov 609: 120-3 |
| PMID | 26484506 |
| Title | Dopamine D1 receptor (DRD1) 5' region haplotypes significantly affect transcriptional activity in vitro. |
| Abstract | The role of dopamine D1 receptor (DRD1) gene promoter polymorphisms in schizophrenia remains controversial. We aimed to characterize the polymorphisms in the promoter region because little is known about the extent of variance in this region and potential roles in gene transcription activity. In a previous case-control study, we amplified and genotyped the polymorphisms of DRD1 gene. According to its haplotype estimation, we identified eight SNPs and confirmed ten different haplotypes by cloning and sequencing the fragment spanning -1990 to +10. The promoter activity of these haplotypes was analyzed using dual luciferase assays in SH-SY5Y and HEK293 cells. Compared with the reference haplotype, the constructed haplotypes containing different variation sites could significantly alter the luciferase activity. Additionally, the prediction of the transcription factor binding sites was performed. Our examination could provide the informative reference for the role of DRD1 gene promoter in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | Psychiatry Res 2015 Sep 229: 586-8 |
| PMID | 26213377 |
| Title | Meta-analysis of dopamine receptor D1 rs4532 polymorphism and susceptibility to antipsychotic treatment response. |
| Abstract | Previous association results between dopamine D1 receptor (DRD1) rs4532 polymorphism and antipsychotic treatment response in schizophrenia and schizoaffective subjects have been conflicting. Thus, we have conducted a systematic review followed by a meta-analysis. Our results indicated no association between DRD1 rs4532 polymorphism and overall antipsychotic response or clozapine monotherapy response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | Neurosci. Lett. 2015 Jan 584: 178-83 |
| PMID | 25179995 |
| Title | Association of dopamine receptor D1 (DRD1) polymorphisms with risperidone treatment response in Chinese schizophrenia patients. |
| Abstract | Evidence suggests that dopamine receptor D1 (DRD1) may be involved in the pathophysiology of schizophrenia and the pharmacodynamics of antipsychotics. We conducted a comprehensive pharmacogenomics study to investigate the association of genetic polymorphisms in DRD1 with treatment response to risperidone. Two independent cohorts of Han Chinese schizophrenic patients (n = 185) from two different geographic areas treated with risperidone monotherapy for 4 weeks and four SNPs (rs5326, rs4867798, rs4532 and rs686) in the DRD1 gene were analyzed. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). The definition of risperidone response is based on a cut-off of 50% in terms of corrected percent change of PANSS score. The significant confounding effects of non-genetic factors were included as covariates for adjustment. No significant association of DRD1 polymorphisms with risperidone treatment response was found in either single marker or haplotype analysis in this study. The current results provide the first evidence that DRD1 polymorphisms may not influence the clinical efficacy of risperidone in Chinese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Neurosci. Lett. 2015 Jan 584: 178-83 |
| PMID | 25179995 |
| Title | Association of dopamine receptor D1 (DRD1) polymorphisms with risperidone treatment response in Chinese schizophrenia patients. |
| Abstract | Evidence suggests that dopamine receptor D1 (DRD1) may be involved in the pathophysiology of schizophrenia and the pharmacodynamics of antipsychotics. We conducted a comprehensive pharmacogenomics study to investigate the association of genetic polymorphisms in DRD1 with treatment response to risperidone. Two independent cohorts of Han Chinese schizophrenic patients (n = 185) from two different geographic areas treated with risperidone monotherapy for 4 weeks and four SNPs (rs5326, rs4867798, rs4532 and rs686) in the DRD1 gene were analyzed. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). The definition of risperidone response is based on a cut-off of 50% in terms of corrected percent change of PANSS score. The significant confounding effects of non-genetic factors were included as covariates for adjustment. No significant association of DRD1 polymorphisms with risperidone treatment response was found in either single marker or haplotype analysis in this study. The current results provide the first evidence that DRD1 polymorphisms may not influence the clinical efficacy of risperidone in Chinese schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | 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 |