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

The serotonin and dopamine neurotransmitter systems are candidate pathways in the development of schizophrenia because of the assumed causal relationship with the observed symptoms as well as effective targeting of the corresponding receptors by antipsychotic drugs. However, genetic association studies have systematically focused on a limited set of genes and single nucleotide polymorphisms (SNPs), including T102C at HTR2A and Ser9Gly at DRD3. Meta-analyses of the associations between these two markers and schizophrenia revealed a true increase in risk, the magnitude of the effect being very low. In the present study we analyzed 260 schizophrenic patients and 354 control subjects from a homogeneous population, the Galician population, using an extensive linkage disequilibrium (LD) mapping approach, genotyping a total of 47 SNPs to test for the existence of additional variants that confer higher risk. We detected nominal significant association with schizophrenia for several haplotype tag SNPs (htSNPs) at HTR2A, although the significance was lost after multiple test corrections. In addition, haplotype analyses involving a sliding window approach, with window size 2 to 4 SNPs, revealed significant differences in frequencies of the DRD3 haplotypes at the 3' half of the gene region. This difference, which remains clearly significant after multiple test corrections (p=0.002, 0.0001, and 0.0025, for window sizes 2, 3, and 4, respectively), was mainly due to over-representation of several rare haplotypes in patients, at the expense of a single common haplotype; this represents interesting evidence of rare haplotypes for susceptibility detected using common htSNPs due to their strong effect.
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PMID:Extensive linkage disequilibrium mapping at HTR2A and DRD3 for schizophrenia susceptibility genes in the Galician population. 1712 70

This study aims to further evaluate the controversial association between the Ser9Gly polymorphism in codon 9 of the D3 dopamine receptor gene (DRD3) and schizophrenia in psychiatric inpatients acutely hospitalized in two general hospitals in Madrid, Spain. The Ser9Gly polymorphism of the DRD3 was examined in 178 schizophrenic patients, 286 patients with other psychiatric diagnoses, and 132 controls recruited. Genotype frequencies were in Hardy-Weinberg equilibrium. No association was found between schizophrenia and the Ser9Gly polymorphism of the D3 dopamine receptor gene.
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PMID:No association between the Ser9Gly polymorphism of the dopamine D3 receptor gene and schizophrenia in a Spanish sample. 1717 62

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.
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PMID:Genetics of Alzheimer's disease. A rapidly evolving field. 1785 Nov 96

Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.
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PMID:Molecular mechanisms of schizophrenia. 1798 52

We evaluated the hypothesis that dopaminergic polymorphisms are risk factors for schizophrenia (SZ). In stage I, we screened 18 dopamine-related genes in two independent US Caucasian samples: 150 trios and 328 cases/501 controls. The most promising associations were detected with SLC6A3 (alias DAT), DRD3, COMT and SLC18A2 (alias VMAT2). In stage II, we comprehensively evaluated these four genes by genotyping 68 SNPs in all 478 cases and 501 controls from stage I. Fifteen (23.1%) significant associations were found (p < or = 0.05). We sought epistasis between pairs of SNPs providing evidence of a main effect and observed 17 significant interactions (169 tests); 41.2% of significant interactions involved rs3756450 (5' near promoter) or rs464049 (intron 4) at SLC6A3. In stage III, we confirmed our findings by genotyping 65 SNPs among 659 Bulgarian trios. Both SLC6A3 variants implicated in the US interactions were overtransmitted in this cohort (rs3756450, p = 0.035; rs464049, p = 0.011). Joint analyses from stages II and III identified associations at all four genes (p(joint) < 0.05). We tested 29 putative interactions from stage II and detected replication between seven locus pairs (p < or = 0.05). Simulations suggested our stage II and stage III interaction results were unlikely to have occurred by chance (p = 0.008 and 0.001, respectively). In stage IV we evaluated rs464049 and rs3756450 for functional effects and found significant allele-specific differences at rs3756450 using electrophoretic mobility shift assays and dual-luciferase promoter assays. Our data suggest that a network of dopaminergic polymorphisms increase risk for SZ.
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PMID:A network of dopaminergic gene variations implicated as risk factors for schizophrenia. 1804 77

Dopamine D3 receptor (DRD3) binds antipsychotic drugs and is abundant in the limbic system of the brain. It has been shown to play important roles in schizophrenia. A number of studies investigated the Ser9Gly polymorphism of the DRD3 gene to test its possible association with schizophrenia; however, the results were inconsistent. Our study aims to further evaluate the possible association between the Ser9Gly polymorphism and schizophrenia using a case-control association study within the Han Chinese population as well as a meta-analysis covering all previous studies. Our study, based on 329 schizophrenic patients and 288 controls, found no significant difference in the genotype or allele distributions of Ser9Gly polymorphism, the meta-analysis showed that the Ser9Gly polymorphism was not associated with Schizophrenia. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.
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PMID:The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis. 1829 56

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI), as well as in the medial temporal lobe structures has been implicated in schizophrenia, while its genetic mechanism is unknown. This magnetic resonance imaging study investigated the effect of the genotypic combination of the dopamine D3 receptor (DRD3) Ser9Gly and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms on the AI length and volumetric measures of the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) in 33 schizophrenia patients and 29 healthy controls. The subjects with a combination of the Ser/Ser genotype of DRD3 and Met-containing genotypes of BDNF (high-risk combination) had a shorter AI than those without it in the healthy controls, but not in the schizophrenia patients. The subjects carrying the high-risk combination had a smaller posterior hippocampus than those without it for both diagnostic groups. These genotypic combination effects on brain morphology were not explained by the independent effect of each polymorphism. These findings suggest the effect of gene-gene interaction between the DRD3 and BDNF variations on brain morphology in midline and medial temporal lobe structures, but do not support its specific role in the pathogenesis of schizophrenia.
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PMID:The association of genotypic combination of the DRD3 and BDNF polymorphisms on the adhesio interthalamica and medial temporal lobe structures. 1847 2

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case-control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case-control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: chi(2) = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: chi(2) = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48-0.88). However in a meta-analysis of nine Japanese case-control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel-Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97-1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.
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PMID:Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis. 1870 16

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics.
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PMID:Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics. 1878 56

The number and frequency of susceptibility alleles at loci associated to most psychiatric disorders is largely unknown, in spite of its relevance for the design of studies aiming to find these alleles. Both, common polymorphisms and rare mutations may contribute to the genetic susceptibility to complex psychiatric disorders, being the relative relevance of each type of variation currently under debate. Here, we confirmed the existence of a common protective haplotype against schizophrenia at the dopamine D(3) receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel-Haenszel chi(2) P value = 0.00227; OR = 0.79, 95% CI 0.68-0.92, based on 794 cases and 1,078 controls from three independent populations of European origin). This protective haplotype is at very low frequency in Sub-Saharan Africans (median 0.06) and at intermediate frequencies in other populations (median 0.25). We also revealed, by examining the patterns of linkage disequilibrium around this gene, that the protective haplotype has reached high frequency in non-African populations due to selection acting, most probably, on a linked functional polymorphism, the non-synonymous single nucleotide polymorphism Ser9Gly (rs6280), also at DRD3. Thus, this finding shows that the natural selection may play a role in the existence of common alleles conferring different susceptibility to schizophrenia.
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PMID:A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia. 1898 89


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