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)

Though Kraepelin's century-old division of major mental illness into mood disorder and schizophrenia remains in place, debate abounds over the most appropriate classification. Although these arguments previously rested solely on clinical grounds, they now are rooted in genetics and neurobiology. This article reviews evidence from the fields of genetic epidemiology, linkage, association, cytogenetics, and gene expression. Taken together, these data suggest some overlap in the genes that predispose to bipolar disorder and schizophrenia. One gene, DAOA (D-amino acid oxidase activator, also known as G72), has been repeatedly implicated as an overlap gene, while DISC1 and others may constitute additional shared susceptibility genes. Further, some evidence implicates syndromes of co-occurring mood and psychotic symptoms in association with the putative risk alleles in overlap genes. From a nosologic perspective, the existence of overlap genes, coupled with the genotype-phenotype correlations discovered to date, supports the reality of the much debated schizoaffective disorder. Potential non-overlap syndromes--such as nonpsychotic bipolar disorder or cyclothymic temperament, on the one hand, and negative symptoms or the deficit syndrome, on the other--could turn out to have their own unique genetic determinants. If genotypes are to be the anchor points of a clinically useful system of classification, they must ultimately be shown to inform prognosis, treatment, and prevention. No gene variants have yet met these tests in bipolar disorder or schizophrenia.
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PMID:Carving chaos: genetics and the classification of mood and psychotic syndromes. 1660 72

Schizophrenia has long been approached from a translational perspective; however, new findings from the past decade have radically affected the dominant accounts of this illness. It is now possible to derive a consistent account of one contributing cause of schizophrenia across multiple levels of analysis, from genes to receptors, functional neuroanatomy, cognition, and symptoms. To this end, we summarize the data attributing the disorganization symptoms of schizophrenia to a failure of executive, prefrontal cortical processes. We describe the hypothesis that this failure reflects an impairment in N-methyl-D-aspartate (NMDA) glutamatergic neurotransmission, that is likely to involve both the dysregulated function of NMDA synapses, as well as the physical loss of NMDA synapses, particularly in prefrontal cortex. Dysregulation in NMDA synaptic function can be in turn attributed to polymorphisms in a variety of genes (regulator of G-protein signaling 4, dystrobrevin binding protein I, neuregulin-1, D-amino acid oxidase activator, and others) that have been linked to schizophrenia and are likely to impact NMDA-mediated synaptic neuroplasticity. Although the science of schizophrenia is not yet at a point where any domain or set of findings provides strong constraints across other levels of analysis, the further development of evidence for this chain of causation can provide increasingly strong tests of the NMDA synapse deficit theory.
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PMID:Translational and developmental perspective on N-methyl-D-aspartate synaptic deficits in schizophrenia. 1715 4

A number of linkage studies have previously implicated the region of chromosome 13q34 in schizophrenia. Chumakov and colleagues (2002) identified a gene complex called G72 (now termed D-amino acid oxidase activator: DAOA)/G30 in this region and performed association analyses of the DAOA/G30 as well as the D-amino-acid oxidase (DAAO) gene with schizophrenia. DAAO oxidizes D-serine, a potent activator of the N-methyl-D-aspartate (NMDA) type glutamate receptor in the human brain whereas the DAOA protein is considered an activator of DAAO. The interaction of these two genes has thus been implicated in the NMDA receptor regulation pathway in schizophrenia. To date, several studies have shown a relatively consistent positive association between schizophrenia and DAOA/G30, but not with DAAO. The aim of our study was to further evaluate the contributions of these genes to the susceptibility to schizophrenia using two different sample sets. Our sample consisted of 168 matched case-control pairs as well as a family-based sample (n=113) for transmission disequilibrium test. Significant associations between the DAOA/G30 M-7 and M-18 polymorphisms and schizophrenia were observed in our case-control sample whereas no associations were observed for DAAO markers. We also observed significant or suggestive transmission disequilibrium for DAOA/G30 M-7, M-23, and M-24 to probands with schizophrenia in our family-based sample. Subsequent analysis of haplotypes made up of four DAOA/G30 markers, one marker selected from each of two linkage disequilibrium blocks that were observed in our sample as well as both ends (M-7 and M-25), were also associated with schizophrenia. Our data provide further evidence that the DAOA/G30 locus may play a role in the pathophysiology of schizophrenia. Although no direct link to genetic polymorphism in these genes and NMDA receptor function has been revealed, the present findings support previous reports implicating DAOA/G30 as susceptibility genes for schizophrenia. Further research is warranted to determine the functional variation underlying these findings and to relate this to the pathophysiology of schizophrenia.
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PMID:Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia. 1762 36

A series of genetic studies have identified the D-amino acid oxidase (DAO) gene as potentially contributing to schizophrenia susceptibility. An interacting gene, D-amino acid oxidase activator (DAOA) has also been implicated and it has been suggested that variation at these genes may influence the efficiency of glutamate gating at N-methyl-D-aspartate-type (NMDA) receptors. However, recent data suggests that DAOA may influence susceptibility to mood episodes across the spectrum of psychotic disorders rather than contributing to a specific psychosis phenotype. The aim of this study was to determine whether risk variation at DAO is similarly associated with affective or other clinical symptoms in psychosis. We have previously reported association between risk variation at DAO and schizophrenia in an Irish case-control sample. In this study we investigated the relationship between a defined genetic risk variant at DAO and PANSS-derived clinical symptom factors in a sample of 249 patients using principal component and Kruskal-Wallis analyses. Carriers of the DAO risk variant scored significantly higher on the 'depression/anxiety' factor than non-carriers (H=9.02, d.f.=2, p=0.01). These data suggest a potential role for DAO in susceptibility to depressive symptoms in schizophrenia, but a more general role for DAO in affective disorders cannot be excluded.
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PMID:D-amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia. 1789 6

The G72/G30 gene complex (G72 also known as D-amino acid oxidase activator, DAOA) and its chromosomal region 13q32-34 have been linked and associated with both schizophrenia (SCZ) and bipolar disorder (BP) in multiple studies, including our initial association report on BP. However, the inconsistency of associated variants across studies is obvious. Previous meta-analyses had small data sets. The present meta-analysis combined 18 association articles published before April of 2007. There were 19 independent studies of SCZ, with 4304 cases, 5423 controls, and 1384 families, and four independent studies of BP with 1145 cases, 1829 controls, and 174 families. Of 15 single nucleotide polymorphisms (SNPs) analyzed in the 95-kb G72/G30 gene region, M18/rs947267 and M22/rs778293 showed association with SCZ in Asians, and M24/rs1421292 with SCZ in Europeans. The associations of C allele at M18 and A allele at M22 with SCZ in Asians survived conservative Bonferroni correction for multiple testing for 15 markers and subgroup analysis (adjusted P=0.0000253 for M18; adjusted P=0.009 for M22). No single maker showed evidence of overall association with BP. These results suggest that G72/G30 may influence susceptibility to schizophrenia with weak effects.
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PMID:Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis. 1802 49

Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenia patients. However the role of specific-genes in the development of cognitive deficit remains unclear. The article aims at reviewing the current studies devoted to association between gene polymorphisms and cognitive dysfunctions in schizophrenic patients. Main attention is drawn to the association between the Val158Met polymorphism of the COMT gene and cognitive traits that has been consistently replicated and has a biological and neuropsychological support. The association studies on the genes for dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase and D-amino acid oxidase activator are reviewed as well.
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PMID:[Molecular genetics of cognitive deficit in schizophrenia]. 1898 32

G72 is one of the most widely tested genes for association with schizophrenia. As G72 activates the D-amino acid oxidase (DAO), G72 is termed D-amino acid oxidase activator (DAOA). The aim of this study is to investigate the association between G72 and schizophrenia in a Japanese population, using the largest sample size to date (1774 patients with schizophrenia and 2092 healthy controls). We examined eight single nucleotide polymorphisms (SNPs), which had been associated with schizophrenia in previous studies. We found nominal evidence for association of alleles, M22/rs778293, M23/rs3918342 and M24/rs1421292, and the genotype of M22/rs778293 with schizophrenia, although there was no association of allele or genotype in the other five SNPs. We also found nominal haplotypic association, including M15/rs2391191 and M19/rs778294 with schizophrenia. However, these associations were no longer positive after correction for multiple testing. We conclude that G72 might not play a major role in the risk for schizophrenia in the Japanese population.
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PMID:Association study of the G72 gene with schizophrenia in a Japanese population: a multicenter study. 1923 67

Antipsychotics, the drugs used currently for the treatment of schizophrenia, produce their therapeutic effects via the blockade of dopamine receptors. These compounds are, however, limited in their therapeutic efficacy and have side effect liabilities that also limit their use. Agents that produce antipsychotic effects by enhancing NMDA receptor function represent a viable alternative to dopamine antagonists. D-serine, is the prototype of this approach acting as a positive allosteric modulator of the NMDA receptor to enhance antipsychotic efficacy in the clinic. A newer approach to modulating NMDA receptor function, identified by gene association studies, is pLG72/DAOA (D-amino acid oxidase activator) a peptide that modulates D-amino acid oxidase (DAAO) activity, increasing endogenous levels of D-serine. While the initial association of DAOA with schizophrenia and its functional effects on DAAO activity have not been replicated, its identification has led to the development of several DAAO inhibitors, e.g., AS057278, CBIO and Compound 8, that are active in animal models of antipsychotic action. The complications in validating the G72 association with schizoprenia highlight the inherent challenges in translating gene-based, disease-related associations to drug discovery targets.
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PMID:Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges. 1959 8

The genetic factors determining the progression of prodromal syndromes to first episode schizophrenia have remained enigmatic to date. In a unique prospective multicentre trial, we assessed whether variants at the D-amino acid oxidase activator (DAOA)/G72 locus influence progression to psychosis. Young subjects with a prodromal syndrome were observed prospectively for up to 2 years to assess the incidence of progression to schizophrenia or first episode psychosis. Of the 82 probands with a prodromal syndrome, 21 probands experienced progression to psychosis within the observation period. Assessment of nine common variants in the DAOA/G72 locus yielded two variants with the predictive value for symptom progression: all four probands with the rs1341402 CC genotype developed psychosis compared with 17 out of 78 probands with the TT or CT genotypes (chi(2) = 12.348; df = 2; p = 0.002). The relative risk for progression to psychosis was significantly increased in the CC genotype: RR = 4.588 (95% CI = 2.175-4.588). Similarly, for rs778294, 50% of probands with the AA genotype, but only 22% of probands with a GG or GA genotype progressed to psychosis (chi(2) = 7.027; df = 2; p = 0.030). Moreover, haplotype analysis revealed a susceptibility haplotype for progression to psychosis. This is one of the first studies to identify a specific genetic factor for the progression of prodromal syndromes to schizophrenia, and further underscores the importance of the DAOA/G72 gene for schizophrenia.
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PMID:DAOA/G72 predicts the progression of prodromal syndromes to first episode psychosis. 1976 62

The D-amino acid oxidase activator gene (G72) has been found associated with several psychiatric disorders such as schizophrenia, major depression, and bipolar disorder. Impaired performance in verbal fluency tasks is an often replicated finding in the mentioned disorders. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and lateral temporal areas and could possibly constitute an endophenotype. Therefore, it is of interest whether genes associated with the disorders, such as G72, modulate verbal fluency performance and its neural correlates. Ninety-six healthy individuals performed a semantic verbal fluency task while brain activation was measured with functional MRI. All subjects were genotyped for two single nucleotide polymorphisms (SNP) in the G72 gene, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with the above-mentioned disorders. The effect of genotype on brain activation was assessed with fMRI during a semantic verbal fluency task. Although there were no differences in performance, brain activation in the right middle temporal gyrus (BA 39) and the right precuneus (BA 7) was positively correlated with the number of M24 risk alleles in the G72 gene. G72 genotype does modulate brain activation during language production on a semantic level in key language areas. These findings are in line with structural and functional imaging studies in schizophrenia, which showed alterations in the right middle temporal gyrus.
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PMID:Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals. 2033 55


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