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)

Methamphetamine psychosis is considered as one of the pharmacological models of schizophrenia, and a hyperdopaminergic one. However, many lines of experimental evidence indicate that glutamatergic signaling is also involved in development of methamphetamine psychosis. Several genes related to glutamate function, e.g. the DTNBP1, G72, and GRM3 genes, were shown to be associated with schizophrenia susceptibility. Recently, we found significant association of the DTNBP1 gene with methamphetamine psychosis. This finding prompted us to examine the G72 gene encoding the d-amino acid oxidase activator (DAOA), which metabolizes d-serine, an NMDA co-agonist, in methamphetamine psychosis. Six SNPs of the G72 gene, which previously showed significant association with schizophrenia, were analyzed in 209 patients with methamphetamine psychosis and 291 age- and sex-matched normal controls. One SNP of M22 (rs778293) showed a significant association with methamphetamine psychosis (genotype: p=0.00016, allele: p=0.0015). Two haplotypes G-A of M12 (rs3916965)-M15 (rs2391191) (p=0.00024) and T-T of M23 (rs947267)-M24 (rs1421292) (p=0.00085) also showed associations with methamphetamine psychosis. The present findings suggest that the G72 gene may contribute to a predisposition to not only schizophrenia but also to methamphetamine psychosis.
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PMID:G72 gene is associated with susceptibility to methamphetamine psychosis. 1948 54

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

Schizophrenia is a neurodevelopmental psychiatric disorder characterized by a variety of structural brain abnormalities that appear to progress across the course of illness. Schizophrenia also is highly heritable, and one gene that has emerged as a possible susceptibility factor is G72. G72 influences brain development and activity by an as-yet unclear mechanism, and multiple studies have reported associations between G72 and schizophrenia. We were interested in linking these domains of investigation by determining whether G72 also influences the rate of longitudinal structural brain changes in individuals with schizophrenia. As part of the Iowa Longitudinal Study of Recent Onset Psychoses, we genotyped four G72 polymorphisms previously associated with schizophrenia in 110 subjects with schizophrenia or schizoaffective disorder from whom we had obtained two brain MRI scans an average of 3 years apart. The four polymorphisms captured three haplotypes, one of which was strongly associated with an increased rate of frontal lobe volume decrement. This same haplotype was also associated with more severe psychotic symptoms at the time of the second scan. These data thus suggest that variation in G72 modulates the progressive brain changes that characterize schizophrenia.
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PMID:G72 influences longitudinal change in frontal lobe volume in schizophrenia. 1976 Jun 75

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

Polymorphisms in the G72 (also named d-amino acid oxidase activator, DAOA) gene increase the vulnerability for schizophrenia and affective psychosis. Three recent genetic neuroimaging studies showed that variation in G72 influences the brain activity in the medial temporal lobe (MTL), supporting the hypothesis that G72 might play a modulatory role on brain activity in MTL structures. In the present study we therefore investigated the effect of G72 on the neural correlates of long-term memory encoding and retrieval in a large sample of healthy subjects (n=83) using functional magnetic resonance imaging. A face encoding and a face retrieval memory task were chosen because on the one hand they specifically activate MTL structures and on the other hand they tap into memory processes that are compromised in patients with schizophrenia and affective disorder. Despite a strong a-priori hypothesis of genotype group activation differences in the MTL along with a large sample size we did neither find an effect of G72 genotype status on brain activity in the MTL nor in any other brain regions. The present data therefore do not support the view of a general modulatory role of G72 on MTL brain activity, at least not in the domain of long-term memory encoding and retrieval. Our results highlight the importance of replication studies in genetic neuroimaging.
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PMID:The effect of G72 genotype on neural correlates of memory encoding and retrieval. 2000 95

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

Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-d-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and d-amino acid oxidase/G72 that regulate brain d-serine synthesis. Reductions in plasma and brain glycine, d-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.
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PMID:N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia? 2041 96

D-amino acid oxidase (DAAO) is a flavoenzyme that degrades D-amino acids through the process of oxidative deamination. DAAO regulation of D-amino acid levels has been associated with several physiological processes ranging from hormone secretion to synaptic transmission and cognition. Recent genetic studies have identified a mutation on chromosome 13 in schizophrenia patients that encodes two gene products (G30 and G72) that are associated with DAAO. Furthermore, DAAO expression and enzyme activity has been reported to be increased in post mortem brain tissue samples from patients with schizophrenia compared to healthy controls. D-serine, a D-amino acid that is regulated by DAAO, is a potent, endogenous co-agonist of the N-methyl-D-aspartic acid (NMDA) receptor. Because NMDA receptor dysfunction is thought to be involved in the positive (psychotic), negative and cognitive symptoms in schizophrenia, there has been much interest in developing potent and selective DAAO inhibitors for the treatment of this disease. Several research reports have been published that describe the synthesis and biological effects of novel, selective, small molecule inhibitors of DAAO. Many of these compounds have been shown, when given systemically, to increase D-serine concentrations in the blood and brain. However, the efficacy of these compounds in behavioral assays that measure antipsychotic potential and pro-cognitive effects in laboratory animals has been inconsistent. This article highlights and reviews research advances for DAAO inhibitors published in peer reviewed journals.
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PMID:The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors. 2064 22

The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients.
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PMID:Contributions of the D-serine pathway to schizophrenia. 2129 46

Recent studies have described G72 and DAAO as susceptibility genes for schizophrenia and bipolar disorder. Both genes modulate glutamate neurotransmission, which plays a key role in neurocognitive function and is thought to be altered in these disorders. Moreover, in vitro transcription studies indicate that the two genes interact with each other at the molecular level. However, it is unclear how these genes affect cortical function and whether their effects interact with each other. The aim of this study was therefore to examine the impact of G72 rs746187 and DAAO rs2111902 genotypes on brain function in schizophrenia, bipolar disorder and healthy volunteers. We used functional magnetic resonance imaging and an overt verbal fluency paradigm to examine brain function in a total of 120 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar I disorder and 47 healthy volunteers. A significant 3 way interaction between G72, DAAO and diagnosis was detected in the right middle temporal gyrus (x=60 y=-12 z=-12; z-score: 5.32; p < 0.001 after family-wise error correction), accounting for 8.5% of the individual variance in activation. These data suggest that there is a nonadditive interaction between the effects of variations in the genes implicated in glutamate regulation that affects cortical function. Also, the nature of this interaction is different in patients and healthy controls, providing support for altered glutamate function in psychosis. Future studies could explore the effects of DAAO and G72 in individuals with prodromal symptoms of psychosis, in order to elucidate glutamate dysfunction in this critical phase of the disorder.
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PMID:Genetic vulnerability to psychosis and cortical function: epistatic effects between DAAO and G72. 2223 82


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