D-amino Acid Oxidase Activator Gene Research Articles

The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population

Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N-methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene (NOS1AP), disrupted in schizophrenia 1 gene (DISC1), d-amino acid oxidase activator gene (DAOA), and glycogen synthase kinase 3-beta gene (GSK3B). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP, 2 in DISC1, 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p=0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p<0.001; p<0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B- rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP, DISC1, DAOA, and GSK3B polymorphisms (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B-rs6438552) in EOS susceptibility.

The DAOA gene is associated with schizophrenia in the Taiwanese population

The gene D-amino acid oxidase activator (DAOA), which has a former name of G72, and the D-amino acid oxidase (DAO) gene have been suggested as candidate genes of schizophrenia. However, association studies have so far yielded equivocal results. We analyzed one single nucleotide polymorphism (SNP) for DAO (rs3741775) and seven SNPs for G72 (rs3916956, rs2391191, rs9558562, rs947267, rs778292, rs3918342, and rs1421292) in this study enrolling 248 schizophrenia cases and 267 controls in the Taiwanese samples. In SNP-based single locus association analyses, the rs778292 in the DAOA gene showed significant association with schizophrenia. The rs3741775 in the DAO gene could not withstand statistically significant after multiple corrections. Additionally, a three-SNP haplotype (rs778292-rs3918342-rs1421292) in the DAOA gene were observed to be significantly associated with schizophrenia. Among them, the TCT haplotype presented higher prevalence in controls than in cases whereas the TTT and CTT haplotype were significantly more frequent in cases than in controls. The study also provides significant evidence for epistatic interactions among DAOA and DAO gene in the development of schizophrenia. These results provide additional evidence and indicate that the DAOA gene and DAOA-DAO gene-gene interactions might play a role for schizophrenia in a Taiwanese sample.

Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study

BackgroundGlutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients’ cognitive performance. MethodsThe sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses. ResultsThe haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results. ConclusionsOur findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.

An association study of D-Amino Acid Oxidase and D-Amino Acid Oxidase Activator polymorphisms and schizophrenia in patients from Turkey

Objective: Schizophrenia is a highly heritable complex disease. The genetic interactions underlying this heritability is still needs to be understood. Linkage studies pointed out the D-amino acid oxidase (DAO) and D-amino acid oxidase activator (DAOA-G72) genes as candidate genes in susceptibility to schizophrenia. The association studies of interaction partners D-amino acid oxidase and D-amino acid oxidase activator gene polymorphisms and schizophrenia has been performed in different studies with different ethnic origins. However these studies showed conflicting results. In this study, it is aimed to examine the effects of several DAO and DAOA polymorphisms in Turkish schizophrenia patients. Methods: In the present study two single nucleotide polymorphisms (SNPs) within DAO gene (rs2111902 and rs3741775) and one in DAOA gene (rs2391191) were genotyped in individuals with Turkish origin from Malatya region on eastern part of Turkey. 96 schizophrenia patients and 100 mentally healthy individuals are the subjects of this study. Results: No significant difference was found in between the controls and schizophrenia sample for the SNPs rs2111902 and rs3741775 of DAO gene but a significant association was found on the allelic level of rs2391191 of DAOA gene. The relationship between aggressive behavior, suicide attempts and genotypes were also evaluated in the patient group. Discussion: A significant association for the G allele of rs2391191 at the allelic level was found, on the other hand no association could be shown between the examined rs2111902 and rs3741775 polymorphisms and the pathology of the disorder in the group of Turkish schizophrenia patients included in this study.

Association between DAOA gene polymorphisms and the risk of schizophrenia, bipolar disorder and depressive disorder

Schizophrenia (SCZ), bipolar disorder (BD) and depressive disorder (DD) are common psychiatric disorders, which show common genetic vulnerability. Previous gene-disease association studies have reported correlations between d-amino acid oxidase activator (DAOA) gene polymorphisms and the three psychiatric disorders. However, the findings were contradictory. A meta-analysis was therefore conducted to provide more robust investigations into DAOA polymorphisms and the risk of SCZ, BD and DD. This meta-analysis recruited 46 published studies up to July 2013, including 17,515 cases and 25,189 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the association between three specific DAOA SNPs and SCZ, BD and DD. Publication bias was tested by Begg's test and funnel plot, and heterogeneity was assessed by the Cochran's chi-square-based Q statistic and the inconsistency index (I(2)). Moreover, the robustness of the findings was estimated by cumulative meta-analysis. DAOA genetic polymorphisms (M15, M18 and M23) were not found to confer a statistically significant increased risk of SCZ, BD or DD in the overall sample, or in Caucasians and Asians following subgroup analysis. The current study indicated that M15, M18 and M23 might not be the risk factor for SCZ, BD or DD. However, further studies are required to provide robust evidence to estimate the association between DAOA polymorphisms and psychiatric disorders.

Schizophrenia: brain morphology and treatment aspects

Since the first findings of enlarged ventricles in computer tomography studies and with the development of MRIbased segmentation, brain morphology findings in schizophrenia point to abnormal structural findings in several brain regions involved in neuronal circuits [1]. One of the often cited environmental risk factors in schizophrenia is cannabis abuse. In an invited review, Malchow et al. [2], however, found inconclusive results with respect to alterations in brain morphology. They assume that chronic cannabis abuse may induce structural changes, whereas in first-episode and high-risk patients, studies need replication. In subjects at high risk and patients with schizophrenia, the gyrification index as a measure of cortico-cortical connection differed from healthy controls in the frontal and parietal cortex [3]. This may be based on the neurodevelopmental abnormalities, since the gyrification pattern is determined during the perinatal period. Accordingly, in a recent postmortem study, a reduced gyrification index has been observed in the parietal cortex in schizophrenia [4] showing no differences between monozygotic twins compared to dizygotic twin pairs which points to the influence of different intrauterine and postnatal factors [5]. Postmortem studies with a resolution on the cellular and even molecular level with, for example, focus on synaptic structural elements [6] may contribute to elucidate the pathophysiology of schizophrenia. Williams et al. [7] investigated neuronal cell density and found decreased pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia patients. They additionally report decreased astrocyte density in the subgenual cingulated cortex and callosal genu for their sample [8], which extends neurobiological hypotheses on the dysfunction of astrocytes in maintaining synaptic stability. Investigations in healthy subjects are indispensable to elucidate risk factors influencing brain volumes and for exclusion of confounding factors such as other diseaserelated and treatment effects. Beside environmental factors, schizophrenia risk genes may contribute to altered brain structures. Trost et al. [9] found a dysbindin-1 gene variant to be associated with hippocampal and prefrontal gray matter volumes. On the molecular level, another risk gene such as brain-derived neurotrophic factor (BDNF) val66met polymorphism has been shown to affect the glutamate system [10]. Moreover, D-amino acid oxidase activator gene (DAOA) variation has been found to affect homovanillic acid levels in cerebrospinal fluid [11]. Unraveling neurobiological effects of such risk factors may contribute to develop a more personalized medicine in psychiatry [12]. Even effects of traditional neuroleptic treatment strategies may be influenced by genetic factors. Giegling et al. [13] found that three haplotype blocks, one among ankyrin repeat and kinase domain containing 1 (ANKK1) and two among dopamine receptor D2 (DRD2) genes, were associated with better clinical improvement in schizophrenia patients. These often are heavy smokers attempting to treat negative and cognitive symptoms themselves. In a clinical trial investigating effects of transdermal nicotine patch, Chen et al. [14], however, found no correlation with replacement doses and only a low smoking cessation rate. They recommend more effective smoking cessation programs for this group of hospitalized patients. Due to restricted therapeutic effects of current treatment strategies in severe psychiatric disorders, the editorial A. Schmitt (&) P. Falkai Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nusbaumstr. 7, 80336 Munich, Germany e-mail: Andrea.Schmitt@med.uni-muenchen.de

Schizophrenia: from risk genes to outcome and comorbidity

Springer-Verlag 2012 Dedicated to neurobiology, therapy and outcome of schizophrenia, this issue opens with the effects of the schizophrenia risk gene D-amino acid oxidase activator (DAOA) in healthy probands. During the last years, there is increasing evidence of the involvement of risk genes in the pathophysiology of severe psychiatric diseases, but neurobiological consequences of these gene variants are widely unknown. The DAOA polymorphism has been shown to be associated with a dysfunction of the glutamatergic NMDA receptor that in turn influences dopaminergic and serotonergic metabolism. Andreou et al. [1] investigated effects of DAOA SNPs on the major dopamine metabolite homovanillic acid (HVA), the serotonine metabolite 5-HIAA and the noradrenaline metabolite MHPG in cerebrospinal fluid of healthy probands. They found an association of two polymorphisms with HVA concentrations and one of them with 5-HIAA levels. This suggests DAOA gene variants to possibly affect dopamine turnover. Investigation of gene effects in healthy probands is recommended to avoid the influence of other disease factors and treatment, but as a next step neurobiological consequences should be assessed in schizophrenia patients. Ayesa-Arriola et al. [2] investigated the relationship between elevated plasma homocysteine levels and cognitive deficits in a large sample of first-episode schizophrenia patients and controls. However, despite very sophisticated neuropsychological testing, they found no evidence for a respective tie, which points to another neurobiological background than in neurological diseases. Since plasma

Genotypic Association of the DAOA Gene with Resting-State Brain Activity in Major Depression

Compelling evidence suggests that the glutamatergic system may contribute to the pathophysiology of major depression (MDD). While the D-amino acid oxidase activator (DAOA) gene can affect glutamatergic function, its genetic associations with MDD and abnormal resting-state brain activity have yet to be elucidated. A total of 488 patients with MDD and 480 controls were recruited to examine MDD association for the DAOA gene in a Chinese population, of whom 53 medication-free patients and 46 well-matched controls underwent resting-state functional magnetic resonance imaging for regional homogeneity (ReHo) analysis. The differences in ReHo between genotypes of interest were initially tested by the Student's t test, and the 2 × 2 (genotypes × disease status) ANOVA was then performed to identify the main effects of genotypes, disease status, and their interactions in MDD. Allelic association of the DAOA gene with MDD was observed for rs2391191, rs3918341, and rs778294 and haplotypic association for 2- and 3-SNP haplotypes. Six clusters in the cerebellum, right middle frontal gyrus and left middle temporal gyrus showed genotypic association between altered ReHo and rs2391191. The main effects of rs2391191 genotypes were found in the right culmen and right middle frontal gyrus. The left uvula and left middle temporal gyrus showed a genotypes × disease status interaction. Our results suggest that the DAOA gene may confer genetic risk of MDD. Genotypic effect of rs2391191 and its interaction with disease status may contribute to the altered ReHo in patients with MDD. Glutamatergic modulation may play an important role in alteration of the resting-state brain activities.

D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians

The d-amino acid oxidase activator (DAOA) protein regulates the function of d-amino oxidase (DAO), an enzyme that catalyzes the oxidative deamination of d-3,4-dihydroxyphenylalanine (D-DOPA) and d-serine. D-DOPA is converted to l-3,4-DOPA, a precursor of dopamine, whereas d-serine participates in glutamatergic transmission. We hypothesized that DAOA polymorphisms are associated with dopamine, serotonin and noradrenaline turnover in the human brain. Four single-nucleotide polymorphisms, previously reported to be associated with schizophrenia, were genotyped. Cerebrospinal fluid (CSF) samples were drawn by lumbar puncture, and the concentrations of the major dopamine metabolite homovanillic acid (HVA), the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the major noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured. Two of the investigated polymorphisms, rs3918342 and rs1421292, were significantly associated with CSF HVA concentrations. Rs3918342 was found to be nominally associated with CSF 5-HIAA concentrations. None of the polymorphisms were significantly associated with MHPG concentrations. Our results indicate that DAOA gene variation affects dopamine turnover in healthy individuals, suggesting that disturbed dopamine turnover is a possible mechanism behind the observed associations between genetic variation in DAOA and behavioral phenotypes in humans.

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

In modern medicine, vigorous efforts are being made in the prediction and prevention of diseases. Mental disorders are suitable candidates for the application of this program. The currently known neurobiological and psychosocial risk indicators for schizophrenia do not have a predictive power sufficient for selective prevention in asymptomatic patients at risk. However, once predictive basic and later pre-psychotic high risk symptoms of psychosis develop into the five-year initial prodrome, the impending outbreak of the disease can be predicted with high accuracy. Research findings suggest a differential strategy of indicated prevention with cognitive behavioral therapy in early initial prodromal states and low dosage atypical antipsychotics in late initial prodromal states. The most important future tasks are the improvement of the predictive power by risk enrichment and stratification, as well as the confirmation of the existing and the development of new prevention strategies, with a stronger focus on the etiology of the disorder. In addition, the prediction and prevention approach would benefit from the inclusion of risk symptoms in the DSM-5 criteria.

Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals.

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.

Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia

BackgroundPrevious linkage and association studies have implicated the D-amino acid oxidase activator gene (DAOA)/G30 locus or neighbouring region of chromosome 13q33.2 in the genetic susceptibility to both schizophrenia and bipolar disorder. Four single nucleotide polymorphisms (SNPs) within the D-amino acid oxidase (DAO) gene located at 12q24.11 have also been found to show allelic association with schizophrenia.MethodsWe used the case control method to test for genetic association with variants at these loci in a sample of 431 patients with schizophrenia, 303 patients with bipolar disorder and 442 ancestrally matched supernormal controls all selected from the UK population.ResultsTen SNPs spanning the DAOA locus were genotyped in these samples. In addition three SNPs were genotyped at the DAO locus in the schizophrenia sample. Allelic association was detected between the marker rs3918342 (M23), 3' to the DAOA gene and both schizophrenia (χ2 = 5.824 p = 0.016) and bipolar disorder (χ2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, χ2 = 3.675 p = 0.055) and rs1421292 (M24; χ2 = 3.499 p = 0.062). A test of association between a three marker haplotype comprising of the SNPs rs778293 (M22), rs3918342 (M23) and rs1421292 (M24) and schizophrenia gave a global empirical significance of p = 0.015. No evidence was found to confirm the association of genetic markers at the DAO gene with schizophrenia.ConclusionOur results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder.

Genetic variation in the DAOA gene complex: Impact on susceptibility for schizophrenia and on cognitive performance

IntroductionThe genetic region coding for d-amino acid oxidase activator (DAOA) is considered an intriguing susceptibility locus for schizophrenia. However, association studies have often resulted in conflicting findings, and the risk-conferring variants and their biological impact remain elusive. Our aim in this study was to investigate the relationship between DAOA variation and schizophrenia, and the influence of DAOA on cognitive performance. MethodsWe analyzed block structure and association patterns of a ~173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance. ResultsWe identified multiple haplotypes within the region containing the DAOA gene. Of these, one was significantly associated with schizophrenia, being over-represented in schizophrenia versus healthy controls. This haplotype was also associated with one aspect of cognitive performance, semantic fluency. Carriers of the risk haplotype showed better semantic fluency than non-carriers. ConclusionsWe report a significant effect of DAOA variation on risk for schizophrenia. Moreover, we identified a relationship between DAOA genetic variation and specific aspects of neurocognitive function. As the identified DAOA risk haplotype was associated with better performance on a semantic fluency measure, further work is required to identify the mechanism of DAOA action on CNS function, including the possibility of a role for balanced selection at this locus.

Association of DAOA polymorphisms with schizophrenia and clinical symptoms or therapeutic effects

The present study examined the correlation between variants in the d-amino acid oxidase activator ( DAOA) locus and clinical symptoms and response to antipsychotics in schizophrenia. Case–control analysis and the family-based association test (FBAT) were performed to investigate whether four single nucleotide polymorphisms (SNPs) at DAOA gene are associated with schizophrenia. The association between the DAOA risk haplotype and clinical symptoms were examined by the positive and negative syndrome scale (PANSS) and the brief psychiatric rating scale (BPRS). Our findings showed that the SNP rs947267 was significantly associated with schizophrenia in both case control and familial trio samples (A > C, χ 2 = 8.36, p = 0.004; Z = 2.335, p = 0.019), as well as with specific haplotypes, in particular those formed by the A allele of rs947267. In addition, the risk haplotype AAG was significantly correlated with negative, depression and cognitive impairment factors of PANSS, even with the BPRS change scores after 6-week treatment of atypical antipsychotic drugs ( p < 0.05). These results support the hypothesis that variations in DAOA may play a role in schizophrenia and clinical characteristics.