| 1 | Nature 2004 Apr 428: 522-8 |
|---|---|
| PMID | 15057823 |
| Title | The DNA sequence and analysis of human chromosome 13. |
| Abstract | Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 2 | J. Med. Genet. 2005 Mar 42: 193-204 |
| PMID | 15744031 |
| Title | The genetics of schizophrenia and bipolar disorder: dissecting psychosis. |
| Abstract | Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 3 | Trends Genet. 2005 Sep 21: 518-25 |
| PMID | 16009449 |
| Title | Schizophrenia: genes at last? |
| Abstract | Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is largely genetic, reflecting alleles of moderate to small effect in multiple genes. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and evidence is accumulating in favour of several positional candidate genes. Currently, the positional candidate genes for which we consider the evidence to be strong are those encoding dysbindin (DTNBP1) and neuregulin 1 (NRG1). For other genes, disrupted in schizophrenia 1 (DISC1), D-amino-acid oxidase (DAO), D-amino-acid oxidase activator (DAOA, formerly known as G72) and regulator of G-protein signalling 4 (RGS4), the data are promising but not yet compelling. The identification of these, and other susceptibility genes, will open up new avenues for research aimed at understanding the pathogenesis of schizophrenia, and will catalyse a re-appraisal of the classification of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 4 | Am J Psychiatry 2005 Nov 162: 2101-8 |
| PMID | 16263850 |
| Title | Genotype-phenotype studies in bipolar disorder showing association between the DAOA/G30 locus and persecutory delusions: a first step toward a molecular genetic classification of psychiatric phenotypes. |
| Abstract | The authors previously reported an association between the D-amino acid oxidase activator (DAOA)/G30 locus and both schizophrenia and bipolar affective disorder. Given the presumed role of DAOA/G30 in the neurochemistry of psychosis and its localization in a schizophrenia and bipolar affective disorder linkage region (13q34), it was hypothesized that the bipolar affective disorder finding would be mainly due to an association with psychotic features. The marker/haplotype associations obtained in a subset of 173 bipolar affective disorder patients with psychotic features were similar to those in the overall patient group, suggesting that stratification on the basis of psychotic features in general might be too crude a procedure. The authors therefore tested whether confining caseness to specific psychotic features would improve detection of genotype-phenotype correlations. In a logistic regression, "persecutory delusions" were found to be the only significant explanatory variable for the DAOA/G30 risk genotype among 21 OPCRIT symptoms of psychosis. The authors therefore tested for association between DAOA/G30 and bipolar affective disorder in the 90 cases with a history of persecutory delusions. Whereas this subset showed strong association (odds ratio=1.83 for the best marker), the remaining larger sample of 165 patients with no such history did not differ from comparison subjects, suggesting that the association between DAOA/G30 and bipolar affective disorder is due to persecutory delusions. This was confirmed in an independent study of 294 bipolar affective disorder patients and 311 comparison subjects from Poland, in which an association between bipolar affective disorder and DAOA/G30 was only seen when case definition was restricted to cases with persecutory delusions. These data suggest that bipolar affective disorder with persecutory delusions constitutes a distinct subgroup of bipolar affective disorder that overlaps with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 5 | Curr Opin Psychiatry 2006 Mar 19: 158-64 |
| PMID | 16612196 |
| Title | An update on the genetics of schizophrenia. |
| Abstract | This paper reviews recent molecular genetic studies of schizophrenia and evaluates claims implicating specific genes as susceptibility loci. Molecular genetic studies have identified several potential regions of linkage and two associated chromosomal abnormalities, and the evidence is accumulating in favour of several positional candidate genes. Currently, the strongest evidence for putative schizophrenia susceptibility loci relates to the genes encoding dysbindin (DTNBP1) and neuregulin (NRG1). For other genes, disrupted in schizophrenia (DISC1), D-amino acid oxidase activator (DAOA), regulator of G-protein signalling 4 (RGS4) and V-AKT murine thymoma viral oncogene homolog 1 (AKT1) the data are promising but not yet compelling. In the most convincing cases, the risk haplotypes appear to be associated with small effect sizes and do not fully explain the linkage findings that prompted each study. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research. Despite the accumulation of significant genetic data, however, the susceptibility variants have yet to be identified and detailed follow-up studies are now required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 6 | Eur. J. Hum. Genet. 2006 Jun 14: 660-8 |
| PMID | 16721402 |
| Title | Genetics of affective (mood) disorders. |
| Abstract | The enormous public health importance of mood disorders, when considered alongside their substantial heritabilities, has stimulated much work, predominantly in bipolar disorder but increasingly in unipolar depression, aimed at identifying susceptibility genes using both positional and functional molecular genetic approaches. Several regions of interest have emerged in linkage studies and, recently, evidence implicating specific genes has been reported; the best supported include BDNF and DAOA but further replications are required and phenotypic relationships and biological mechanisms need investigation. The complexity of psychiatric phenotypes is demonstrated by (a) the evidence accumulating for an overlap in genetic susceptibility across the traditional classification systems that divide disorders into schizophrenia and mood disorders, and (b) evidence suggestive of gene-environment interactions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 7 | Neuron 2006 Oct 52: 139-53 |
| PMID | 17015232 |
| Title | Neurobiology of schizophrenia. |
| Abstract | With its hallucinations, delusions, thought disorder, and cognitive deficits, schizophrenia affects the most basic human processes of perception, emotion, and judgment. Evidence increasingly suggests that schizophrenia is a subtle disorder of brain development and plasticity. Genetic studies are beginning to identify proteins of candidate genetic risk factors for schizophrenia, including dysbindin, neuregulin 1, DAOA, COMT, and DISC1, and neurobiological studies of the normal and variant forms of these genes are now well justified. We suggest that DISC1 may offer especially valuable insights. Mechanistic studies of the properties of these candidate genes and their protein products should clarify the molecular, cellular, and systems-level pathogenesis of schizophrenia. This can help redefine the schizophrenia phenotype and shed light on the relationship between schizophrenia and other major psychiatric disorders. Understanding these basic pathologic processes may yield novel targets for the development of more effective treatments. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 8 | Schizophr Bull 2006 Jan 32: 9-16 |
| PMID | 16319375 |
| Title | Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. |
| Abstract | It has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent Emil Kraepelin's traditional dichotomous classification of the so-called "functional" psychoses and form the basis of modern diagnostic practice. However, findings emerging from many fields of psychiatric research do not fit well with this model. In particular, the pattern of findings emerging from genetic studies shows increasing evidence for an overlap in genetic susceptibility across the traditional classification categories-including association findings at DAOA(G72), DTNBP1 (dysbindin), COMT, BDNF, DISC1, and NRG1. The emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, DISC1 and NRG1 may confer susceptibility to a form of illness with mixed features of schizophrenia and mania. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualization for psychiatric research rather than continuing to rely heavily on the traditional Kraepelinian dichotomy. As psychosis susceptibility genes are identified and characterized over the next few years, this will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 9 | Schizophr. Res. 2006 Oct 87: 15-20 |
| PMID | 16842973 |
| Title | No association of G72 and D-amino acid oxidase genes with schizophrenia. |
| Abstract | The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 10 | Neuropsychopharmacology 2006 Sep 31: 2022-32 |
| PMID | 16554747 |
| Title | The G72/G30 gene complex and cognitive abnormalities in schizophrenia. |
| Abstract | A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 11 | Neuropsychopharmacology 2006 Sep 31: 2022-32 |
| PMID | 16554747 |
| Title | The G72/G30 gene complex and cognitive abnormalities in schizophrenia. |
| Abstract | A recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for D-amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p=0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p=0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 12 | Arch. Gen. Psychiatry 2006 Apr 63: 366-73 |
| PMID | 16585465 |
| Title | Variation at the DAOA/G30 locus influences susceptibility to major mood episodes but not psychosis in schizophrenia and bipolar disorder. |
| Abstract | Variation at the DAOA/G30 locus has been described to be associated with both schizophrenia and bipolar disorder, but there is little consistency between studies of the tested polymorphisms or variants showing association. To obtain a stringent replication of association in large samples of both disorders using consistent clinical and laboratory methods, and to test the hypothesis that association at DAOA/G30 identifies an underlying domain of psychopathological abnormalities that cuts across traditional diagnostic categories. A systematic study of polymorphisms at DAOA/G30 using genetic case-control association analysis. Subjects were unrelated and ascertained from general psychiatric inpatient and outpatient services. White persons from the United Kingdom meeting criteria for DSM-IV schizophrenia (n = 709) or bipolar I disorder (n = 706) and 1416 ethnically matched controls. Nine polymorphisms that tag common genetic variations at DAOA/G30 were genotyped in all of the individuals, and comparisons were made between affected and unaffected individuals. We identified significant association (P = .01-.047) between 3 single-nucleotide polymorphisms and bipolar disorder but failed to find association with schizophrenia. Analyses across the traditional diagnostic categories revealed significant evidence (P = .002-.02) for association with 4 single-nucleotide polymorphisms in the subset of cases (n = 818) in which episodes of major mood disorder had occurred (gene-wide P = .009). We found a similar pattern of association in bipolar cases and in schizophrenia cases in which individuals had experienced major mood disorder. In contrast, we found no evidence for association in the subset of cases (n = 1153) in which psychotic features occurred (all P>.08). Despite being originally described as a schizophrenia susceptibility locus, our data suggest that variation at the DAOA/G30 locus does not primarily increase susceptibility for prototypical schizophrenia or psychosis. Instead, our results imply that variation at the DAOA/G30 locus influences susceptibility to episodes of mood disorder across the traditional bipolar and schizophrenia categories. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 13 | Nervenarzt 2006 Nov 77 Suppl 2: S65-74; quiz S75-6 |
| PMID | 17072567 |
| Title | [Advances in neurobiological understanding of schizophrenia. Perspectives for new therapeutic concepts]. |
| Abstract | Causal treatment options for schizophrenia are lacking due to our restricted knowledge of its etiology and pathogenesis. However, recently three postulated disposition genes for schizophrenia have been increasingly better confirmed: dysbindin, neuregulin-1, and G(72)/DAOA genes. These genes code proteins involved in processes ranging from brain development to the maintenance of glutamatergic transmission in the mature brain. Current interpretation of neuroanatomical findings points at reminiscences of disturbed brain development and a loss of nonneuronal elements, the so-called neuropil, as a correlate of brain atrophy. This reduction in neuropil is mainly caused by synaptic elements. Biochemical findings supporting this show that besides the dopaminergic and serotonergic system, glutamatergic transmission is also disturbed in schizophrenia. All these findings fit very well with the presumed functions of the disposition genes. Hypothesis-free approaches in structural brain imaging and the combination of functional imaging with relevant gene variants open new avenues for using markers from brain imaging to improve the diagnosis of schizophrenia and judge the response to neuroleptic treatment. Despite the enormous increase in knowledge for example in genetic research, the risk variants known until now provide no contribution to early diagnosis of schizophrenia. Furthermore, pharmacogenetics is currently unable to give a clear answer as to whether a single patient is responding to treatment or not. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 14 | Psychiatr. Genet. 2007 Oct 17: 313 |
| PMID | 17728673 |
| Title | No association between polymorphisms of DAO and DAOA genes and homicidal behaviors in Korean schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 15 | Mol. Psychiatry 2007 Sep 12: 795-6 |
| PMID | 17767147 |
| Title | DAOA ARG30LYS and verbal memory function in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 16 | Schizophr Bull 2007 Nov 33: 1343-53 |
| PMID | 17329232 |
| Title | eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? |
| Abstract | Bipolar disorder and schizophrenia share common chromosomal susceptibility loci and many risk-promoting genes. Oligodendrocyte cell loss and hypomyelination are common to both diseases. A number of environmental risk factors including famine, viral infection, and prenatal or childhood stress may also predispose to schizophrenia or bipolar disorder. In cells, related stressors (starvation, viruses, cytokines, oxidative, and endoplasmic reticulum stress) activate a series of eIF2-alpha kinases, which arrest protein synthesis via the eventual inhibition, by phosphorylated eIF2-alpha, of the translation initiation factor eIF2B. Growth factors increase protein synthesis via eIF2B activation and counterbalance this system. The control of protein synthesis by eIF2-alpha kinases is also engaged by long-term potentiation and repressed by long-term depression, mediated by N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors. Many genes reportedly associated with both schizophrenia and bipolar disorder code for proteins within or associated with this network. These include NMDA (GRIN1, GRIN2A, GRIN2B) and metabotropic (GRM3, GRM4) glutamate receptors, growth factors (BDNF, NRG1), and many of their downstream signaling components or accomplices (AKT1, DAO, DAOA, DISC1, DTNBP1, DPYSL2, IMPA2, NCAM1, NOS1, NOS1AP, PIK3C3, PIP5K2A, PDLIM5, RGS4, YWHAH). They also include multiple gene products related to the control of the stress-responsive eIF2-alpha kinases (IL1B, IL1RN, MTHFR, TNF, ND4, NDUFV2, XBP1). Oligodendrocytes are particularly sensitive to defects in the eIF2B complex, mutations in which are responsible for vanishing white matter disease. The convergence of natural and genetic risk factors on this area in bipolar disorder and schizophrenia may help to explain the apparent vulnerability of this cell type in these conditions. This convergence may also help to reconcile certain arguments related to the importance of nature and nurture in the etiology of these psychiatric disorders. Both may affect common stress-related signaling pathways that dictate oligodendrocyte viability and synaptic plasticity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 17 | Neurosci. Lett. 2007 Oct 426: 97-100 |
| PMID | 17890006 |
| Title | D-amino acid oxidase (DAO) genotype and mood symptomatology in schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 18 | Biol. Psychiatry 2007 May 61: 1195-9 |
| PMID | 17055463 |
| Title | Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. |
| Abstract | schizophrenia is a complex psychiatric disorder with a strong genetic component. Past linkage studies have implicated several chromosomal regions in the etiology of schizophrenia. Within these regions, several genes have been identified via candidate gene association studies as strong schizophrenia susceptibility loci, including DAO, DAOA, DISC1, DTNBP1, and RGS4. The present study attempted to replicate these association findings by analyzing a total of 120 markers across these genes in 311 schizophrenia subjects, 140 schizoaffective subjects, and 291 control subjects. Our study found no association for DAOA and DTNBP1 with schizophrenia. Although no association was seen with DAOA and DTNBP1, several other markers in the other genes resulted in significant association with schizophrenia (p < .05). However, after a conservative Bonferroni correction for multiple testing, only one marker, rs3918346, within DAO remained significant (odds ratio = 1.71, confidence interval = 1.32-2.22, p = 4 x 10(-5)). This significant association was concordant with previous DAO genetic findings. Our results significantly support DAO as a susceptibility locus for schizophrenia and offer some support for the implication of both RGS4 and DISC1 in the etiology of schizophrenia. However, we see no evidence to support either DAOA or DTNBP1 as schizophrenia disease loci. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 19 | Neurosci. Lett. 2007 Apr 416: 96-100 |
| PMID | 17293043 |
| Title | Association of DAOA polymorphisms with schizophrenia and clinical symptoms or therapeutic effects. |
| Abstract | 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, chi(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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 20 | Hum. Genet. 2007 Feb 120: 889-906 |
| PMID | 17006672 |
| Title | Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. |
| Abstract | Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 21 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Oct 144B: 949-53 |
| PMID | 17492767 |
| Title | Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample. |
| Abstract | The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675-13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 22 | Biol. Psychiatry 2007 Oct 62: 784-92 |
| PMID | 17336946 |
| Title | Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. |
| Abstract | Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 23 | Biol. Psychiatry 2007 Oct 62: 784-92 |
| PMID | 17336946 |
| Title | Impact of schizophrenia candidate genes on schizotypy and cognitive endophenotypes at the population level. |
| Abstract | Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia. We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated. The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected. The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 24 | Neuromolecular Med. 2007 -1 9: 169-77 |
| PMID | 17627036 |
| Title | Association analyses of the DAOA/G30 and D-amino-acid oxidase genes in schizophrenia: further evidence for a role in schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 25 | Biol. Psychiatry 2008 Sep 64: 438-42 |
| PMID | 18466879 |
| Title | Association of a nonsynonymous variant of DAOA with visuospatial ability in a bipolar family sample. |
| Abstract | Bipolar disorder and schizophrenia are hypothesized to share some genetic background. In a two-phase study, we evaluated the effect of five promising candidate genes for psychotic disorders, DAOA, COMT, DTNBP1, NRG1, and AKT1, on bipolar spectrum disorder, psychotic disorder, and related cognitive endophenotypes in a Finnish family-based sample ascertained for bipolar disorder. In initial screening of 362 individuals from 63 families, we found only marginal evidence for association with the diagnosis-based dichotomous classification. Those associations did not strengthen when we genotyped the complete sample of 723 individuals from 180 families. We observed a significant association of DAOA variants rs3916966 and rs2391191 with visuospatial ability (Quantitative Transmission Disequilibrium Test [QTDT]; p = 4 x 10(-6) and 5 x 10(-6), respectively) (n = 159) with the two variants in almost complete linkage disequilibrium. The COMT variant rs165599 also associated with visuospatial ability, and in our dataset, we saw an additive effect of DAOA and COMT variants on this neuropsychological trait. The ancestral allele (Arg) of the nonsynonymous common DAOA variant rs2391191 (Arg30Lys) was found to predispose to impaired performance. The DAOA gene may play a role in predisposing individuals to a mixed phenotype of psychosis and mania and to impairments in related neuropsychological traits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 26 | Am J Psychiatry 2008 Apr 165: 497-506 |
| PMID | 18198266 |
| Title | No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. |
| Abstract | The authors carried out a genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF). This study tested the hypothesis of association of schizophrenia with common single nucleotide polymorphisms (SNPs) in these genes using the largest sample to date that has been collected with uniform clinical methods and the most comprehensive set of SNPs in each gene. The sample included 1,870 cases (schizophrenia and schizoaffective disorder) and 2,002 screened comparison subjects (i.e. controls), all of European ancestry, with ancestral outliers excluded based on analysis of ancestry-informative markers. The authors genotyped 789 SNPs, including tags for most common SNPs in each gene, SNPs previously reported as associated, and SNPs located in functional domains of genes such as promoters, coding exons (including nonsynonymous SNPs), 3' untranslated regions, and conserved noncoding sequences. After extensive data cleaning, 648 SNPs were analyzed for association of single SNPs and of haplotypes. Neither experiment-wide nor gene-wide statistical significance was observed in the primary single-SNP analyses or in secondary analyses of haplotypes or of imputed genotypes for additional common HapMap SNPs. Results in SNPs previously reported as associated with schizophrenia were consistent with chance expectation, and four functional polymorphisms in COMT, DRD2, and HTR2A did not produce nominally significant evidence to support previous evidence for association. It is unlikely that common SNPs in these genes account for a substantial proportion of the genetic risk for schizophrenia, although small effects cannot be ruled out. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 27 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Sep 147B: 914-7 |
| PMID | 18165970 |
| Title | Association of DAO and G72(DAOA)/G30 genes with bipolar affective disorder. |
| Abstract | There is growing evidence of partial aetiological overlap between schizophrenia and bipolar disorder (BP) from linkage analysis, genetic epidemiology and molecular genetics studies. In the present study we investigated whether individual polymorphisms or haplotypes of the DAO and G72(DAOA)/G30 genes, which have been previously implicated in schizophrenia, are also associated with bipolar disorder. For each gene, we genotyped 213 cases and 197 controls for SNPs previously associated with schizophrenia: rs2111902 (MDAAO-4), rs3918346 (MDAAO-5), rs3741775 (MDAAO-6) and rs3918347 (MDAAO-7) in DAO and rs746187 (M7), rs3916966 (M13), rs2391191 (M15) and rs3916972 (M25) in G72. Although none of the individual SNPs in these genes reached statistical significance, we found haplotype wise associations with bipolar disorder for both genes. These included a two-SNP haplotype in DAO (rs2111902-A and rs3918346-T; global P = 0.003, individual P = 0.002, Z = 3.1) and a two-SNP haplotype for G72(DAOA)/G30 (rs746187-G and rs3916972-G; global P = 0.05; individual P = 0.005, Z = 2.81). However, we found no evidence for an epistatic interaction between the SNPs and/or haplotypes of the two genes. In summary, our findings provide some support for the individual involvement of DAO and G72(DAOA)/G30 in the etiology of bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 28 | Eur Arch Psychiatry Clin Neurosci 2008 Jun 258 Suppl 2: 37-40 |
| PMID | 18516516 |
| Title | Common risk genes for affective and schizophrenic psychoses. |
| Abstract | The familial-genetic relationship between affective and schizophrenic disorders is receiving a re-emergence of interest. The reasons are a series of cross-diagnostic molecular-genetic discoveries: specific alleles in the genes for dysbindin (DTNBP1), neuregulin (NRG1) and DAOA (G72/G30) reveal associations for each of both groups of disorders in the same direction in some but not all reported studies. These findings cannot just be false positives because of confirming metaanalyses. Furthermore there is some pathophysiological support: the mentioned genes are involved in biochemical pathways, which are contributing to both disorders partly in a similar and partly in a different manner. The new levels of evidence enrich the classical continuity/discontinuity debate on the relationship between both groups of disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 29 | BMC Psychiatry 2008 -1 8: 94 |
| PMID | 19077230 |
| Title | Investigation of G72 (DAOA) expression in the human brain. |
| Abstract | Polymorphisms at the G72/G30 locus on chromosome 13q have been associated with schizophrenia or bipolar disorder in more than ten independent studies. Even though the genetic findings are very robust, the physiological role of the predicted G72 protein has thus far not been resolved. Initial reports suggested G72 as an activator of D-amino acid oxidase (DAO), supporting the glutamate dysfunction hypothesis of schizophrenia. However, these findings have subsequently not been reproduced and reports of endogenous human G72 mRNA and protein expression are extremely limited. In order to better understand the function of this putative schizophrenia susceptibility gene, we attempted to demonstrate G72 mRNA and protein expression in relevant human brain regions. The expression of G72 mRNA was studied by northern blotting and semi-quantitative SYBR-Green and Taqman RT-PCR. Protein expression in human tissue lysates was investigated by western blotting using two custom-made specific anti-G72 peptide antibodies. An in-depth in silico analysis of the G72/G30 locus was performed in order to try and identify motifs or regulatory elements that provide insight to G72 mRNA expression and transcript stability. Despite using highly sensitive techniques, we failed to identify significant levels of G72 mRNA in a variety of human tissues (e.g. adult brain, amygdala, caudate nucleus, fetal brain, spinal cord and testis) human cell lines or schizophrenia/control post mortem BA10 samples. Furthermore, using western blotting in combination with sensitive detection methods, we were also unable to detect G72 protein in a number of human brain regions (including cerebellum and amygdala), spinal cord or testis. A detailed in silico analysis provides several lines of evidence that support the apparent low or absent expression of G72. Our results suggest that native G72 protein is not normally present in the tissues that we analysed in this study. We also conclude that the lack of demonstrable G72 expression in relevant brain regions does not support a role for G72 in modulation of DAO activity and the pathology of schizophrenia via a DAO-mediated mechanism. In silico analysis suggests that G72 is not robustly expressed and that the transcript is potentially labile. Further studies are required to understand the significance of the G72/30 locus to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 30 | J Psychiatr Res 2008 Mar 42: 278-88 |
| PMID | 17408693 |
| Title | Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. |
| Abstract | Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 31 | Curr Psychiatry Rep 2008 Apr 10: 178-89 |
| PMID | 18474212 |
| Title | The genetics of psychotic bipolar disorder. |
| Abstract | Psychotic features, defined as delusions or hallucinations, commonly occur in bipolar disorder (BP) and may be indicative of a more homogeneous form of the illness, with possible etiologic ties to schizophrenia. Several studies have shown that psychotic features aggregate in bipolar families, and increased interest in the molecular genetics of psychotic BP is emerging. Although preliminary, linkage studies of psychotic BP show replicated evidence for suggestive genome-wide linkage to chromosomes 8p and 13q, which have been implicated in prior linkage studies of schizophrenia and BP. Association studies of psychotic BP and subtypes such as mood-incongruent psychotic BP have uncovered modest positive results for several candidate schizophrenia susceptibility genes, including dysbindin, DAOA/G30, Disrupted-in-schizophrenia-1, and neuregulin 1. These tentative results are consistent with the hypothesis that the subphenotype of psychotic BP may represent a clinical manifestation of "overlap" genes between schizophrenia and mood disorder syndromes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 32 | Schizophr. Res. 2008 Jan 98: 89-97 |
| PMID | 18023149 |
| Title | Allelic association of G72/G30 with schizophrenia and bipolar disorder: a comprehensive meta-analysis. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 33 | Biol. Psychiatry 2008 Sep 64: 428-33 |
| PMID | 18423426 |
| Title | Genetic variation in the DAOA (G72) gene modulates hippocampal function in subjects at high risk of schizophrenia. |
| Abstract | Strong evidence exists for an association between genetic variation in the gene DAOA (D-amino acid oxidase activator, also known as G72) and risk for schizophrenia. Preliminary evidence in healthy control subjects has implicated genetic variation in the DAOA gene in the modulation of hippocampal complex and prefrontal cortex activation. Assessment was performed on 61 subjects at high genetic risk of schizophrenia for familial reasons. All subjects were genotyped for two closely linked single nucleotide polymorphisms in the DAOA gene complex, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with schizophrenia. The effect of genotype on brain activation was assessed with functional magnetic resonance imaging data gathered during performance of the verbal initiation section of the Hayling Sentence Completion Task. Differences between DAOA genotype groups were seen in the activation of the left hippocampus and parahippocampus in the contrast of sentence completion versus rest. In addition the DAOA genotype groups differed in their recruitment of right inferior prefrontal cortex in relation to increasing task difficulty. The effects of genotype on brain activation could not be explained in terms of differences in grey matter density. These results support the view that genetic variation in the DAOA gene influences hippocampal complex and prefrontal cortex function, an effect that might be particularly prominent in the context of enhanced genetic risk for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 34 | Schizophr. Res. 2008 Aug 103: 169-77 |
| PMID | 18541412 |
| Title | Genetic variation in the DAOA gene complex: impact on susceptibility for schizophrenia and on cognitive performance. |
| Abstract | The 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. We analyzed block structure and association patterns of an approximately 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. We 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. We 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 35 | Neurosci. Lett. 2009 Sep 462: 105-8 |
| PMID | 19560517 |
| Title | Evidence for transmission disequilibrium at the DAOA gene locus in a schizophrenia family sample. |
| Abstract | Recently, the DAOA gene locus on chromosome 13q32-q34 has been implicated in the etiology of schizophrenia. We genotyped three single-nucleotide polymorphisms (SNPs: rs778294, rs779293 and rs3918342) in this region in 126 Chinese family trios. In this study, we have identified statistically significant transmission disequilibrium in two markers rs778293 (P=0.01) and rs3918342 (P=0.02), and a highly significant under-transmission between haplotype CAT (P=0.0005) and schizophrenia. The results provide further evidence to support that DAOA gene locus is involved in conferring susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 36 | Neuroscience 2009 Nov 164: 331-43 |
| PMID | 19358880 |
| Title | The genetics of bipolar disorder. |
| Abstract | Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) have raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 37 | Neuropsychobiology 2009 -1 59: 142-50 |
| PMID | 19439994 |
| Title | DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. |
| Abstract | Several studies of the dystrobrevin-binding protein 1 gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid oxidase (DAO), DAO activator (DAOA, G72), and metabotropic glutamate receptor 3 (GRM3) genes have suggested an association between variants of these genes and schizophrenia. In a replication attempt, single-nucleotide polymorphisms of the DTNBP1, NRG1, DAO, DAOA, and GRM3 genes were analyzed in three independent Scandinavian schizophrenia case-control samples. One DTNBP1 and three GRM3 single-nucleotide polymorphisms showed nominal significant associations to the disease. However, after correction for multiple testing, there were no statistically significant allele, genotype or haplotype case-control differences. The present Scandinavian results do not verify previous associations between the analyzed DTNBP1, NRG1, DAO, DAOA, and GRM3 gene polymorphisms and schizophrenia. Additional studies and meta-analyses are warranted to shed further light on these relationships. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 38 | Schizophr. Res. 2009 Apr 109: 80-5 |
| PMID | 19237267 |
| Title | Association study of the G72 gene with schizophrenia in a Japanese population: a multicenter study. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 39 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Aug 33: 1046-9 |
| PMID | 19482054 |
| Title | G72 gene is associated with susceptibility to methamphetamine psychosis. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 40 | J. Neurogenet. 2009 -1 23: 341-52 |
| PMID | 19225952 |
| Title | Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip). |
| Abstract | It has been difficult to identify disease-causing alleles in schizophrenia (SZ) and bipolar disorder (BD) candidate genes. One reason is that responsible functional variants may exist in unidentified regulatory domains. With the advent of microarray technology and high throughput sequencing, however, it is now feasible to screen genes for such regulatory domains relatively easily by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. In ChIP-chip, regulatory sequences can be captured from chromatin immunoprecipitates prepared with antibodies against covalently modified histones that mark certain regulatory domains; DNA extracted from such immunoprecipitates can then be used as microarray probes. As a first step toward demonstrating the feasibility of this approach in psychiatric genetics, we used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. Genetic variants within these regions would be of interest to study as potential disease-associated alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 41 | Behav Brain Funct 2009 -1 5: 28 |
| PMID | 19586533 |
| Title | 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. |
| Abstract | Previous 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. We 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. Ten 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 (chi2 = 5.824 p = 0.016) and bipolar disorder (chi2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, chi2 = 3.675 p = 0.055) and rs1421292 (M24; chi2 = 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. Our results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 42 | Biochem. Pharmacol. 2009 Dec 78: 1360-5 |
| PMID | 19591808 |
| Title | Commentary: genome-based CNS drug discovery: D-amino acid oxidase (DAAO) as a novel target for antipsychotic medications: progress and challenges. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 43 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 1007-12 |
| PMID | 19089835 |
| Title | G72/G30 (DAOA) and juvenile-onset mood disorders. |
| Abstract | The chromosome 13q region has been linked to bipolar disorder in a number of genome scans as well as focused linkage studies. Previously we identified linkage to the 13q32 region in a genome scan of 146 affected sibling pair families from Hungary with juvenile-onset mood disorders. Within this region are the overlapping genes G72/G30, with G72 now officially named as D-amino-acid oxidase activator (DAOA). This locus has been associated with panic disorder, schizophrenia, and bipolar disorder. In this study, we tested for association to 11 markers in these genes and mood disorders in a sample of 646 nuclear families identified with a proband with onset of a mood disorder before 14.9 years of age. We identified evidence for association to three markers within the gene (rs2391191, rs3918341, rs1935062), two of which had been associated with bipolar disorder in previous studies. When corrected for the number of markers tested, the results were no longer significant, however the prior evidence for association of this gene in multiple studies points to this gene as a potential contributor to juvenile-onset mood disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 44 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Dec 34: 1375-80 |
| PMID | 20600464 |
| Title | Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis. |
| Abstract | There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 45 | Neuroimage 2010 Nov 53: 1001-6 |
| PMID | 20005295 |
| Title | The effect of G72 genotype on neural correlates of memory encoding and retrieval. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 46 | Psychiatry Res 2010 Jul 178: 430-2 |
| PMID | 20471098 |
| Title | Influence of DAOA gene variants on antipsychotic response after switch to aripiprazole. |
| Abstract | We investigated possible influences of 3 single nucleotide polymorphisms in the d-amino acid oxidase activator (rs2391191, rs947267, rs3918342) on clinical outcomes and side effects in 86 Korean schizophrenia patients treated with aripiprazole for 8weeks, finding that individuals carrying rs2391191 A allele had significantly lower brief psychiatric rating scale scores than subjects carrying the G allele at each time point. Further research is needed to determine the role of DAOA on the response to antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 47 | Psychiatry Res 2010 Sep 179: 126-9 |
| PMID | 20483474 |
| Title | Testing the antagonistic pleiotropy model of schizophrenia susceptibility by analysis of DAOA, PPP1R1B, and APOL1 genes. |
| Abstract | schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance (DAOA and PPP1R1B) or protection against pathogens (APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 48 | Psychiatry Res 2010 Sep 179: 126-9 |
| PMID | 20483474 |
| Title | Testing the antagonistic pleiotropy model of schizophrenia susceptibility by analysis of DAOA, PPP1R1B, and APOL1 genes. |
| Abstract | schizophrenia is a common disease associated with reduced fertility. Therefore, the existence of common susceptibility alleles not removed by natural selection may be considered an evolutionary paradox. The antagonistic pleiotropy model, proposed to explain this paradox, states that an allele may be common because of its overall selective advantage, in spite of deleterious effects on specific traits. Recent work on DAOA, PPP1R1B, and APOL1 suggests that these genes present common alleles associated to increase risk of schizophrenia but conferring an overall selective advantage, related to better cognitive performance (DAOA and PPP1R1B) or protection against pathogens (APOL1). To test if these genes fit the antagonistic pleiotropy model, we searched for recent natural selection at these loci applying the long-range haplotype test on data from the HapMap Project; and performed case-control association analysis in a well-powered sample, including 301 schizophrenic patients and 604 controls from Spain. For DAOA and PPP1R1B, we genotyped the Single-nucleotide polymorphisms (SNPs) needed to replicate previous associations, while for APOL1, we genotyped 15 tagSNPs, and seven putative functional SNPs. We did not detect evidence of recent natural selection. Furthermore, we did not find significant associations. Thus, these genes do not fit the antagonistic pleiotropy model. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 49 | Eur Arch Psychiatry Clin Neurosci 2010 Apr 260: 209-15 |
| PMID | 19763662 |
| Title | DAOA/G72 predicts the progression of prodromal syndromes to first episode psychosis. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 50 | Biol. Psychiatry 2011 May 69: 1006-8 |
| PMID | 21215384 |
| Title | Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex. |
| Abstract | Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹??Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹??Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹??Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors. With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back). As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC. The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 51 | Biol. Psychiatry 2011 May 69: 1006-8 |
| PMID | 21215384 |
| Title | Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex. |
| Abstract | Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹??Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹??Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹??Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors. With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back). As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC. The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 52 | Int J Psychiatry Clin Pract 2011 Nov 15: 303-10 |
| PMID | 22122005 |
| Title | DAOA variants and schizophrenia: influence on diagnosis and treatment outcomes. |
| Abstract | The present study explored whether d-amino acid oxidase activator (DAOA) variants were associated with schizophrenia and whether they could predict the clinical outcomes of patients treated with various antipsychotics. Two hundred and twenty-one (221) patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for seven DAOA single-nucleotide polymorphisms (SNPs) (rs3916966, rs3916967, rs2391191, rs3916968, rs7139958, rs9558571 and rs778293). We also administered baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), to patients with schizophrenia. None of the SNPs under investigation was associated with the development of schizophrenia. However, the rs7139958 AA and rs9558571 TT as well as the rs7139958 A and rs9558571 T genotypes were associated with higher scores on the PANSS positive subscale among patients with schizophrenia, possibly reflecting their greater susceptibility to the development of more severe positive symptoms. No other allele, genotype, or haplotype under investigation was significantly associated with any of the clinical parameters, including clinical improvement, in patients with schizophrenia. Our results suggested that rs7139958 and rs9558571 SNPs may be associated with more severe baseline positive symptoms in patients with schizophrenia. However, further research is needed to draw more definitive conclusions given the limitations of our study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 53 | Neuropsychopharmacology 2011 Jul 36: 1747-53 |
| PMID | 21508934 |
| Title | Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia. |
| Abstract | In light of current etiological concepts the glutamatergic system plays an essential role for the pathophysiology of the disorder, offering multiple options for new treatment strategies. The D-amino oxidase activator (DAOA) gene is closely connected to the glutamatergic system and its therapeutic and pathophysiological relevance for schizophrenia is therefore intensively debated. In a further step to shed light on the role of DAOA in schizophrenia, we aimed to investigate the association of the functional DAOA Arg30Lys (rs2391191) variant and cortical thickness in schizophrenia. Cortical thickness was computed by an automated surface-based technique (FreeSurfer) in 52 genotyped patients with schizophrenia and 42 healthy controls. Cortical thickness of the entire cortex was compared between risk carriers and non-risk carriers regarding the Arg30Lys polymorphism in patients and healthy controls on the basis of a node-by-node procedure and an automated clustering approach. Risk carriers with schizophrenia show significantly thinner cortex in two almost inversely arranged clusters on the left and right hemisphere comprising middle temporal, inferior parietal, and lateral occipital cortical areas. The clusters encompass an area of 1174 mm(2) (left) and 1156 mm(2) (right). No significant effect was observed in healthy controls.The finding of our study that the Arg30Lys risk variant is associated with a distinct cortical thinning provides new evidence for the pathophysiological impact of DAOA in schizophrenia. The affected areas are mostly confined to cortical regions with a crucial role in the ToM network and visual processing, which both can be influenced by glutamatergic modulation. Our finding thus underlines the importance of DAOA and related glutamatergic processes as a putative target for therapeutic interventions in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 54 | Bipolar Disord 2011 Mar 13: 198-207 |
| PMID | 21443574 |
| Title | Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia. |
| Abstract | The D-amino acid oxidase activator (DAOA, or G72) is involved in the oxidation of D-serine, an endogenous modulator of N-methyl-D-aspartate receptors and thus represents an important candidate in psychotic disorders. Several studies reported the DAOA/G72 gene to be associated with schizophrenia (SZ) and bipolar disorder (BD); however, the associated polymorphisms varied between SZ and BD. This study attempts to replicate the DAOA/G72 findings in BD and to conduct subgroup analyses based on the presence or absence of psychotic symptoms. Five polymorphisms of the DAOA/G72 gene (rs1341402, rs1935062, rs2391191, rs947267, and rs778294) were analysed for association with BD in a family-based study design (303 core families including 916 individuals). We also conducted a meta-analysis of DAOA/G72 polymorphisms in BD and SZ. Marker rs1935062 was significantly associated with BD diagnosis in our sample (Z-score for C-allele= -2.33, p=0.02, uncorrected for genome-wide multiple comparisons). When we examined the subset of BD patients with psychotic symptoms (157 families), no significant results were obtained. Our meta-analysis yielded negative findings for DAOA/G72 markers in BD and positive findings for marker rs2391191 in SZ in East Asians. However, significant heterogeneity across studies limits interpretation. Our results provide evidence that suggests a possible role of the DAOA/G72 gene in BD and SZ. Marker rs1935062 may be specifically associated with BD, while marker rs2391191 may be associated with SZ but not with BD. Together with previous studies, these findings suggest that the DAOA/G72 gene confers susceptibility to both BD and SZ, but that different polymorphisms may potentially differentiate between these two disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 55 | Hum Brain Mapp 2012 Jan 33: 143-53 |
| PMID | 21391259 |
| Title | Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency. |
| Abstract | The D-Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D-amino acid oxidase (DAO), which metabolizes D-serine, a co-agonist of NMDA-type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. To examine the influence of G72 variation on brain function in the healthy population. Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task-dependent functional connectivity during word generation was compared between different rs746187 genotypes. G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task-dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D-amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 56 | Eur Arch Psychiatry Clin Neurosci 2012 Oct 262: 549-56 |
| PMID | 22454242 |
| Title | D-amino acid oxidase activator gene (DAOA) variation affects cerebrospinal fluid homovanillic acid concentrations in healthy Caucasians. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 57 | Mol Cytogenet 2012 -1 5: 2 |
| PMID | 22214315 |
| Title | Isochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder. |
| Abstract | A small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder. Karyotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms. We report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 58 | Neuropsychiatr Dis Treat 2013 -1 9: 1573-82 |
| PMID | 24143106 |
| Title | Evidence for single nucleotide polymorphisms and their association with bipolar disorder. |
| Abstract | Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 59 | Schizophr Bull 2013 May 39: 518-26 |
| PMID | 22499782 |
| Title | Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia. |
| Abstract | Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 60 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 64-9 |
| PMID | 23778016 |
| Title | Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia. |
| Abstract | Recently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 61 | Genet Test Mol Biomarkers 2013 Jun 17: 504-7 |
| PMID | 23495896 |
| Title | Investigation of epistasis between DAOA and 5HTR1A variants on clinical outcomes in patients with schizophrenia. |
| Abstract | In two recent studies of our group, rs10042486, a single-nucleotide polymorphism (SNP) within 5HTR1A, and rs7139958, a SNP within the d-amino acid oxidase activator (DAOA) were found to be associated with clinical improvement, as detected by the positive symptom subscale of the Positive and Negative Symptoms Scale (PANSS) in a sample 221 Korean schizophrenia patients treated with various antipsychotics. The existence of possible epistatic interactions between rs10042486 and rs7139958 influencing PANSS-positive subscale improvement scores in the same sample was investigated. No significant epistatic interaction was observed. Furthermore, the independent associations observed between rs10042486, rs7139958, and PANSS-positive subscale improvement scores in earlier studies were no longer significant when they were included in our model. Although limited by some methodological shortcomings, our results preliminarily point to the possibility that positive genetic associations observed in some samples could not be replicated in different samples because of the existence of consistent differences in the genotype frequencies of other genetic polymorphisms that epistatically interact with the specific variants under investigation in a given study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 62 | BMC Med. Genet. 2013 -1 14: 33 |
| PMID | 23497497 |
| Title | Schizophrenia susceptibility and NMDA-receptor mediated signalling: an association study involving 32 tagSNPs of DAO, DAOA, PPP3CC, and DTNBP1 genes. |
| Abstract | Recent studies supported associations between four NMDA-receptor-mediated signalling genes (D-amino acid oxidase, DAO; D-amino acid oxidase activator, DAOA; protein phosphatase 3 catalytic subunit gamma isoform, PPP3CC; dystrobrevin-binding protein 1, DTNBP1) and schizophrenia susceptibility, even though with contrasting results. In an attempt to replicate these findings for the first time in an Italian population, a panel of 32 tagSNPs was analysed in a representative case-control sample involving 879 subjects. An association in the allele frequency was observed for the estimated PPP3CC CAG triplotype in the SNP window rs4872499 T/C-rs11780915 A/G-rs13271367 G/A (pcorrect = 0.001). Similarly, the clustered genotype frequencies of the estimated/phased CAG triplotype differed between cases and controls (p = 0.004), with the carriers having a higher frequency in the control population (p = 0.002, odd ratio OR = 0.59, 95% confident interval CI: 0.43-0.82).Following the phenotypic dissection strategy, the analysis of single SNPs evidenced a protective effect in males of rs11780915 and rs13271367 in PPP3CC gene (pcorrect = 0.02, pcorrect = 0.04 respectively). Moreover the estimated/phased GT diplotype (rs2070586A/G-rs3741775G/T) carriers of the DAO gene were more highly represented in female controls (p = 0.017, OR = 0.58, 95% CI: 0.37-0.90), as were the estimated/phased CAG triplotype carriers of the PPP3CC gene in females (p = 0.01, OR = 0.53, 95% CI: 0.32-0.87). In addition, we performed an interaction analysis, and a 66% (p = 0.003, OR = 0.34, 95% CI: 0.17-0.70) lower risk of developing schizophrenia for female (CAG + GT) carriers versus non-CAG or -GT carriers was observed. For DTNBP1, we found a protective effect in males for the rs6459409 (pcorrect = 0.02) and the estimated/phased CT diplotype (rs6459409-rs9476886) carriers (p = 3x10-4, OR = 0.46, 95% CI: 0.30-0.70).In relation to diagnostic subtypes, the estimated/phased DAO GT diplotype and PPP3CC CAG triplotype female carriers were found to show relative risk ratio (RRR) values of 0.52 and 0.54 lower risk for a paranoid phenotype respectively. Although the results are preliminary and needed replication in a larger sample, this study suggests that NMDA receptor-mediated signalling genes (DAO, PPP3CC, DTNBP1) might be involved in schizophrenia pathogenic mechanisms related to gender. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 63 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Mar 162B: 191-200 |
| PMID | 23335491 |
| Title | A combined study of genetic association and brain imaging on the DAOA gene in schizophrenia. |
| Abstract | While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting-state patients with schizophrenia, a two-stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging in 48 first-episode medication-free patients and 43 well-matched controls. 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 schizophrenia. The stage-1 study showed association of the DAOA and PSEN2 genes with schizophrenia in a small sample; the stage-2 study with an expanded sample confirmed the disease association for 2-SNP and 3-SNP haplotypes, and the cis-phase interactions between rs2391191 and some other SNPs in the DAOA gene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype × disease status interaction. In conclusion, the DAOA gene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 64 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Mar 162B: 191-200 |
| PMID | 23335491 |
| Title | A combined study of genetic association and brain imaging on the DAOA gene in schizophrenia. |
| Abstract | While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting-state patients with schizophrenia, a two-stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging in 48 first-episode medication-free patients and 43 well-matched controls. 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 schizophrenia. The stage-1 study showed association of the DAOA and PSEN2 genes with schizophrenia in a small sample; the stage-2 study with an expanded sample confirmed the disease association for 2-SNP and 3-SNP haplotypes, and the cis-phase interactions between rs2391191 and some other SNPs in the DAOA gene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype × disease status interaction. In conclusion, the DAOA gene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 65 | Theor Biol Med Model 2013 -1 10: 3 |
| PMID | 23286827 |
| Title | Structural, phylogenetic and docking studies of D-amino acid oxidase activator (DAOA), a candidate schizophrenia gene. |
| Abstract | schizophrenia is a neurodegenerative disorder that occurs worldwide and can be difficult to diagnose. It is the foremost neurological disorder leading to suicide among patients in both developed and underdeveloped countries. D-amino acid oxidase activator (DAOA), also known as G72, is directly implicated in the glutamateric hypothesis of schizophrenia. It activates D-amino acid oxidase, which oxidizes D-serine, leading to modulation of the N-methyl-D-aspartate receptor. MODELLER (9v10) was utilized to generate three dimensional structures of the DAOA candidate gene. The HOPE server was used for mutational analysis. The Molecular Evolutionary Genetics Analysis (MEGA5) tool was utilized to reconstruct the evolutionary history of the candidate gene DAOA. AutoDock was used for protein-ligand docking and Gramm-X and PatchDock for protein-protein docking. A suitable template (1ZCA) was selected by employing BLASTp on the basis of 33% query coverage, 27% identity and E-value 4.9. The Rampage evaluation tool showed 91.1% favored region, 4.9% allowed region and 4.1% outlier region in DAOA. ERRAT demonstrated that the predicted model had a 50.909% quality factor. Mutational analysis of DAOA revealed significant effects on hydrogen bonding and correct folding of the DAOA protein, which in turn affect protein conformation. Ciona was inferred as the outgroup. Tetrapods were in their appropriate clusters with bifurcations. Human amino acid sequences are conserved, with chimpanzee and gorilla showing more than 80% homology and bootstrap value based on 1000 replications. Molecular docking analysis was employed to elucidate the binding mode of the reported ligand complex for DAOA. The docking experiment demonstrated that DAOA is involved in major amino acid interactions: the residues that interact most strongly with the ligand C28H28N3O5PS2 are polar but uncharged (Gln36, Asn38, Thr 122) and non-polar hydrophobic (Ile119, Ser171, Ser21, Ala31). Protein-protein docking simulation demonstrated two ionic bonds and one hydrogen bond involving DAOA. Lys-7 of the receptor protein interacted with Lys-163 and Asp-2037. Tyr-03 interacted with Arg-286 of the ligand protein and formed a hydrogen bond. The predicted interactions might serve to inhibit the disease-related allele. It is assumed that current bioinformatics methods will contribute significantly to identifying, analyzing and curing schizophrenia. There is an urgent need to develop effective drugs for schizophrenia, and tools for examining candidate genes more accurately and efficiently are required. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 66 | Hum Brain Mapp 2013 Sep 34: 2244-58 |
| PMID | 22438288 |
| Title | Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function. |
| Abstract | The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 67 | Genes Brain Behav. 2014 Jan 13: 104-17 |
| PMID | 23927712 |
| Title | Theory of mind and the social brain: implications for understanding the genetic basis of schizophrenia. |
| Abstract | Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging-based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 68 | J Affect Disord 2014 Oct 168: 91-7 |
| PMID | 25043320 |
| Title | DISC1-TSNAX and DAOA genes in major depression and citalopram efficacy. |
| Abstract | Major depressive disorder (MDD) is a common disease with high morbidity and still unsatisfying treatment response. Both MDD pathogenesis and antidepressant effect are supposed to be strongly affected by genetic polymorphisms. Among promising candidate genes, distrupted in schizophrenia 1 (DISC1), translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) were suggested since their regulator role in neurodevelopment, neuroplasticity and neurotransmission, and previous evidence of cross-involvement in major psychiatric diseases. The present paper investigated the role of 13 SNPs within the reported genes in MDD susceptibility through a case-control (n=320 and n=150, respectively) study and in citalopram efficacy (n=157). Measures of citalopram efficacy were response (4th week) and remission (12th week). Pharmacogenetic findings were tested in the STAR(?)D genome-wide dataset (n=1892) for replication. Evidence of association among rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) and MDD was found (p=0.004, p=0.0019, and p=0.008, respectively). A trend of association between remission and DISC1 rs821616 and DAOA rs778294 was detected, and confirmation was found for rs778294 by repeated-measure ANOVA (p=0.0008). In the STAR(?)D a cluster of SNPs from 20 to 40Kbp from DISC1 findings in the original sample was associated with citalopram response, as well as rs778330 (12,325bp from rs778294). Relatively small size of the original sample and focus on only three candidate genes. The present study supported a role of DISC1-TSNAX variants in MDD susceptibility. On the other hand, genetic regions around DAOA rs778294 and DISC1 rs6675281-rs1000731 may influence citalopram efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 69 | IEEE Trans Biomed Eng 2014 Mar 61: 946-56 |
| PMID | 24557696 |
| Title | A genetically informed, group FMRI connectivity modeling approach: application to schizophrenia. |
| Abstract | While neuroimaging data can provide valuable phenotypic information to inform genetic studies, the opposite is also true: known genotypes can be used to inform brain connectivity patterns from fMRI data. Here, we propose a framework for genetically informed group brain connectivity modeling. Subjects are first stratified according to their genotypes, and then a group regularized regression model is employed for brain connectivity modeling utilizing the time courses from a priori specified regions of interest (ROIs). With such an approach, each ROI time course is in turn predicted from all other ROI time courses at zero lag using a group regression framework which also incorporates a penalty based on genotypic similarity. Simulations supported such an approach when, as previously studies have indicated to be the case, genetic influences impart connectivity differences across subjects. The proposed method was applied to resting state fMRI data from schizophrenia and normal control subjects. Genotypes were based on D-amino acid oxidase activator (DAOA) single-nucleotide polymorphisms (SNPs) information. With DAOA SNPs information integrated, the proposed approach was able to more accurately model the diversity in connectivity patterns. Specifically, connectivity with the left putamen, right posterior cingulate, and left middle frontal gyri were found to be jointly modulated by DAOA genotypes and the presence of schizophrenia. We conclude that the proposed framework represents a multimodal analysis approach for incorporating genotypic variability into brain connectivity analysis directly. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 70 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jun 51: 89-98 |
| PMID | 24447945 |
| Title | Association between DAOA gene polymorphisms and the risk of schizophrenia, bipolar disorder and depressive disorder. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 71 | J Psychiatr Res 2015 Jan 60: 1-13 |
| PMID | 25287955 |
| Title | Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. |
| Abstract | Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 72 | Biomed Res Int 2015 -1 2015: 429253 |
| PMID | 26539492 |
| Title | Identification of pLG72-Induced Oxidative Stress Using Systemic Approaches. |
| Abstract | G72 is a schizophrenia-susceptible gene encoding a polypeptide with 153 amino acids. In 2002, it was originally proposed as an activator of D-amino acid oxidase (DAOA) that could enhance the activity of DAAO and subsequently reduce the neurotransmission of N-methyl-D-aspartate receptors. However, several controversial findings have been reported recently. Due to a number of inconsistent descriptions of pLG72's biofunctions, this study aims to identify the cellular effects induced by pLG72 in U87 cells using systems biology approaches. The analyses of transcriptomics and biological networks showed that pLG72 might be involved in the induction of oxidative stress. To confirm the in silico prediction, we tested and discovered that overexpression of pLG72 effectively enhanced reactive oxygen species (ROS) in U87 cells and, furthermore, this induction can be quenched by Tempol, a general ROS scavenger. Therefore, G72-transgenic mice presenting some psychiatric symptoms, along with the pLG72 level being significantly increased in the serum of patients with schizophrenia, have led us to propose that the ROS enhancement in mental diseases may be from the overexpression of pLG72 in brain cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 73 | Drug Des Devel Ther 2015 -1 9: 3471-80 |
| PMID | 26170631 |
| Title | Adaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms. |
| Abstract | schizophrenia (SZ), a chronic mental and heritable disorder characterized by neurophysiological impairment and neuropsychological abnormalities, is strongly associated with D-amino acid oxidase activator (DAOA, G72). Research studies emphasized that overexpression of DAOA may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like SZ. In the present study, a hybrid approach of comparative modeling and molecular docking followed by inhibitor identification and structure modeling was employed. Screening was performed by two-dimensional similarity search against selected inhibitor, keeping in view the physiochemical properties of the inhibitor. Here, we report an inhibitor compound which showed maximum binding affinity against four selected isoforms of DAOA. Docking studies revealed that Glu-53, Thr-54, Lys-58, Val-85, Ser-86, Tyr-87, Leu-88, Glu-90, Leu-95, Val-98, Ser-100, Glu-112, Tyr-116, Lys-120, Asp-121, and Arg-122 are critical residues for receptor-ligand interaction. The C-terminal of selected isoforms is conserved, and binding was observed on the conserved region of isoforms. We propose that selected inhibitor might be more potent on the basis of binding energy values. Further analysis of this inhibitor through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful in designing novel therapeutic targets to cure SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 74 | Eur Arch Psychiatry Clin Neurosci 2015 Jun 265: 291-301 |
| PMID | 25031104 |
| Title | Genetic variation in the G72 gene is associated with increased frontotemporal fiber tract integrity. |
| Abstract | G72 (syn. DAOA, D-amino acid oxidase activator) is a susceptibility gene for both schizophrenia and bipolar disorder. Diffusion tensor imaging studies hint at changes in fiber tract integrity in both disorders. We aimed to investigate whether a G72 susceptibility haplotype causes changes in fiber tract integrity in young healthy subjects. We compared fractional anisotropy in 47 subjects that were either homozygous for the M23/M24 risk haplotype (n = 20) or homozygous for M23(rs3918342)/M24(rs1421292) wild type (n = 27) using diffusion tensor imaging with 3 T. Tract-based spatial statistics, a method especially developed for diffusion data analysis, was used to delineate the major fiber tracts. We found clusters of increased FA values in homozygous risk haplotype carriers in the right periinsular region and in the right inferior parietal lobe (IPL). We did not find clusters indicating decreased FA values. The insula and the IPL have been implicated in both schizophrenia and bipolar pathophysiology. Increased FA values might reflect changes in dendritic morphology as previously described by in vitro studies. These findings further corroborate the hypothesis that a shared gene pool between schizophrenia and bipolar disorder might lead to neuroanatomic changes that confer an unspecific vulnerability for both disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 75 | Psychiatry Res 2015 Sep 229: 497-504 |
| PMID | 26142836 |
| Title | Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis. |
| Abstract | Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 76 | Psychiatry Clin. Neurosci. 2016 Jun 70: 227-44 |
| PMID | 26969211 |
| Title | Biological aspects and candidate biomarkers for psychotic bipolar disorder: A systematic review. |
| Abstract | We carried out a systematic review of the available literature about potential biomarkers of psychotic bipolar disorder (BD-P), a specific subset presenting worse outcome and greater risk of relapse than non-psychotic bipolar disorder (BD-NP). We searched the main psychiatric databases (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles with the main topic of BD-P compared to schizophrenia/BD-NP/healthy controls (HC) written in English from 1994 to 2015 were included. BD-P patients presented higher kynurenic acid levels in the cerebrospinal fluid, elevated anti- S accharomyces cerevisiae antibodies levels, and lower serum levels of dehydroepiandrosterone sulfate and progesterone than BD-NP/HC. Event-related potentials abnormalities have been identified in BD-P with respect to BD-NP. BD-P patients also presented bigger ventricles but similar hippocampal volumes compared to BD-NP/HC. Although the results are contrasting, some cognitive deficits seemed to be related to the psychotic dimension of bipolar affective disorder, such as impairment in verbal/logical memory, working memory, verbal and semantic fluency and executive functioning. Finally, polymorphisms of genes, such as NRG1, 5HTTLPR (s), COMT, DAOA and some chromosome regions (16p12 and 13q), were positively associated with BD-P. Data about the identification of specific biomarkers for BD-P are promising, but most of them have not yet been replicated. They could lead the clinicians to an early diagnosis and proper treatment, thus ameliorating outcome of BD-P and reducing the biological changes associated with a long duration of illness. Further studies with bigger samples are needed to detect more specific biological markers of the psychotic dimension of bipolar affective disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 77 | Cell. Mol. Life Sci. 2016 May 73: 2029-39 |
| PMID | 26914235 |
| Title | G72 primate-specific gene: a still enigmatic element in psychiatric disorders. |
| Abstract | Numerous studies have demonstrated a link between genetic markers on chromosome 13 and schizophrenia, bipolar affective disorder, and other psychiatric phenotypes. The G72/G30 genes (transcribed in opposite directions) are located on chromosome 13q33, a region demonstrating strong evidence for linkage with various neuropsychiatric disorders. G72/G30 was identified in 2002 as a schizophrenia susceptibility locus; however, subsequent association studies did not reach consensus on single SNPs within the locus. Simultaneously, a new vision for the genetic architecture of psychiatric disorders suggested that schizophrenia was a quantitative trait, therefore ascribable to potentially hundreds of genes and subjected to the vagaries of the environment. The main protein product of G72 gene is named pLG72 or D-amino acid oxidase activator DAOA (153 amino acids) and its function is still debated. Functional analyses, also showing controversial results, indicate that pLG72 contributes to N-methyl-D-aspartate receptor modulation by affecting activity of the flavoprotein D-amino acid oxidase, the enzyme responsible for degrading the neuromodulator D-serine. In this review we, for the first time, summarize findings from molecular genetic linkage and association studies concerning G72 gene, cellular and molecular studies on pLG72, and investigations performed on G72/G30 transgenic mice. This will help elucidate the role of psychosis susceptibility genes, which will have a major impact on our understanding of disease pathophysiology and thus change classification and treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |
| 78 | Eur. Psychiatry 2016 Feb 32: 42-7 |
| PMID | 26803614 |
| Title | Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study. |
| Abstract | Glutamatergic 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. The 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. The 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. Our 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizotypy |