Variation at the DAOA/G30 Locus Influences Susceptibility to Major Mood Episodes but Not Psychosis in Schizophrenia and Bipolar Disorder

Department of Psychological Medicine and Biostatistics and Bioinformatics Unit, Wales School of Medicine, Cardiff University.
Archives of General Psychiatry (Impact Factor: 14.48). 05/2006; 63(4):366-73. DOI: 10.1001/archpsyc.63.4.366
Source: PubMed


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.

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    • "A number of studies showed positive association with BD (rs1935058; rs1341402, rs1935062, rs778294; rs947267; haplotypes: rs2111902A-rs3918346T and rs746187G-rs3916972G; haplotypes: CGCAT, TAACT, CGACT, TGCAT of five SNPs: rs1935058, rs2391191, rs1935062, rs947267, rs954581).54–57 Further evidence was reported in a large study analyzing nine polymorphisms that tag the common genetic variations in DAOA in association with susceptibility to mood episodes in BD (rs391695, rs1341402, DAOA_3′UTR_SNP12).58 However, associations of the studied DAOA polymorphisms (rs2391191G, rs778294T, rs1341402T, rs1935058C, and rs1935062C) were not confirmed in a meta-analysis by Shi et al.59 "
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    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.
    Neuropsychiatric Disease and Treatment 10/2013; 9:1573-1582. DOI:10.2147/NDT.S28117 · 1.74 Impact Factor
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    • "Another gene locus associated with SZ and BPD is G72/G30 (Bass et al., 2009; Boks et al., 2007; Chumakov et al., 2002; Hattori et al., 2003; Prata et al., 2008; Williams et al., 2006). While no gene product has yet been identified for G30, G72 (D-amino acid oxidase activator) encodes a protein that is expressed in cerebellum, hippocampus, amygdala, and cortex, including DLPFC (Boks et al., 2007; Kvajo et al., 2008; Lang et al., 2007; Otte et al., 2009). "
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    ABSTRACT: Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 05/2011; 29(3):311-24. DOI:10.1016/j.ijdevneu.2010.08.007 · 2.58 Impact Factor
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    • "Interestingly, G72 is also a top candidate gene for bipolar disorder (Hattori et al., 2003; Chen et al., 2004; Schumacher et al., 2004; Fallin et al., 2005; Williams et al., 2006a; Prata et al., 2008; Bass et al., 2009; Zhang et al., 2009). Furthermore, G72 has been implicated in susceptibility to methamphetamine psychosis (Kotaka et al., 2009) and symptoms of depression and anxiety in patients with schizophrenia and bipolar disorder (Williams et al., 2006a; Gawlik et al., 2010; Grigoroiu-Serbanescu et al., 2010). This may indicate that G72 affects brain functions and psychiatric symptoms across traditional clinical categories. "
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    ABSTRACT: The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients.
    Neuropharmacology 02/2011; 62(3):1484-503. DOI:10.1016/j.neuropharm.2011.01.030 · 5.11 Impact Factor
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