Is the G72/G30 locus associated with schizophrenia? single nucleotide polymorphisms, haplotypes, and gene expression analysis

Korostishevsky, Michael; Kaganovich, M.; Cholostoy, Alina; Ashkenazi, Maya; Ratner, Yaël; Dahary, Dvir; Bernstein, Jeanne; Bening-Abu-Shach, Ullrike; Ben-Asher, Edna; Lancet, Doron; Ritsner, Michael S.; Navon, Ruth

doi:10.1016/j.biopsych.2004.04.006

Cited by 173 publications

(131 citation statements)

References 38 publications

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“…Our data supporting an association of variation in this chromosomal region with schizophrenia are at least partially consistent with a number of previous haplotype-based association (Chumakov et al, 2002;Goldberg et al, 2006;Korostishevsky et al, 2004;Ma et al, 2006;Schumacher et al, 2004;Zou et al, 2005). However, inconsistencies in markers genotyped and allelic heterogeneity are common findings in this region, as noted in a recent review by Abou Jamra et al (2006).…”

Section: Discussionsupporting

confidence: 92%

“…Messenger RNA expression of the gene has been shown to be increased in schizophrenic patients in postmortem studies (Korostishevsky et al 2004). The presumed function of the gene, suggested by in vitro transcription / translation assays appears to involve the regulation of the NMDA-type glutamate receptor, which is intriguing in light of the proposed relationship between glutamatergic dysfunction and the pathophysiology of schizophrenia (Harrison and Owen, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, multiple association studies, investigating several of the previously associated SNPs, have also yielded significant results in case-control (Korostishevsky et al, 2004;Ma et al, 2006;Schumacher et al, 2004;Wang et al, 2004) and family-based designs (Mulle et al, 2005;Zou et al, 2005). Despite the number of positive association studies, however, the literature is marked by considerable allelic heterogeneity; few studies have reported compatible results for the same SNPs.…”

Section: Introductionmentioning

confidence: 99%

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

Opgen‐Rhein

Lencz

Burdick

et al. 2008

Schizophrenia Research

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Introduction-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.Methods-We analyzed block structure and association patterns of a ~173 kb region on chromosome 13q33, applying genotype data of 55 SNPs derived from Caucasian North American sample (178 cases, 144 healthy controls). Haplotypes were assigned using the program PHASE and frequencies compared between cases and controls. We applied MANOVA to investigate the relationship between the identified risk haplotype on cognitive performance.Results-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.Conclusions-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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Opgen‐Rhein

Lencz

Burdick

et al. 2008

Schizophrenia Research

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“…Gene expression analysis of G72 and G30 exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of G72 mRNA in schizophrenic post-mortem dorsolateral prefrontal cortex of 44 schizophrenic patients compared with 44 control participants [5].…”

Section: Introductionmentioning

confidence: 95%

Association of G72/G30 polymorphisms with early-onset and male schizophrenia

Yue¹,

Z²,

Kang³

et al. 2006

NeuroReport

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To explore the e¡ect of G72/G30 polymorphisms on the clinical manifestations of schizophrenia, especially on the age at onset and sex of patients, we examined three single nucleotide polymorphisms in 216 schizophrenic patients and 321 healthy controls. Signi¢cant associations of schizophrenia with the A allele of rs947267 (P ¼ 0.012) and haplotype A-A-G (rs2391191-rs947267-rs778294) (P ¼ 0.008) were found in early-onset schizophrenic patients. So did the same allele (P ¼ 0.034) and haplotype (P ¼ 0.009) as mentioned above in male patients. These ¢ndings suggest that the G72/G30 gene may modulate the age at onset and there might be a potential interaction between this locus and sex in the pathogenesis of schizophrenia. NeuroReport17:1899^1902 c 2006 Lippincott Williams & Wilkins.Keywords: age at onset, association study, G72/G30, polymorphism, schizophrenia IntroductionSchizophrenia is a major psychiatric disorder that affects almost 1% of the world's population and accounts for about 2.5% of healthcare costs [1]. Symptoms usually begin in late adolescence or early adulthood. Involvement of neurodevelopmental mechanism, especially glutamatergic transmission via N-methyl-D-aspartate receptors and synaptic plasticity in schizophrenia, has been recently suggested, on the basis of several lines of evidence [2]. Linkage analyses on diverse samples have provided accumulating evidence that chromosome 13q32-q33 may be involved in susceptibility to schizophrenia. A meta-analysis of genomewide linkage studies further identified 13q32-q33 as significantly linked to schizophrenia [3].Chumakov et al.[4] first reported that genetic variations near G72 (MIN 607408) and G30 (MIN 607415) locus on 13q34 were associated with schizophrenia in FrenchCanadian and Russian cohorts. G72 and G30 overlap on complementary chromosomal strands and are therefore transcribed in opposite directions. By yeast two-hybrid experiments, Chumakov et al.[4] also identified that the G72 protein interacts with the enzyme D-amino acid oxidase (MIN 124050), which regulates glutamatergic signaling through an N-methyl-D-aspartate receptor pathway. Gene expression analysis of G72 and G30 exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of G72 mRNA in schizophrenic post-mortem dorsolateral prefrontal cortex of 44 schizophrenic patients compared with 44 control participants [5].Hattori et al. [6] suggested that a susceptibility variant for both bipolar illness and schizophrenia exists in the vicinity of the G72/G30 gene in two series of pedigrees. Findings from several subsequent studies tend to advance a role for G72/G30 in the overall risk for schizophrenia and bipolar disorder from various populations, including a metaanalysis study and a research based on a sample of childonset schizophrenia [7][8][9][10][11][12][13][14]. The majority of replication studies have, however, been inconsistent with respect to the associated alleles or haplotypes. Moreover, negative associations of G72/G30 pol...

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“…Shortly afterward, the G72/ G30 gene complex (G72 is now officially known as D-aminoacid oxidase activator, DAOA) was associated, independently, with each disorder (Chumakov et al, 2002;Hattori et al, 2003). An association has been reported in multiple independent studies (Addington et al, 2004;Chen et al, 2004;Fallin et al, 2005;Hall et al, 2004;Hong et al, 2006;Korostishevsky et al, 2004;Korostishevsky et al, 2006;Ma et al, 2006;Schulze et al, 2005;Schumacher et al, 2004;Wang et al, 2004;Williams et al, 2006;Yue et al, 2006;Yue et al, 2007;Zou et al, 2005). However, several studies did not find association with traditional BP or SCZ phenotype (Bakker et al, 2007;Goldberg et al, 2006;Liu et al, 2006;Mulle et al, 2005;Vilella et al, 2007;Wood et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

Shi

Badner

Gershon

et al. 2008

Schizophrenia Research

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

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Is the G72/G30 locus associated with schizophrenia? single nucleotide polymorphisms, haplotypes, and gene expression analysis

Cited by 173 publications

References 38 publications

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

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

Association of G72/G30 polymorphisms with early-onset and male schizophrenia

Allelic association of G72/G30 with schizophrenia and bipolar disorder: A comprehensive meta-analysis

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