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

doi:10.1016/j.biopsych.2004.04.006

Biological Psychiatry

Volume 56, Issue 3, 1 August 2004, Pages 169-176

https://doi.org/10.1016/j.biopsych.2004.04.006 Get rights and content

Abstract

Background

The genes G72/G30 were recently implicated in schizophrenia in both Canadian and Russian populations. We hypothesized that 1) polymorphic changes in this gene region might be associated with schizophrenia in the Ashkenazi Jewish population and that 2) changes in G72/G30 gene expression might be expected in schizophrenic patients compared with control subjects.

Methods

Eleven single nucleotide polymorphisms (SNPs) encompassing the G72/G30 genes were typed in the genomic deoxyribonucleic acid (DNA) from 60 schizophrenic patients and 130 matched control subjects of Ashkenazi ethnic origin. Case–control comparisons were based on linkage disequilibrium (LD) and haplotype frequency estimations. Gene expression analysis of G72 and G30 was performed on 88 postmortem dorsolateral prefrontal cortex samples.

Results

Linkage disequilibrium analysis revealed two main SNP blocks. Haplotype analysis on block II, containing three SNPs external to the genes, demonstrated an association with schizophrenia. Gene expression analysis exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of the G72 gene in schizophrenic brain samples of 44 schizophrenic patients compared with 44 control subjects.

Conclusions

It is likely that the G72/G30 region is involved in susceptibility to schizophrenia in the Ashkenazi population. The elevation in expression of the G72 gene coincides with the glutamatergic theory of schizophrenia.

Section snippets

Subjects

The study enrolled 60 unrelated Ashkenazi schizophrenic patients and 130 matched control subjects. Patients included in the study were 18–65 years old (average = 38.6, SD = 9.5) and met DSM-IV (American Psychiatric Association 1994) criteria for schizophrenia. Patients with associated diagnoses of mental retardation, organic brain disease, severe physical disorders, drug or alcohol abuse, and those with low comprehension skills were not enrolled in the study. The patients were from Sha'ar

Genotype and allele frequency

Genotype and allele frequency of the 11 SNPs located in the G72/G30 region in Ashkenazi schizophrenic patients (n = 60) and matched control subjects (n = 130) are shown in Table 1. All the SNPs were highly polymorphic in both samples. A departure from HWE was tested separately in case and control samples. A lack of heterozygotes for two adjacent SNPs was observed in the patient sample: rs778293 (p = .03) and rs3918342 (p = .03). An excess of heterozygotes was found in another pair of adjacent

Discussion

In this study we used two different research strategies for investigating the genetic basis of neuropsychiatric illness: SNP and haplotype association as well as gene expression.

Eleven SNPs spread out along approximately 82.5 kb in the 13q32–33 encompassing the G72/G30 genes were typed in Ashkenazi Jewish schizophrenic patients and matched control subjects. Additionally, a set of five unlinked markers was typed and used by the Structure software program to check whether the sample's genotypes

Acknowledgements

This work was supported in part by grants from the Stanley Medical Research Institute and by Adams Super Center for Brain Studies, Tel Aviv University (RN).

We thank all the patients who took part in the study as well as the Ashkenazi control donors group. Postmortem specimens were donated by The Stanley Medical Research Institute Brain Collection, courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. We also thank Dr. W. Perelman for critical reading of

References (48)

N.C Andreasen
Symptoms, signs, and diagnosis of schizophrenia
Lancet
(1995)
L.M Brzustowicz et al.
Linkage of familial schizophrenia to chromosome 13q32
Am J Hum Genet
(1999)
E Hattori et al.
Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series
Am J Hum Genet
(2003)
C Konradi et al.
Molecular aspects of glutamate dysregulationImplications for schizophrenia and its treatment
Pharmacol Ther
(2003)
D.F Levinson et al.
Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13qSchizophrenia linkage collaborative group III
Am J Hum Genet
(2000)
B Mazumder et al.
Translational control by the 3′-UTRThe ends specify the means
Trends Biochem Sci
(2003)
A Nebel et al.
The Y chromosome pool of Jews as part of the genetic landscape of the middle east
Am J Hum Genet
(2001)
M.G Thomas et al.
Founding mothers of Jewish communitiesGeographically separated Jewish groups were independently founded by very few female ancestors
Am J Hum Genet
(2002)
E.F Torrey et al.
The Stanely Foundation Brain Collection and Neuropathology Consortium
Schizophr Res
(2000)
A.F Wilson et al.
Equivalence of single- and multilocus markersPower to detect linkage with composite markers derived from biallelic loci
Am J Hum Genet
(2000)

J Zlotogora et al.

Molecular basis of mendelian disorders among Jews

Mol Genet Metab

(2000)

J.H Abramson et al.

Computer Program for Epidemiologists. PEPI version 3

(1999)

Z Ankory

Origin and history of Ashkenazi Jewry (8th to 18th century)

Diagnostic and Statistical Manual of Mental Disorders

(1987)

Diagnostic and Statistical Manual of Mental Disorders

(1994)

J.A Badner et al.

Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

Mol Psychiatry

(2002)

T.B Ball et al.

Improved mRNA quantitation in LightCycler RT-PCR

Int Arch Allergy Immunol

(2003)

Behar DM, Hammer MF, Garrigan D, Villems R, Bonne-Tamir B, Richards M, et al (2004): MtDNA evidence for a genetic...

E.M Blackwood et al.

Going the distanceA current view of enhancer action

Science

(1998)

J.L Blouin et al.

Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21

Nat Genet

(1998)

G.G Carmichael

Antisense starts making more sense

Nat Biotechnol

(2003)

S.L Christian et al.

An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia

Genomics

(2002)

I Chumakov et al.

Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia

Proc Natl Acad Sci U S A

(2002)

Cited by (159)

A role for endothelial NMDA receptors in the pathophysiology of schizophrenia
2022, Schizophrenia Research
Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.
The DAOA gene is associated with schizophrenia in the Taiwanese population
2017, Psychiatry Research
The gene D-amino acid oxidase activator (DAOA), which has a former name of G72, and the D-amino acid oxidase (DAO) gene have been suggested as candidate genes of schizophrenia. However, association studies have so far yielded equivocal results. We analyzed one single nucleotide polymorphism (SNP) for DAO (rs3741775) and seven SNPs for G72 (rs3916956, rs2391191, rs9558562, rs947267, rs778292, rs3918342, and rs1421292) in this study enrolling 248 schizophrenia cases and 267 controls in the Taiwanese samples. In SNP-based single locus association analyses, the rs778292 in the DAOA gene showed significant association with schizophrenia. The rs3741775 in the DAO gene could not withstand statistically significant after multiple corrections. Additionally, a three-SNP haplotype (rs778292-rs3918342-rs1421292) in the DAOA gene were observed to be significantly associated with schizophrenia. Among them, the TCT haplotype presented higher prevalence in controls than in cases whereas the TTT and CTT haplotype were significantly more frequent in cases than in controls. The study also provides significant evidence for epistatic interactions among DAOA and DAO gene in the development of schizophrenia. These results provide additional evidence and indicate that the DAOA gene and DAOA-DAO gene-gene interactions might play a role for schizophrenia in a Taiwanese sample.
Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study
2016, European Psychiatry
Citation Excerpt :
Substantial evidence indicates that DAOA could be involved in the pathophysiology of psychotic disorders. For example, SZ patients have been shown to have lower d-serine levels in serum [13] and cerebrospinal fluid [14] than healthy controls, while increased DAOA expression has been reported in the pre-frontal cortex (PFC) [15]. d-serine treatment has also been reported as having a beneficial effect on the negative symptoms of SZ [16].
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.
Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis
2015, Psychiatry Research
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.
A systematic review of the effect of genes mediating neurodevelopment and neurotransmission on brain morphology: Focus on schizophrenia
2015, Neurology Psychiatry and Brain Research
Structural brain abnormalities have been extensively investigated as potential endophenotypes of schizophrenia. Apart from enlarged ventricles and whole brain volume reductions, no other consistently replicated brain morphometric abnormalities have emerged from these studies. The differential effect of genetic variants on brain morphometry could be a major source of variability underlying such inconsistent findings. Schizophrenia is a polygenic disorder, wherein the complex interplay between common risk variants of small effect, rare risk alleles of large effect as well as epigenetic interactions confer vulnerability and mediate the final expression of the clinical phenotype. A comprehensive understanding of the effect of risk genes on brain morphometry is essential for linking the structural endophenotype/s that can be linked with the genetic diathesis for development of schizophrenia. We systematically reviewed published literature to examine the effect of genes mediating neurodevelopment and brain signalling on brain morphometry. A majority of polymorphisms of the above genes was shown to be associated with whole brain and regional volumetric reductions; but importantly, many genes showed mixed effects, i.e., both volume reductions and increases. Modelling such complex interactions of the large number of risk genes on brain volume in vivo poses considerable practical challenges in having adequate sample sizes as well as imaging data for reliable quantification. Therefore, it is recommended that the field should move beyond association studies of the morphometric effect of single or limited number of gene polymorphisms in clinical populations to modelling the complex epistatic and epigenetic interactions in silico or using animal and cellular models.
Association between DAOA gene polymorphisms and the risk of schizophrenia, bipolar disorder and depressive disorder
2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Considerable evidences for the overexpression of DAOA in schizophrenic brains have been found in post-mortem brain studies (Bendikov et al., 2007; Korostishevsky et al., 2004) and decreased levels of plasma glutamate have been observed in the first-episode schizophrenic patients (Palomino et al., 2007). The DAOA gene, also known as the G72/G30 gene, is located on chromosome 13q32–33 and physically overlaps with G30, which transcribes protein from the opposite DNA strand and regulates DAOA expression (Chumakov et al., 2002; Korostishevsky et al., 2004). The association between the DAOA gene and SCZ was first identified by Chumakov et al. (2002), and has been replicated by Korostishevsky et al. (2004) and Corvin et al. (2007).
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 (I²). 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.

View all citing articles on Scopus

View full text

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

Abstract

Background

Methods

Results

Conclusions

Section snippets

Subjects

Genotype and allele frequency

Discussion

Acknowledgements

Lancet

Am J Hum Genet

Am J Hum Genet

Pharmacol Ther

Am J Hum Genet

Trends Biochem Sci

Am J Hum Genet

Am J Hum Genet

Schizophr Res

Am J Hum Genet

Mol Genet Metab

Computer Program for Epidemiologists. PEPI version 3

Origin and history of Ashkenazi Jewry (8th to 18th century)

Diagnostic and Statistical Manual of Mental Disorders

Diagnostic and Statistical Manual of Mental Disorders

Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

Mol Psychiatry

Improved mRNA quantitation in LightCycler RT-PCR

Int Arch Allergy Immunol

Going the distanceA current view of enhancer action

Science

Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21

Nat Genet

Antisense starts making more sense

Nat Biotechnol

An evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia

Genomics

Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia

Proc Natl Acad Sci U S A

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