No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk

Verga, M.; Macciardi, Fabìo; Pedrini, Silvia; Cohen, Susanna R.; Smeraldi, Enrico

doi:10.1016/s0920-9964(97)00013-3

Cited by 27 publications

(24 citation statements)

References 14 publications

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“…It is not yet clear if the Cys allele confers excess risk for schizophrenia directly or if it is in linkage disequilibrium with a causative allele at another locus. Family-based studies of this association, of which only one currently exists (OR ¼ 1.7), 6 should be considered a high priority if this association is to be confirmed, validated, and widely recognized.…”

Section: Discussionmentioning

confidence: 99%

“…The application of these criteria yielded 24 studies eligible for meta-analysis, of which 23 used case-control designs, 3,4, and one utilized both a case-control and a family-based strategy. 6 Only the case-control samples were included in the metaanalysis.…”

Section: Inclusion Criteriamentioning

confidence: 99%

“…Thus, the initial finding of association has come to be regarded as a type-I inferential error. 6 Yet, it is uncertain if this failure to identify consistently an association has been because of the low power of individual studies to detect a small effect, etiological heterogeneity, or random error in the absence of a true effect. To derive a powerful estimate of the true association between the Cys311Ser DRD2 polymorphism and schizophrenia, we performed a meta-analysis of all 24 published case-control studies in which this relation was examined.…”

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Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia

2003

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The D2 subtype of dopamine receptor has been widely implicated in the pathogenesis of schizophrenia. Early evidence supporting an association between the Cys311Ser polymorphism of the D2 receptor gene (DRD2) and schizophrenia was subsequently refuted and, eventually, dismissed. From all 24 published case-control studies, we calculated a pooled estimate of this association. The pooled odds ratio was 1.3 for the Cys allele, which was highly significant (P = 0.007). The odds ratio derived from each study was unrelated to the ethnicity or gender composition of the sample, or the age of the control group. There was no evidence of publication bias or excessive influence attributable to any given study. Although more familybased studies are needed to confirm this relation, our results provide strong evidence that DRD2 influences susceptibility to schizophrenia. Molecular Psychiatry (2003) 8, 911-915. doi:10.1038/sj.mp.4001321Keywords: meta-analysis; association; dopamine; D2 receptor; gene; schizophrenia Dopamine system dysfunction has been widely implicated in the pathogenesis of schizophrenia. The most effective known treatments for schizophrenia are those that principally antagonize the D2 subtype of dopamine receptor.1 In fact, the D2 receptorbinding efficacy of neuroleptics is highly correlated with their ability to ameliorate symptoms.2 Furthermore, D2 receptor-binding density is increased in the brains of schizophrenic patients.2 When a functional variant of the D2 receptor gene (DRD2) was discovered 3 and found to be associated with the disorder, 4 a role for DRD2 in the genesis of schizophrenia was postulated. This mutation, a C-to-G transversion in codon 311, results in the substitution of cysteine (Cys) for serine (Ser) in the protein and, consequently, alters the physiology and function of the receptor. For example, the Cys variant of the D2 receptor has approximately half of the affinity for dopamine as that exhibited by the wild-type receptor. In addition, signal transduction in cells expressing this variant is reduced by 44%, an effect that is not because of impaired G-protein coupling but which may be mediated by lower efficiency of the variant-containing protein in activating the a subunit of the associated G-protein heterotrimer. Although the early evidence for association noted by Arinami et al 4 was strong, 21 of 22 subsequent studies of this putative association with schizophrenia failed to detect a significant relation. Thus, the initial finding of association has come to be regarded as a type-I inferential error.6 Yet, it is uncertain if this failure to identify consistently an association has been because of the low power of individual studies to detect a small effect, etiological heterogeneity, or random error in the absence of a true effect. To derive a powerful estimate of the true association between the Cys311Ser DRD2 polymorphism and schizophrenia, we performed a meta-analysis of all 24 published case-control studies in which this relation was examined. Materials and methods Literature sea...

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Section: Discussionmentioning

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Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia

2003

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“…4 S311C has been proposed as a genetic risk factor for schizophrenia following the observation of an excess of S311C variants among schizophrenics. 5 Nevertheless a number of replications failed to confirm the initial report, [6][7][8][9][10][11][12][13][14] with only one replication in Caucasian schizophrenics. 15 Mood disorders have also been investigated.…”

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Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

et al. 2000

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The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses. Molecular Psychiatry (2000) The D2 receptor is the major binding site of many typical and atypical neuroleptic drugs and its gene has been cloned and mapped to 11q22-23.2 Itokawa et al 3 reported a polymorphism causing a structural change from Serine to Cysteine at codon 311 of DRD2 (S311C); this substitution occurs in the third intracellular loop of the receptor. Preliminary results showed that DRD2 rarer TaqI variants were associated with higher levels of the monoamine metabolites homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in lumbar cerebrospinal fluid in controls. 4 S311C has been proposed as Correspondence: A Serretti MD,

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“…However, 21 of 22 subsequent replication attempts failed, after which the result obtained by Arinami et al 2 became widely regarded as a type-I inferential error and the possibility of an association was considered remote. 3 Yet, as we previously documented, 4 this pattern of nonreplication was most likely attributable to low statistical power among the replication studies which had, on average, a 55.7% chance of detecting an effect as large as that observed by Arinami et al 2 (odds ratio (OR) of 3.1), but only a 7.5% chance of detecting what we identified by metaanalysis 5 as the 'best estimate' of the magnitude of this polymorphism's effect on risk for schizophrenia (OR = 1.3). In addition to the statistical significance of the OR determined from our meta-analysis, the reliability of this association was bolstered by several facts including (1) there was no evidence that the effect was attributable to publication bias, where only positive reports might be accepted into the literature and contribute to the meta-analysis; (2) there was no evidence of heterogeneity among the studies, suggesting that the effect of DRD2 was consistent across samples; and perhaps most importantly, (3) the significance of the overall effect observed by meta-analysis persisted even when the large and influential study by Arinami et al 2 was removed from the analysis.…”

Section: Introductionmentioning

confidence: 99%

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

Glatt

Faraone

et al. 2008

Mol Psychiatry

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The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior casecontrol studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous singlenucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a familybased study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps < 0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.

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No association of the Ser/Cys311 DRD2 molecular variant with schizophrenia using a classical case control study and the haplotype relative risk

Cited by 27 publications

References 14 publications

Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia

Meta-analysis identifies an association between the dopamine D2 receptor gene and schizophrenia

Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

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