Elsevier

Biological Psychiatry

Volume 54, Issue 6, 15 September 2003, Pages 629-635
Biological Psychiatry

Original article
Schizophrenia is not associated with DRD448-base-pair-repeat length or individual alleles: results of a meta-analysis

https://doi.org/10.1016/S0006-3223(03)00180-XGet rights and content

Abstract

Background

The gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies.

Methods

We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2300 cases and 2100 controls from 14–16 studies.

Results

The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele.

Conclusions

Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.

Introduction

Schizophrenia is a complex disease with a strong genetic component. Its heritability is estimated at between 60–70% McGue et al 1983, Tsuang et al 1999, and mulifactorial polygenic inheritance is supported Tsuang et al 1991, Tsuang et al 1999. In light of the inconsistent findings from genetic linkage studies of schizophrenia, allelic association studies have been touted as a more powerful means of identifying the numerous susceptibility genes for the illness, each of which may have only a slight effect on risk (Borecki and Suarez 2001). In fact, using this approach, some candidate genes have already been shown to have a small but reliable association with the disorder Dubertret et al 1998, Glatt et al, Williams et al 1997, Williams et al 1998.

Based on the upregulation of the D4 subtype of dopamine receptor in postmortem brain tissue from schizophrenic patients (Seeman et al 1993), and the affinity of this receptor for the highly effective atypical antipsychotic clozapine (Van Tol et al 1991), the gene (DRD4, chromosome 11p15.5) that codes for this protein was considered a good candidate for allelic association with schizophrenia. When a 48-base-pair variable-number tandem-repeat polymorphism was identified in exon 3 of DRD4 (Lichter et al 1993), this polymorphism became the marker of choice for association studies of DRD4 and schizophrenia because of its putative functional significance (Van Tol et al 1992). Numerous studies of schizophrenia and DRD4 have been published, with the overwhelming majority finding no statistically significant evidence for linkage disequilibrium. Yet it remains possible that these studies were underpowered to detect a small but significant association.

To resolve this uncertainty, we sought to determine if this DRD4 polymorphism was, in fact, not associated with schizophrenia or if the relationship was of such a small magnitude that typical association studies lacked sufficient power to detect it. In this work, we performed four separate meta-analyses of the association between this polymorphism and schizophrenia. The first three analyses were used to establish the schizophrenia risk attributable to each of the three most prevalent alleles of the 48-base-pair-repeat polymorphism of DRD4, and the fourth was used to determine if the length of the repeated segment reliably predicted risk for the illness.

Section snippets

Literature search

To identify studies eligible for meta-analysis, MEDLINE citations (January 1966–January 2002) were surveyed using the National Library of Medicine’s PubMed online search engine with “schizophrenia” and “DRD4” as key words. The retrieved abstracts were read to identify studies that examined the allelic association between a polymorphism within the DRD4 gene and schizophrenia. Studies of this type were then read in their entirety to assess their appropriateness for inclusion in the meta-analysis.

Individual DRD4 48-base-pair-repeat-length alleles as risk factors

The ORs and 95% CIs for each study included in the meta-analyses of the two-, four-, and seven-repeat alleles of the 48-base-pair-repeat polymorphism of DRD4 are presented in Table 2. The ORs from studies of the two-repeat allele comprised a homogeneous group (χ2(15) = 14.36, p = .499), with values ranging from .4–1.8. The pooled OR derived from 2493 cases and 2497 control subjects was .9 (95% CI = .8–1.0), which was not significant (z = 1.28, p = .199). The sequential omission of individual

Acknowledgements

Preparation of this work was supported in part by Grant Nos. RO1 MH43518, R01 MH59624, and R01 MH60485 from the National Institute of Mental Health (NIMH) to Dr. Ming T. Tsuang. This work was completed when Dr. Glatt was a trainee in the NIMH-funded Psychiatric Genetics Training Program at the Harvard Institute of Psychiatric Epidemiology and Genetics (Grant No. R25 MH60485, M. Tsuang, principal investigator).

References (53)

  • Y. Okuyama et al.

    A genetic polymorphism in the promoter region of DRD4 associated with expression and schizophrenia

    Biochem Biophys Res Commun

    (1999)
  • M.T. Tsuang et al.

    The genetics of schizophreniaCurrent knowledge and future directions

    Schizophr Res

    (1991)
  • J. Williams et al.

    Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group European Multicentre Association Study of Schizophrenia

    Lancet

    (1997)
  • C.L. Barr et al.

    Alleles at the dopamine D4 receptor locus do not contribute to the genetic susceptibility to schizophrenia in a large Swedish kindred

    Am J Med Genet (Neuropsychiat Genet)

    (1993)
  • I.B. Borecki et al.

    Linkage and associationBasic concepts

    Adv Genet

    (2001)
  • J. Daniels et al.

    Repeat length variation in the dopamine D4 receptor gene shows no evidence of association with schizophrenia

    Am J Med Genet (Neuropsychiat Genet)

    (1994)
  • H.W. Deng

    Population admixture may appear to mask, change or reverse genetic effects of genes underlying complex traits

    Genetics

    (2001)
  • Y.C. Ding et al.

    Evidence of positive selection acting at the human dopamine receptor D4 gene locus

    Proc Natl Acad Sci U S A

    (2002)
  • C. Dubertret et al.

    Meta-analysis of DRD3 gene and schizophreniaEthnic heterogeneity and significant association in Caucasians

    Am J Med Genet (Neuropsychiat Genet)

    (1998)
  • S.V. Faraone et al.

    Genetics of Mental DisordersA Guide for Students, Clinicians, and Researchers

    (1999)
  • Y. Fujiwara et al.

    Polymorphism of dopamine receptors and transporter genes in neuropsychiatric diseases

    Eur Neurol

    (1997)
  • Glatt SJ, Faraone SV, Tsuang MT (in press): Meta-analysis identifies an association between the dopamine D2 receptor...
  • C.J. Hong et al.

    Dopamine D4 receptor variants in Chinese sporadic and familial schizophrenics

    Am J Med Genet (Neuropsych Genet)

    (1997)
  • E. Jonsson et al.

    A search for association between schizophrenia and dopamine-related alleles

    Eur Arch Psychiatry Clin Neurosci

    (1996)
  • E.G. Jonsson et al.

    No association between a promoter dopamine D(4) receptor gene variant and schizophrenia

    Am J Med Genet (Neuropsychiat Genet)

    (2001)
  • R. Kaiser et al.

    Dopamine D4 receptor 48-bp repeat polymorphismNo association with response to antipsychotic treatment, but association with catatonic schizophrenia

    Mol Psychiatry

    (2000)
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