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