A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia [published erratum appears in Mol Psychiatry 1998 Sept;3:458]

University of Milan, Milano, Lombardy, Italy
Molecular Psychiatry (Impact Factor: 14.5). 04/1998; 3(2):141-9. DOI: 10.1038/
Source: PubMed


We performed a meta-analysis of over 30 case-control studies of association between schizophrenia and a bi-allelic, Bali polymorphism in exon 1 of the dopamine D3 receptor gene. We observed a significant excess of both forms of homozygote in patients (P = 0.0009, odds ratio (OR) = 1.21, 95% Confidence Interval (CI) = 1.07-1.35) in the combined sample of 5351 individuals. No significant heterogeneity was detected between samples and the effects did not appear to be the product of publishing bias. In addition we undertook an independent, family-based association study of this polymorphism in 57 parent/proband trios, taken from unrelated European multiplex families segregating schizophrenia. A transmission disequilibrium test (TDT) showed a significant excess of homozygotes in schizophrenic patients (P = 0.004, odds ratio (OR) = 2.7, 95% CI = 1.35-5.86). Although no significant allelic association was observed, a significant association was detected with the 1-1 genotype alone (P = 0.02, OR = 2.32, 95% CI = 1.13-4.99). In addition when the results of the family-based association study were included in the meta-analysis, the homozygosity effect increased in significance (P = 0.0002, OR = 1.23, 95% CI = 1.09-1.38). The results of the meta-analysis and family-based association study provide independent support for a relationship between schizophrenia and homozygosity at the Bali polymorphism of the D3 receptor gene, or between a locus in linkage disequilibrium with it.

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    • "Therefore, DRD3 is considered a promising functional and positional candidate gene for SZ. One of the most extensively investigated polymorphisms within this gene is the single nucleotide polymorphism (SNP) rs6280 (Ser9Gly) in exon 2, resulting in a serine (Ser) to glycine (Gly) substitution at codon 9. Some studies suggested an association of the Ser allele [Ishiguro et al., 2000], the Gly allele [Kennedy et al., 1995], or homozygotes of both types [Crocq et al., 1992; Williams et al., 1998] with SZ. However, other studies failed to detect a positive association for this marker, in agreement with two recent Grant sponsor: National Natural Science Foundation of China; Grant numbers: 30570430, 81000583, 81000578; Grant sponsor: Tsinghua Yu- Yuan Medical Sciences Fund; Grant number: 20240000518. "
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    ABSTRACT: The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C-allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 07/2011; 156B(5):613-9. DOI:10.1002/ajmg.b.31203 · 3.42 Impact Factor
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    • "All five have an extracellular amino terminus, seven transmembrane domains and an intracellular carboxyl terminus. Abnormalities in dopamine neurotransmission are implicated in the aetiology of neurological and psychiatric disorders including schizophrenia (Williams et al. 1998) and Parkinson's disease (Oliveri et al. 2000). "
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    ABSTRACT: Five subtypes of dopamine receptor exist in two subfamilies: two D(1)-like (D(1) and D(5)) and three D(2)-like (D(2), D(3) and D(4)). We produced novel monoclonal antibodies against all three D(2)-like receptors and used them to localize receptors in Ntera-2 (NT-2) cells, the human neuronal precursor cell line. Most of the immunostaining for all three receptors colocalized with mannose-6-phosphate receptor, a marker for late endosomes formed by internalization of the plasma membrane. This result was obtained with antibodies against three different epitopes on the D(3) receptor, to rule out the possibility of cross-reaction with another protein, and controls without primary antibody or in the presence of competitor antigen were completely negative. In rat cerebral cortex and hippocampus, some of the dopamine receptor staining was found in similar structures in neuronal cell cytoplasm. Only some of the neurons were positive for dopamine receptors and the pattern was consistent with previously-reported patterns of innervation by dopamine-producing neurons. Endosomal dopamine receptors may provide a useful method for identifying cell bodies of dopamine-responsive neurons to complement methods that detect only active receptors in the neuronal cell membrane.
    Journal of Molecular Histology 09/2007; 38(4):333-40. DOI:10.1007/s10735-007-9106-5 · 1.82 Impact Factor
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    • "Yet, at the population level, it can be safely assumed that the Amerindian- La Plata subgroup should have a significantly higher Native American genetic background than that of the non-Amerindian La Plata subgroup. Two lines of evidence support this assumption: 1) DRD2A1, DRD3A1, and DRD4/4R allele frequencies, the DRD4/4R/4R genotype frequency, and the 5HT2CA1 frequency exhibit significant differences between Amerindian and non-Amerindian La Plata subgroups (Tables 1 and 2); 2) the non-Amerindian-La Plata stratum shows DRD3A1 (Ser9) and 5HT2CA1 (Gly855) allele frequencies closer to those reported in Europeans (Lappalainen et al., 1995; Gutierrez et al., 1996; Williams et al., 1998; Lerer et al., 2001; Jönsson et al., 2003, 2004), while DRD2A1 allele frequencies in the Amerindian-La Plata subgroup are similar to those found in our Amerindian population and also those reported in Amerindian communities from other geographic regions (Barr and Kidd, 1993; Goldman et al., 1993; Kidd et al., 1998; Hutz et al., 2000) (Tables 1–3). In addition, DR2DA1 allele frequencies are higher than in our non-American La Plata strata and in European samples previously reported (Turner et al., 1992; Noble, 1998). "
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    ABSTRACT: We report on the frequency of DRD2A1, DRD3A1, DRD4/2R-10R, and 5HT2CA1 variants in the population of the city of La Plata (Argentina) and in Amerindians from Argentina, Paraguay, and Chile. In the Amerindian sample, the prevalence of DRD2A1 and DRD4/4R variants were, respectively, significantly lower and significantly higher than frequencies reported in other Native Americans. Comparison of average allele and genotype frequencies between La Plata and Amerindians showed significant differences for 5HT2CA1 and DRD4. As La Plata is a population with predominant European and Amerindian components, we used mtDNA and Y-specific markers to subdivide the La Plata sample into two strata: Amerindian La Plata and non-Amerindian La Plata. Significant variations between the two strata were detected for DRD2A1, DRD3A1, and DRD4/4R allele frequencies, and for the homozygous DRD4/4R/4R genotype. Several controversial reports suggest a possible association between a variant of DRD and/or 5HT2C receptor genes and the clinical expression of several psychiatric disorders. We suggest that ethnic variations in the prevalence of the allelic forms of these genes may be a confounding factor to be taken into consideration in studies of association between dopaminergic and serotonergic receptor genotypes and neuropsychiatric and mood disorders.
    American Journal of Human Biology 11/2006; 18(6):822-8. DOI:10.1002/ajhb.20565 · 1.70 Impact Factor
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