| Schizophrenia (MIM 181500) is one of the most severe mental disorders, with a worldwide incidence of 1%. Data from twin, family, and adoption studies provide strong evidence that schizophrenia is predominantly a genetic disorder with high heritability. However, the genes evoking schizophrenia remain unclear. Dopamine and glutamate neurotransmitter systems hypothesis, are the classic hypothesis of schizophrenia etiology. Recently, the phosphoinositide (PI) pathway viewed as potential targets for the therapeutic action of lithium, is also considered a potential cause of schizophrenia. This study attempted to analyze schizophrenia susceptibility genes of the three hypotheses to further explain the etiology of schizophrenia.Dopamine D3 receptor (DRD3) was demonstrated to have important implications in schizophrenia, because it binds antipsychotic drugs and is abundant in the limbic system of the brain. The Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) has been the most extensively investigated to find an association between this polymorphism and schizophrenia; however, the results were inconsistent. This study aims to further evaluate the controversial association between the Ser9Gly polymorphism and schizophrenia using a case-control association study in Han Chinese population and meta-analysis including previous and the present Chinese case-control study results. However, we found no significant difference in the genotype or allele distributions between the 329 schizophrenics and 288 controls for the Ser9Gly polymorphism. The meta-analysis showed that the Ser9Gly polymorphism is not associated with Schizophrenia as well. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.DTNBP1, the dystrobrevin binding protein 1 gene, was one of the most frequently studied schizophrenia-susceptibility genes. There have been intense contradictory results in the previous association studies. In the present study, we genotyped 12 SNPs in 707 schizophrenic patients and 689 normal controls recruited from Chinese Han population. Two novel SNPs, rs9476837 and rs9464794, located near an active alternative transcription area of the 3'region, showed significant association with permutation tests. rs9476837 and rs9464794 were in linkage disequilibrium (D'≥0.86, r2≥0.60) with three frequently analyzed SNPs (rs1018381, rs2619522, rs760761) in the 5'region. One haplotype, constructed from these snps and covering the active alternative transcription area, was also significantly associated with schizophrenia. Such findings suggest that the alternative transcription area in the 3'region of DTNBP1 is associated with schizophrenia, and significance in 5'region might be caused by LD with 3'region SNPs. We also performed meta-analysis of this gene using both DerSimonian and Laird's method and the truncated product combination method, including 32 association studies up to June 2007. This meta-analysis included 6645 cases, 6768 controls and 4168 families, covering 20 single nucleotide polymorphisms (SNPs). [7 included SNPs showed great risk allele heterogeneity among different studies with same population]. Two SNPs, rs760761 and rs3213207, which demonstrated the greatest heterogeneity, showed significant locus association with schizophrenia in the overall pooled sample. Instead of ignoring those significances for heterogeneity, we suggest to use a multi-susceptibility-SNP model to explain the result. Our findings supported DTNBP1 as a schizophrenia susceptibility gene and suggest that the inconsistencies of previous studies results from multiple risk variants within DTNBP1. Thus, much denser mapping is required to find exclusive markers tagging the real risk variants.Results from a number of molecular and pharmacological studies suggest that the phosphatidylinositol-4-phosphate 5-kinase IIα(PIP5K2A) gene may be involved in the development of schizophrenia. A recent family-based transmission disequilibrium test in the German and Israeli populations found that four single nucleotide polymorphisms, rs1417374, rs10828317, rs746203 and rs8341 in this gene or nearby intergenic regions are significantly associated with schizophrenia. The objective of our study was to investigate whether these four SNPs are also associated with schizophrenia in the Chinese population. Our study found that SNP rs8341 (p=0.0045, Odds Ratio=1.415, 95%CI=1.113~1.799 for the minor allele) and a haplotype (p =0.0039, Odds Ratio=1.440, 95%CI=1.123~1.845) are significantly associated with schizophrenia. Our results confirm that the PIP5K2A gene merits further study as a susceptible gene for schizophrenia. |
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