[Show abstract][Hide abstract] ABSTRACT: The cholecystokinin type A receptor (CCKAR) gene has been found to be associated with positive symptoms in patients with schizophrenia but the results reported to date are inconsistent. Considering the involvement of allelic heterogeneity in poor replication of the CCKAR finding, we genotyped five single nucleotide polymorphisms (SNPs) located in the 5' putative regulatory region of the CCKAR gene in a Chinese case-control sample and then applied the 5-SNP haplotype analysis to extract allelic heterogeneity information. The results showed that three individual haplotypes were strongly associated with increased risk of schizophrenia (corrected P = 2.9 × 10(-4), P = 2.5 × 10(-5), and P = 1.4 × 10(-5), respectively) and their combination gave an odds ratio (OR) of 6.12 with 95% CI 3.67-10.21 (P = 6.7 × 10(-15)). The haplotypes were also associated with some clinical symptoms including hallucination, suspiciousness, and hostility. Our work provided further evidence in support of the CCKAR hypothesis of schizophrenia and also suggested that haplotype-based association analysis may be a powerful approach for identification of allelic heterogeneity of a disease-underlying gene, which is very likely to be attributable to poor replication of an initial finding due to the reduction of sample power and the complexity of genetic architectures.
No preview · Article · Sep 2012 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
[Show abstract][Hide abstract] ABSTRACT: The dopamine receptor genes have been implicated in the pathogenesis of schizophrenia, but definitive evidence of association is still lacking. To identify whether functional variants of the D2-like receptors (DRD2, DRD3 and DRD4) confer risk of schizophrenia, we conducted a two-stage association study. We firstly examined the SNPs in functional genomic regions, such as mRNA splicing, protein coding and the promoter regions in DRD2, DRD3 and DRD4, respectively, for association in 289 Han Chinese cases with schizophrenia and 367 healthy controls and then further analyzed the significantly associated single nucleotide polymorphisms (SNPs) with this disorder in an additional Han Chinese sample consisted of 1351 cases and 1640 control subjects. In the first stage, the chi-square test (χ(2)) showed disease association for rs1076560 in DRD2 (p=0.040 for allelic association and p=0.033 for genotypic association, respectively). However, rs6280 in DRD3 and rs3758653 in DRD4 failed to show either allelic or genotypic association with the illness. The association between rs1076560 and schizophrenia was replicated in the second stage. The rs1076560-T allele, which shifts splicing from the D2 short isoform (D2S) to the D2 long isoform (D2L), was over-presented in the patient group (44%) than in the control group (41%) (χ(2)=5.19, p=0.023, OR=1.13, 95% CI=1.02-1.25). Therefore, the rs1076560 variant of DRD2 reliably influences risk of schizophrenia in Han Chinese, although more data are required to elucidate the pathophysiological mechanisms of possessing this risk-conferring variant.
No preview · Article · Apr 2012 · Neuroscience Letters
[Show abstract][Hide abstract] ABSTRACT: The dopamine transporter (DAT1) gene has been implicated in the pathogenesis of many neuropsychiatric disorders, including schizophrenia. The present study aimed to investigate association of the DAT1 gene polymorphisms with schizophrenia in a Han Chinese population. Two single nucleotide polymorphisms (SNPs) in the DAT1 gene (rs2975223 and rs2455391) were tested in 368 patients with schizophrenia and 420 healthy controls, of whom 293 patients underwent an assessment of psychotic symptoms through the positive and negative syndrome scale (PANSS). The chi-square test (χ(2)) showed disease association for rs2455391 (corrected p=0.023 for allelic association and p=0.034 for genotypic association, respectively). The rs2975223(G)-rs2455391(C) haplotype was associated with increased risk of the illness (p=0.0012, OR=2.09, 95% CI=1.28-3.42). Quantitative trait analysis showed that rs2455391 was associated with positive symptoms, general symptoms and global symptoms but not with negative symptoms. The present results suggest that the DAT1 gene may be mainly involved in the development of the positive symptoms in the Chinese population.
No preview · Article · Feb 2012 · Neuroscience Letters