Xinzhi Zhao

Functional Variants in the Promoter Region of Chitinase 3–Like 1 (CHI3L1) and Susceptibility to Schizophrenia

The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.

An association between polymorphisms of the interleukin-10 gene promoter and schizophrenia in the Chinese population

Immunological abnormalities have been found to be associated with schizophrenia for decades. Cytokines are key proteins involved in the immune system activation. Interleukin-10 (IL-10), an important immunoregulatory cytokine, is located on chromosome 1q31-32, a region previously reported to be linked to schizophrenia in genetic studies. Thus, a study was carried out on the association between schizophrenia and three single nucleotide polymorphisms in the promoter region of IL-10 gene. Totally, 341 patients and 334 controls of Chinese descent were analyzed. Statistically significant differences were observed in both allelic and genotypic frequencies of the -592A/C polymorphism (Allele, chi(2)=4.43, df=1, P=0.032, odds ratio (OR)=1.26, 95% CI 1.02-1.56; Genotype, chi(2)=6.18, df=2, P=0.044) while the other two polymorphisms did not show such differences. The observed haplotype distributions revealed a significant association with schizophrenia (P=0.0008). These data suggest that the IL-10 gene may confer susceptibility to the development of schizophrenia in the Chinese population.

A Comparative Proteomics Analysis of Rat Mitochondria from the Cerebral Cortex and Hippocampus in Response to Antipsychotic Medications

An increasing number of experiments have found anomalies in mitochondria in the brains of psychotics, which suggests that mitochondrial dysfunction or abnormal cerebral energy metabolism might play an important role in the pathophysiology of schizophrenia (SCZ). We adopted a proteomic approach to identify the differential effects on the cerebral cortex and hippocampus mitochondrial protein expression of Sprague-Dawley (SD) rats by comparing exposure to typical and atypical antipsychotic medications. Differential mitochondrial protein expressions were assessed using two-dimensional (2D) gel electrophoresis for three groups with Chlorpromazine (CPZ), Clozapine (CLZ), quetiapine (QTP) and a control group. A total of 14 proteins, of which 6 belong to the respiratory electron transport chain (ETC) of oxidative phosphorylation (OXPHOS), showed significant changes in quantity including NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 10 (Ndufa10), NADH dehydrogenase (ubiquinone) flavoprotein 2 (Ndufv2), NADH dehydrogenase (ubiquinone) Fe-S protein 3 (Ndufs3), F1-ATPase beta subunit (Atp5b), ATPase, H+ transporting, lysosomal, beta 56/58 kDa, isoform 2 (Atp6v1b2) and ATPase, H+ transporting, V1 subunit A, isoform 1 (Atp6v1a1). The differential proteins subjected to 2D were assessed for levels of mRNA using quantitative real time PCR (Q-RT-PCR), and we also made partial use of Western blotting for assessing differential expression. The results of our study may help to explain variations in SD rats as well as in human response to antipsychotic drugs. In addition, they should improve our understanding of both the curative effects and side effects of antipsychotics and encourage new directions in SCZ research.

Significant Association Between the Genetic Variations in the 5′ End of the N-Methyl-D-Aspartate Receptor Subunit Gene GRIN1 and Schizophrenia

BACKGROUNDnN-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A, are both good candidate genes for schizophrenia.nnnMETHODnWe genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case-control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann-Whitney U test was performed.nnnRESULTSnA highly significant association was detected at the 5 end of GRIN1. Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case-control study: p = .0000013, odds ratio = .61, 95% confidence interval .50-.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms.nnnCONCLUSIONSnOur results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5 untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study.

Family-based association study of synapsin II and schizophrenia.

Synapsin II has been proposed as a candidate gene for vulnerability to schizophrenia on the basis of its function and its location in a region of the genome implicated by linkage studies in families with schizophrenia. We recently reported positive association of synapsin II with schizophrenia in a case-control study (Chen et al. 2004). However, since case-control analyses can generate false-positive results in the presence of minor degrees of population stratification, we have performed a replication study in 366 additional Han Chinese probands and their parents by use of analyses of transmission/disequilibrium for three in/del markers and three single-nucleotide polymorphisms. Positive association was observed for rs2307981 (P =.02), rs2308169 (P =.005), rs308963 (P =.002), rs795009 (P =.02), and rs2307973 (P =.02). For transmission of six-marker haplotypes, the global P value was.0000016 (5 degrees of freedom), principally because of overtransmission of the most common haplotype, CAA/-/G/T/C/- (frequency 53.6%; chi (2) = 20.8; P =.0000051). This confirms our previous study and provides further support for the role of synapsin II variants in susceptibility to schizophrenia.

Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients.

Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P=0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P=0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency.

Effects of the dopamine D3 receptor (DRD3) gene polymorphisms on risperidone response: a pharmacogenetic study.

Previous observations of the anatomical distribution and pharmacological profile of the dopamine D3 receptor (DRD3) have indicated its potential role in antipsychotic drug action. Risperidone, an effective first-line atypical antipsychotic agent, exhibits a relatively high affinity for this receptor. Recent studies have reported an association of the Ser9Gly polymorphism in the DRD3 gene with therapeutic response to risperidone, but the results were inconsistent. We therefore postulated that the Ser9Gly polymorphism might be in linkage disequilibrium with an undetected variant that exerts a direct influence on risperidone efficacy. The present study genotyped eight single nucleotide polymorphisms (SNPs) distributed throughout the DRD3 gene and examined five of these for association with treatment outcome, following an 8-week period of risperidone monotherapy in 130 schizophrenic patients from mainland China. Clinical symptoms were assessed before and after the treatment period, using the Brief Psychiatry Rating Scale (BPRS). The confounding effects of non-genetic factors were estimated and the baseline symptom score was included as a covariate for adjustment. Neither was any association observed between the five polymorphisms and improvement in total BPRS scores nor was any combined effect of these variants detected in the haplotype analysis. The current results indicate that genetic variations within the DRD3 gene may not contribute significantly to interindividual differences in the therapeutic efficacy of risperidone.

Association between a polymorphism of the HTR3A gene and therapeutic response to risperidone treatment in drug-naive Chinese schizophrenia patients.

Objectives Certain components of the serotonin system have been known for some time to be risk factors for schizophrenia. Few studies have, however, focused on the association between the therapeutic responses to atypical antipsychotics, such as risperidone, and polymorphisms of the 5-HT3 receptor, the only ionotropic ligand-gated serotonin receptor, even though there have been some genetic clues linking HTR3A and schizophrenia. We therefore postulated that such a polymorphism might be an explanatory factor in the diversity of response to risperidone treatment. Methods The study recruited 107 drug-naive Chinese schizophrenia patients who were given 8 weeks of risperidone monotherapy and it explored three of four single nucleotide polymorphisms spanning HTR3A for possible association with therapeutic improvement, using the Positive and Negative Symptom Scale. Results Significant correlation between the baseline score and therapeutic improvement was observed in each subscale (P<0.001). Statistical analysis revealed association between genotypes of g.14396A>G polymorphism (rs1176713) and score reductions of negative and general subscales after adjusting for the influence of the baseline scores of each subscale [P (F, d.f.)=0.026 (3.763, 2), 0.023 (3.937, 2) respectively]. One haplotype, C-A-G, contributed to an effective response in general symptoms (χ2=7.3, P=0.007, odds ratio=3.371). Conclusion The results of this study are the first to suggest that the polymorphism of HTR3A may be a useful predictor of therapeutic response to risperidone treatment in Chinese schizophrenic patients, although these conclusions should be treated with caution because of the intricacy of the variety of the therapeutic effects to risperidone.

Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia

Summary.Studies suggest that GAD1 gene is a functional candidate susceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplotype levels. Altogether, we have found 17 variants including 10 SNPs in 5′-flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3′-untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5′-flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P = 0.0063, respectively; odds ratio = 1.83; 95% confidence interval: 1.26–2.65) and the male offsprings the trios (P = 0.0045, respectively; odds ratio = 2.21; 95% confidence interval: 1.37–3.56). Haplotype analysis suggested that rs3762556(C)–rs3791878(G)–rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P = 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the complexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcriptional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia.

No association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Chinese population

Summary.The RTN4R gene is located in the 22q11 region and it encodes a subunit of the receptor complex (RTN4R-p75NTR) which results in neuronal growth inhibitory signals in response to Nogo-66, MAG or OMG signaling. Previous studies have suggested that RTN4R might act as a potential candidate for schizophrenia susceptibility loci. We genotyped four SNPs within the gene and conducted a case-control study and TDT analysis, involving 707 schizophrenic patients, 689 controls and 372 unrelated small nuclear families with schizophrenic offspring in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in both family- and nonfamily-based samples. Our results suggest that there is no significant association between the genetic polymorphisms and schizophrenia in the Han Chinese population.