Association study of a (TG)n dinucleotide repeat at chromosome 15q13.3 and schizophrenia in the Chinese population.

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (TG)n dinucleotide repeat polymorphism at D15S976 and schizophrenia was investigated using two independent samples from the Han Chinese population. In a population-based study, no significant difference was found between the genotype and allele frequency distributions in schizophrenia patients and control subjects. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Further analysis of the parent-of-origin effect found nominally significant allele-wise transmission disequilibrium through maternal transmissions, while 157bp and 159bp alleles showed significant individual allelic transmission disequilibrium from heterozygous mothers to affected offspring. Our results did not support the hypothesis that the (TG)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility in the Chinese population. Further studies are needed to elucidate the putative parent-of-origin effect and its role in schizophrenia susceptibility.

[Association study of an (AC)n dinucleotide repeat and schizophrenia in Asian and European populations].

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (AC)n dinucleotide repeat polymorphism at D15S118 and schizophrenia was investigated using three independent samples from the Han Chinese population and the Scotland population. In the population-based study, a significant difference was found between the allele frequency distributions in schizophrenia patients and control subjects in the Scottish samples (P = 0.04), but was not replicated in the Chinese samples. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Overall, our results did not support the hypothesis that the (AC)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility, at least in the Chinese population. Further studies are needed to elucidate its role in schizophrenia susceptibility in European population.

Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia.

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15-60 years) were given risperidone at dosages ranging from 2-8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal-Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.

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.

The DNA methylation profile within the 5'-regulatory region of DRD2 in discordant sib pairs with schizophrenia.

Studies of discordance in monozygotic twins have demonstrated that environmental effects play an important role in the pathogenesis of schizophrenia. DNA microarray analysis has revealed upregulation of the DRD2 gene in peripheral blood lymphocytes of schizophrenic patients. We hypothesized that this expression alteration could involve the DNA (CpG) methylation status that is implicated to the transcription status of the gene and in this study we used bisulfited sequence analysis to determine the DNA methylation status of a typical CpGs island within the 5'-regulatory region of DRD2 in peripheral blood lymphocytes from 48 discordant sib pairs suffering from schizophrenia. We found that the methylated cytosines occurred mainly in three clusters. No statistically significant difference in frequency of site-specific cytosine methylation modification of DRD2 between patients and normal controls was found nor did we find any significant association between sex, age on admission or age at onset of schizophrenia and methylated cytosines of DRD2. Our study did not support the hypothesis that site-specific cytosine methylation of DRD2 plays a role in the psychopathology of schizophrenia.

Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients.

AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians.

Population-based and family-based association studies of an (AC)n dinucleotide repeat in alpha-7 nicotinic receptor subunit gene and schizophrenia.

The human alpha-7 neuronal nicotinic receptor subunit (CHRNA7) gene, located at chromosome 15q13.2, represents a strong candidate gene for schizophrenia. We have examined an (AC)n dinucleotide repeat in intron 2 of the CHRNA7 gene, which was previously shown to be strongly linked with schizophrenia, using both population-based and family-based association studies. In the population-based study, no significant differences between the genotype and allele frequency distributions in schizophrenia patients and control subjects were observed after correction for multiple testing, although a nominally significant association between the most common allele and schizophrenia was observed (P = 0.023, uncorrected for multiple testing). In the family-based study, there is no significant over-transmission (Transmitted/Non-transmitted: 61/50) of the same allele in 160 family trios. Overall, our results do not support a major role for the (AC)n dinucleotide repeat in schizophrenia susceptibility in Han Chinese. Further large-scale genetic studies based on a set of single nucleotide polymorphisms (SNPs) that fully characterize the linkage disequilibrium patterns at the CHRNA7 gene are necessary to determine the relevance of this gene as a risk factor for schizophrenia susceptibility.

Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis.

BACKGROUND: A common functional polymorphism (Val/Met) in the catechol-O-methyltransferase gene (COMT) that markedly affects enzyme activity has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans. It is hypothesized that the high activity Val allele slightly increases risk for schizophrenia through its effect on dopamine-mediated prefrontal information processing. METHODS: We compared the allele/genotype frequencies of the Val/Met polymorphism in a large independent patient-control sample (862 patient and 928 healthy control subjects) from Han Chinese population, and an update meta-analysis was performed to assess the collective evidence across individual studies. RESULTS: No statistically significant differences were found in allele or genotype frequencies between patient and normal control subjects, although a nonsignificant overrepresentation of the Val allele in schizophrenia patients (odds ratio [OR] = 1.09, 95% confidence interval [CI] = .94-1.26) was suggested. Comparatively, the meta-analysis of all published population-based association studies showed statistically significant evidence for heterogeneity among the group of studies. Stratification of the studies by ethnicity of the samples yielded no significant evidence for an association with the Val allele in Asian population (OR = .96, 95% CI = .85-1.09), nor in European population (OR = 1.06, 95% CI = .95-1.19). CONCLUSIONS: Our data provide minimal evidence that the Val allele is a susceptibility factor for schizophrenia in either European or Asian populations.

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.

Polymorphism of Prodynorphin promoter is associated with schizophrenia in Chinese population.

AIM: To investigate the correlation between single nucleotide polymorphisms (SNPs) of functional candidate gene Prodynorphin (PDYN) and schizophrenia. METHODS: SNPs in the promoter and exon regions of PDYN were screened and genotyped for association study in a cohort of Chinese Han schizophrenia cases and controls. RESULTS: Two SNPs PDYN-1576C>T and PDYN-946C>G were identified in the promoter region but PDYN-946C>G showed significant differences of allele distribution (x2=6.15, P=0.013) and genotype distribution (x2=6.87, P=0.032) between schizophrenic and control subjects. CONCLUSION: PDYN-946C>G polymorphism demonstrated an association with population susceptibility to schizophrenia.

[Transmission disequilibrium test of polymorphisms of serotonin transporter gene and schizophrenia based on family trios].

OBJECTIVE: To investigate the relationship between two polymorphisms (Intronic VNTR and 5-HTTLPR) of the serotonin transporter gene and schizophrenia. METHODS: A set of 314 schizophrenic trio samples collected from Shanghai, Xi'an and Jilin regions of China independently was subjected to analysis of the polymorphisms by transmission/disequilibrium test(TDT). RESULTS: No significantly preferential transmission of any allele was detected from both polymorphisms investigated. CONCLUSION: The results suggest that the serotonin transporter gene is unlikely to have a major contribution to susceptibility to schizophrenia in Han Chinese population.

A family-based association study of T1945C polymorphism in the proline dehydrogenase gene and schizophrenia in the Chinese population.

Previous studies have reported genetic linkage evidence for a candidate gene of schizophrenia on chromosome 22q11 but no genes in this region have been really confirmed to be involved in the etiology of schizophrenia so far. Very recently, the proline dehydrogenase gene (PRODH), located in the most centromeric part of the 22q11 microdeletion region, has been reported to be strongly associated with schizophrenia from three sets of independent samples and the most significant evidence for association was derived from a single nucleotide polymorphism-PRODH*1945(T/C). We genotyped this polymorphism in 166 Chinese family trios with schizophrenia from East China. No evidence for preferential transmission of the PRODH*1945 alleles from parents to affected offsprings was found using either Transmission Disequilibrium Test (P=0.4) or Haplotype-based Haplotype Relative Risk analysis (P=0.35). Our results suggest that the 1945(T/C) polymorphism of the proline dehydrogenase gene is unlikely to play a major role in the susceptibility to schizophrenia in the Chinese population.