Yasong Du

Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population.

Schizophrenia is a chronic and severe mental illness which is characterized by the development of various detrimental clinical features, and its etiology still remains unknown. Based on the evidence from neurobiological and pharmacological research, dysfunctions in central serotonergic transmission may be involved in the development of schizophrenia. Tryptophan hydroxylase 2 (TPH2), a newly identified isoform of tryptophan hydroxylase (the rate limiting enzyme in the biosynthesis of serotonin), regulates the brain-specific serotonin synthesis. To further clarify the role of TPH2 in this disease, we performed a case-control study to examine the association of the TPH2 gene with schizophrenia and its clinical features. We genotyped three putative functional polymorphisms (rs4570625, rs7305115, and rs4290270) within the gene and carried out a case-control study consisting of 304 schizophrenia patients and 362 healthy subjects. The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). The frequencies of genotypes and alleles of rs4570625, rs7305115, and rs4290270 did not differ significantly between schizophrenic patients and controls. However, the PANSS positive symptom subcore was significantly associated with rs4570625 (P = 0.022). These results suggest that rs4570625 of TPH2 may play an important role in the development of positive symptoms in Han Chinese schizophrenic patients.

ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis.

Histological and neuroimaging evidence supports the hypothesis that neuronal disconnectivity may be involved in the pathogenesis of schizophrenia. A genome‐wide association study (GWAS) showed a single nucleotide polymorphism (SNP), rs10761482 in ankyrin 3 (ANK3), a major neuron‐enriched gene, was associated with schizophrenia although inconsistent results had been reported. Two meta analyses reported another SNP rs10994336 in ANK3 gene confers risk to bipolar disorder (BD). Due to evidence of genetic overlap between schizophrenia and BD, we investigated common findings by analyzing the association of ANK3 polymorphisms (rs10761482, rs10994336, and two missenses, rs3808942 and rs3808943) with schizophrenia, using the Han Chinese population. A total of 516 schizophrenia cases, 400 controls, and 81 trios of early onset schizophrenia were recruited for association studies. Furthermore, the published datasets were combined with our results to determine the effect of the loci on schizophrenia. Our association study showed the frequencies of C allele of rs10761482 and T allele of rs10994336 were higher in patients than in controls. Furthermore, allele condition analyses indicated the association signal observed at rs10761482 and rs10994336 was independent. A haplotype analysis revealed the rs10761482–rs3808942–rs3808943 haplotype was associated with schizophrenia. The frequency of the T–T–T haplotype was higher in patients than in controls. In the transmission disequilibrium test analysis, the C allele of rs10761482 and the rs10761482–rs3808942–rs3808943 haplotype were preferentially transmitted in the trios. Meta analysis incorporating previous and current studies also showed rs10761482 and rs10994336 were associated with schizophrenia. We conclude that ANK3 gene has a major influence on susceptibility to schizophrenia across populations.

DNA methyltransferase 3B gene increases risk of early onset schizophrenia.

OBJECTIVE Consistent evidence indicated that aberrant DNA methylation may be involved in the development of schizophrenia. DNA methyltransferase 3B (DNMT3B) is the key methyltransferase in DNA methylation regulations. In this study, we investigated the association between DNMT3B polymorphisms and the susceptibility of early onset schizophrenia in Chinese Han population. METHODS Case-control (patients=381 and controls=472) and family based (trios=103) study was performed through genotyping two tag single nucleotide polymorphisms (rs2424908 and rs6119954) covering the whole DNMT3B gene. Single nucleotide polymorphism association and haplotype analysis were performed. RESULTS The frequency of G allele of rs6119954 was significantly higher in patients than that in controls (P=0.017). Genotype distribution of rs6119954 was significantly different between patients and controls (P=0.046). A haplotype-wise analysis revealed a higher frequency of the T-G (rs2424908-rs6119954) haplotype in patients than that in controls (P=0.033). In the transmission disequilibrium test analysis, G allele of rs6119954 was preferentially transmitted in the trios (P=0.030). CONCLUSION Our findings indicate that DNMT3B may be a candidate gene for susceptibility to early onset schizophrenia.

No genetic association between dopamine D1 receptor gene and [early onset] schizophrenia

Decreased dopaminergic activity in the prefrontal cortex (PFC) has been consistently reported in schizophrenia patients. The dopamine D1 receptor (DRD1) plays an important role in mediating dopaminergic transmission in the PFC. Controversy about this topic still exists despite ample evidence suggesting that the DRD1 gene is associated with performance on neuropsychological tests probing the function of the PFC in schizophrenia, as well as positive and negative symptoms and therapeutic response to antipsychotics. To determine whether this gene is involved in the etiology of schizophrenia, we undertook a case-control study to look for an association. We genotyped five single nucleotide polymorphisms (SNPs) rs4532, rs5326, rs2168631, rs6882300 and rs267418 within the DRD1 involving 373 schizophrenia patients with early age of onset and 379 healthy subjects. No significant differences of genotype, allele or haplotype distribution were identified between patients and controls. Our results do not preclude a possible role of DRD1 in the etiology of schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes. Further relevant studies are warranted.

Identification of ANKK1 rs1800497 Variant in Schizophrenia: New Data and Meta-Analysis

One functional polymorphism (rs1800497) within the ankyrin repeat and kinase domain containing‐1 gene (ANKK1) was reported to be associated with schizophrenia, but results among different studies vary and conclusions remain controversial. The present study sought to clarify this potential association among a population of Han Chinese with early onset schizophrenia using a case‐control (396 patients and 399 controls) and family based study (103 trios). We then performed a meta‐analysis (comprising 11 case‐control and 2 family‐based studies) based on the present literature. Results of the association study revealed no significant difference in allele and genotype frequencies between the cases and controls, and no significant transmission distortion was detected. Kaplan–Meier survival analysis showed that age at onset in schizophrenia was significantly associated with the rs1800497 polymorphism in female patients, but not in males. Female T allele carriers had a lower age at onset than those without T allele (log rank statistic χ2 = 5.16, P = 0.023; corrected P = 0.046). Meta‐analysis results indicated that rs1800497 is not associated with schizophrenia in the overall population (P = 0.77 for the case‐control studies; P = 0.06 for the family‐based studies). Our results support the hypothesis that rs1800497 polymorphism is likely to have a modifying rather than causative effect on schizophrenia. These findings may represent a significant genetic clue for the etiology of schizophrenia in females, but further investigation is required to clarify the exact role of ANKK1 in the development of schizophrenia.

Effect of SOX10 gene polymorphism on early onset schizophrenia in Chinese Han population.

Schizophrenia is one of highly heritable psychiatric disorders. Patients with early onset schizophrenia tend to have a greater genetic loading and may be an attractive subpopulation for genetics studies. A single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10), a candidate gene for schizophrenia, was suggested to be associated with schizophrenia although inconsistent results had been reported. The aim of this study was to evaluate the association between SOX10 rs139887 polymorphism and schizophrenia using an early onset sample in the Chinese Han population. A total of 321 schizophrenic patients with onset before age 18 and 400 healthy controls were recruited for association study. In addition, two populations involved in three studies were selected for meta-analysis to determine the effect of rs139887 on schizophrenia. Our association study results showed that the allele and genotype frequencies were significantly different between schizophrenic patients and controls (P=0.013 and P=0.034, respectively). Interestingly, a significant association in allele and genotype frequencies were found in male patients (P=0.017 and P=0.045, respectively), but not female patients. Moreover, the C/C genotype had a significant association with an earlier age of onset in male schizophrenic patients (Kaplan-Meier log-rank test P=0.029), but not in female patients (Kaplan-Meier log-rank test P=0.876). The meta-analysis result showed the same C allele was significantly associated with schizophrenia (P=0.007). In conclusion, the SOX10 rs139887 polymorphism was related to the development of schizophrenia in a gender-specific manner, and may be a significant genetic marker for managing subgroups and etiological clues in schizophrenia.

Influence of maternal MTHFR A1298C polymorphism on the risk in offspring of schizophrenia

Several lines of evidence have suggested that two functional methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, C677T and A1298C, may be implicated in the etiology of schizophrenia. We examined these MTHFR polymorphisms in 111 families, composed of a patient and their parents, as well as 143 mothers of patients with schizophrenia and 235 age-matched mothers who had healthy children. The maternal MTHFR 1298C allele was associated with a significantly increased risk of schizophrenia (OR=1.63, 95%CI: 1.11-2.39, P=0.01). The haplotype analysis showed a weak association for the 1298C-677C haplotype (OR=1.54, 95%CI=1.03-2.29, P=0.04). Analysis of Transmission Disequilibrium Test (TDT) showed no preferential transmission of 1298C and 677T alleles from parents to probands (P=0.64 and P=0.71, respectively). Our results suggest that deficient MTHFR enzyme activity in pregnant women, related to the A1298C variant, is associated with a higher risk of having offspring affected with schizophrenia. Given the low sample size in this study, the present results seem tentative and need further studies to replicate.

Further evidence that methylenetetrahydrofolate reductase A1298C polymorphism is a risk factor for schizophrenia.

Previous work suggests that the methylenetetrahydrofolate reductase gene (MTHFR) functional polymorphism A1298C may be a risk factor for schizophrenia. In this study, the genetic association between the MTHFR A1298C polymorphism and schizophrenia was investigated in 379 patients with schizophrenia and 380 age- and sex-matched controls subjects. The results showed an association between the 1298C allele and the disorder (OR 1.39, 95% confidence interval 1.08–1.79). This provides further evidence that the MTHFR A1298C polymorphism may play a role in conferring risk for schizophrenia in the Chinese Han population.

A Simple Spatial Working Memory and Attention Test on Paired Symbols Shows Developmental Deficits in Schizophrenia Patients

People with neuropsychiatric disorders such as schizophrenia often display deficits in spatial working memory and attention. Evaluating working memory and attention in schizophrenia patients is usually based on traditional tasks and the interviewers judgment. We developed a simple Spatial Working Memory and Attention Test on Paired Symbols (SWAPS). It takes only several minutes to complete, comprising 101 trials for each subject. In this study, we tested 72 schizophrenia patients and 188 healthy volunteers in China. In a healthy control group with ages ranging from 12 to 60, the efficiency score (accuracy divided by reaction time) reached a peak in the 20–27 age range and then declined with increasing age. Importantly, schizophrenia patients failed to display this developmental trend in the same age range and adults had significant deficits compared to the control group. Our data suggests that this simple Spatial Working Memory and Attention Test on Paired Symbols can be a useful tool for studies of spatial working memory and attention in neuropsychiatric disorders.