Jingyuan Zhao

Activation of Th17 cells in drug naïve, first episode schizophrenia.

OBJECTIVE The present study was to examine the role of pro-inflammatory T helper 17 (Th17) cells in drug naïve, first episode schizophrenia. METHOD Patients with normal weight, drug naïve, first episode schizophrenia and healthy controls were enrolled in the study. Flow cytometric analysis was performed to analyze the proportion of Th17 cells among the CD4(+) T cells. Plasma levels of interleukin-17 (IL-17), interferon-γ (IFN-γ) and interleukin-6 (IL-6) were examined using enzyme-linked immunosorbent assay (ELISA). Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). All measures were repeated for the patient group after 4 weeks of risperidone treatment. RESULTS Sixty-nine patients with normal weight, drug naïve, first episode schizophrenia and 60 healthy controls were enrolled. At baseline, the patient group hadz significantly higher proportions of Th17 cells and plasma levels of IFN-γ and IL-6 compared with the control group (ps<0.01). Within the patient group, there were significant positive relationships between the proportion of Th17 cells, plasma levels of IL-17, IFN-γ, IL-6 and the PANSS total score after controlling for potential confounding variables (ps<0.05). After 4weeks of risperidone treatment, the proportion of Th17 cells decreased significantly (p <0.001), and there was a significant positive relationship between the PANSS total score change rate and the change in proportion of Th17 cells (p = 0.039). CONCLUSIONS Patients with normal weight, drug naïve, first episode schizophrenia present activation of Th17 cells, which might be associated with therapeutic response after risperidone treatment.

Association between Ghrelin gene (GHRL) polymorphisms and clinical response to atypical antipsychotic drugs in Han Chinese schizophrenia patients

BackgroundGhrelin (GHRL) is a pivotal peptide regulator of food intake, energy balance, and body mass. Weight gain (WG) is a common side effect of the atypical antipsychotics (AAPs) used to treat schizophrenia (SZ). Ghrelin polymorphisms have been associated with pathogenic variations in plasma lipid concentrations, blood pressure, plasma glucose, and body mass index (BMI). However, it is unclear whether GHRL polymorphisms are associated with WG due to AAPs. Furthermore, there is no evidence of an association between GHRL polymorphisms and SZ or the therapeutic response to AAPs. We explored these potential associations by genotyping GHRL alleles in SZ patients and controls. We also examined the relation between these SNPs and changes in metabolic indices during AAP treatment in SZ subgroups distinguished by high or low therapeutic response.MethodsFour SNPs (Leu72Met, -501A/C, -604 G/A, and -1062 G > C) were genotyped in 634 schizophrenia patients and 606 control subjects.ResultsThere were no significant differences in allele frequencies, genotype distributions, or the distributions of two SNP haplotypes between SZ patients and healthy controls (P > 0.05). There was also no significant difference in symptom reduction between genotypes after 8 weeks of AAP treatment as measured by positive and negative symptom scale scores (PANSS). However, the -604 G/A polymorphism was associated with a greater BMI increase in response to AAP administration in both APP responders and non-responders as distinguished by PANSS score reduction (P < 0.001). There were also significant differences in WG when the responder group was further subdivided according to the specific AAP prescribed (P < 0.05).ConclusionsThese four GHRL gene SNPs were not associated with SZ in this Chinese Han population. The -604 G/A polymorphism was associated with significant BW and BMI increases during AAP treatment. Patients exhibiting higher WG showed greater improvements in positive and negative symptoms than patients exhibiting lower weight gain or weight loss.

Association study of myelin transcription factor 1-like polymorphisms with schizophrenia in Han Chinese population

Schizophrenia (SZ) is characterized by a variety of complex positive, negative and cognitive symptoms that are differentially expressed in individual patients. Variability in symptom presentation indicates that multiple genes, many involved in neurodevelopment, contribute to the etiology of SZ. The myelin transcription factor 1‐like (MYT1L) gene encodes the MYT1L protein that participates in several neurodevelopment pathways. The copy number variant of MYT1L gene is associated with SZ, and single‐nucleotide polymorphisms (SNPs) of MYT1L contribute to major depressive disorder. To explore the association of MYT1L polymorphisms with SZ, we examined six SNPs of MYT1L in a Han Chinese population consisting of 528 paranoid schizophrenic patients and 528 healthy subjects. Our results showed that rs17039584 was significantly associated with SZ (A>G), even after Bonferroni correction. When subjects were divided by gender, the rs10190125 allele and genotype remained significantly associated with SZ in female patients. Moreover, we found that rs6742365 was associated with a family history of SZ in females. Other SNPs did not achieve statistical significance for SZ but were associated with individual phenotypes, as measured by the Positive and Negative Syndrome Scale (PANSS) inventory. Our findings suggest that MYT1L may represent a susceptibility gene for SZ in the Han Chinese population and show that a specific SNP may increase susceptibility in females.

Association of MicroRNA137 Gene Polymorphisms with Age at Onset and Positive Symptoms of Schizophrenia in a Han Chinese Population

Objectives: MicroRNA137 (miRNA137) regulates several gene expressions involved in brain development, and a recent large genome wide association study (GWAS) revealed a possible association between miRNA137 and schizophrenia. Methods: The allelic variants of rs66642155, a variable number tandem repeat polymorphism, and the single nucleotide polymorphism rs1625579 A/C in the miRNA137 host gene fragment were compared between 300 schizophrenic patients and 300 healthy controls from the Han Chinese population. The association of these polymorphisms with clinical characteristics of schizophrenia was also tested. Results: Genotype and allele frequencies of these polymorphisms were not significantly different between patient and control populations. In patients, however, age at onset was much later in wild type rs66642155 carriers than in mutation carriers. Total positive score on the Positive and Negative Symptom Scale (PANSS), total five-factor model positive score, and the delusions symptom score were all significantly higher in wild type rs66642155 carriers with schizophrenia, while the disturbance of volition symptom score was significantly higher in the mutation carriers with schizophrenia. Conclusions: MiRNA137 may not be a significant susceptibility gene for schizophrenia, but in patients, rs66642155 allelic variant of miRNA137 appears to influence age at onset and the severity of positive symptoms.

Association study of RELN polymorphisms with schizophrenia in Han Chinese population.

Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p=0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p=0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR=0.24, 95%CI=0.14-0.40 for CC and OR=0.40, 95%CI=0.27-0.58 for AC), both in the allele and genotype (p=0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.

Association of serotonin transporter gene (SLC6A4) polymorphisms with schizophrenia susceptibility and symptoms in a Chinese-Han population

Schizophrenia (SZ) is a complex psychiatric disorder with a strong genetic component. The serotonin transporter (SERT), encoded by solute carrier family 6 member 4 (SLC6A4), regulates synaptic concentrations of serotonin and thereby strongly influences perception, mood, emotion, behavior, and cognition, all of which are severely disturbed in SZ. Two variable numbers of tandem repeat (VNTR) polymorphisms and several single nucleotide polymorphisms (SNPs) spread throughout SLC6A4 are involved in both neuropsychiatric diseases (including SZ) and personality traits. In this study, case-control association analysis was performed in the Chinese-Han population to identify additional allelic variants of the SLC6A4 gene that may confer susceptibility to SZ. Ten relatively common SNPs (minor allele frequency >5%) were genotyped in 528 paranoid SZ patients and 528 control subjects. Significant associations were found between SZ and the allele and genotypic frequencies of rs140700G/A (p=2.45×10(-12), 2.34×10(-11), respectively). The frequency of the A allele was lower in SZ patients (17.7%) than in controls (30.9%; OR=1.93, 95%CI=1.58-2.36). In five factor analysis of the positive and negative syndrome scale (PANSS) scores of first episode SZ patients, mean negative factor score (F2,249=3.986, p=0.02) and depression/anxiety factor score (F2, 249=8.766, p=2.11×10(-4)) were significantly different among the rs140700G/A genotypes, with both scores higher for genotype AA than AG+GG. The rs140700G/A allele of SLC6A4 is strongly associated with SZ susceptibility and symptom expression in the Chinese-Han population.

Evaluation of the Relationship between the Znf804A Single Nucleotide Polymorphism Rs1344706 a/c Variant and Schizophrenia Subtype in Han Chinese Patients

Objective: Recent genome wide association studies (GWASs) assessing the relationship between schizophrenia (SZ) and the ZNF804A gene, particularly the single nucleotide polymorphism (SNP) rs1344706, have yielded conflicting results. Schizophrenia is a heterogeneous disorder, so it is possible that an association may be restricted to specific SZ subtypes and that population heterogeneity may obscure a contribution of ZNF804A allelic variation to SZ risk. We thus evaluated the association between rs1344706 and different clinical SZ subtypes in a large Han Chinese patient population. Method: The rs1344706 genotype was determined in 1,025 SZ patients and 977 healthy controls using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLPs). The clinical SZ subtypes included paranoid, catatonic, disintegrated, and undifferentiated, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). Results: No significant differences in genotype and allele frequencies were found between controls and either the total SZ population (A > C, χ2 = 4.339, 2.994; p = 0.227, 0.087, respectively) or paranoid SZ patients (χ2 = 2.053, 0.002; p = 0.562, 0.973, respectively). However, there was a significant association between genotype frequency and SZ subtype (χ2 = 12.632, p = 0.049). Conclusions: We found no evidence that the ZNF804A SNP rs1344706 is a susceptibility locus for SZ. However, conflicting results from previous association studies may be due to genetic heterogeneity between different patient SZ subtypes.

Adjunctive Aripiprazole Treatment for Risperidone-Induced Hyperprolactinemia: An 8-Week Randomized, Open-Label, Comparative Clinical Trial.

Objective The present study aimed to evaluate the efficacy and safety of adjunctive aripiprazole treatment in schizophrenia patients with risperidone-induced hyperprolactinemia. Methods One hundred and thirteen patients who were receiving a stable dose of risperidone were randomly assigned to either adjunctive aripiprazole treatment (10 mg/day) (aripiprazole group) or no additional treatment (control group) at a 1:1 ratio for 8 weeks. Schizophrenia symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). Rating scales and safety assessments (RSESE, BARS, UKU) were performed at baseline and at weeks 4 and 8. Serum levels of prolactin were determined at baseline and at weeks 2, 4, 6 and 8. Metabolic parameters were determined at baseline and again at weeks 4 and 8. Results One hundred and thirteen patients were enrolled in this study, and 107 patients completed the study (54 in the aripiprazole group, and 53 in the control group). PANSS-total scores in the aripiprazole group decreased significantly at week 4 (P = 0.003) and week 8 (P = 0.007) compared with the control group. PANSS-negative scores in the aripiprazole group also decreased significantly at week 4 (P = 0.005) and week 8 (P< 0.001) compared with the control group. Serum levels of prolactin in the aripiprazole group decreased significantly at week 2 (P< 0.001), week 4 (P< 0.001), week 6 (P< 0.001) and week 8 (P< 0.001) compared with the control group. There were no significant differences in changes of Fasting Plasma Glucose, Total cholesterol, Triglycerides and High Density Lipoprotein within each group at week 4 and 8 execpt low density lipoproteins. There was no significant difference in the incidence of adverse reactions between the two groups. Conclusions Adjunctive aripiprazole treatment may be beneficial in reducing serum levels of prolactin and improving negative symptoms in schizophrenia patients with risperidone-induced hyperprolactinemia. Trial Registration chictr.org ChiCTR-IOR-15006278

Association of estrogen receptor alpha gene polymorphism with age at onset, general psychopathology symptoms, and therapeutic effect of schizophrenia

BackgroundEstrogen is believed to play an important role in the central nervous system (CNS) and exert a protective role against schizophrenia. Estrogen receptor alpha (ESRα) mediates the biological action of estrogen. Rs2234693 and rs9340799, single nucleotide polymorphisms of ESRα, may be related to many psychiatric disorders, while their association with schizophrenia has not been clarified.MethodsGenotypes rs2234693 and rs9340799 were detected in 303 schizophrenic patients and 292 healthy controls in a Chinese population. The positive and negative syndrome scale (PANSS) was used to estimate symptoms and therapeutic effects. The association of these polymorphisms with schizophrenia and clinical characteristics was analyzed by the chi-square test, analysis of variance, and others.ResultsThe distribution of genotypes and allele frequencies of rs2234693 and rs9340799 exhibited no significant differences between patients and controls, while haplotypes consisting of these polymorphisms had significant differences. For 2234693, T-allele carriers had an earlier age at onset. CC-homozygote carriers had a higher general psychopathology score and its percentage reduction in male and paranoid patients, respectively. CC-homozygote carriers had a higher tension (G4) and poor impulse control (G14) score, mainly in paranoid patients. Furthermore, patients with the CC homozygote had higher reductions of G4 and G14 scores when treated by aripirazole and risperidone, respectively.ConclusionsHaplotypes consisting of these two polymorphisms in ESRα may be strongly associated with schizophrenia. The rs2234693 was related to age at onset, general psychopathology, G4 and G14 symptoms, even the therapeutic effect in different groups.

Association of ARHGAP18 polymorphisms with schizophrenia in the Chinese-Han population.

Numerous developmental genes have been linked to schizophrenia (SZ) by case-control and genome-wide association studies, suggesting that neurodevelopmental disturbances are major pathogenic mechanisms. However, no neurodevelopmental deficit has been definitively linked to SZ occurrence, likely due to disease heterogeneity and the differential effects of various gene variants across ethnicities. Hence, it is critical to examine linkages in specific ethnic populations, such as Han Chinese. The newly identified RhoGAP ARHGAP18 is likely involved in neurodevelopment through regulation of RhoA/C. Here we describe four single nucleotide polymorphisms (SNPs) in ARHGAP18 associated with SZ across a cohort of >2000 cases and controls from the Han population. Two SNPs, rs7758025 and rs9483050, displayed significant differences between case and control groups both in genotype (P = 0.0002 and P = 7.54×10−6) and allelic frequencies (P = 4.36×10−5 and P = 5.98×10−7), respectively. The AG haplotype in rs7758025−rs9385502 was strongly associated with the occurrence of SZ (P = 0.0012, OR = 0.67, 95% CI = 0.48–0.93), an association that still held following a 1000-times random permutation test (P = 0.022). In an independently collected validation cohort, rs9483050 was the SNP most strongly associated with SZ. In addition, the allelic frequencies of rs12197901 remained associated with SZ in the combined cohort (P = 0.021), although not in the validation cohort alone (P = 0.251). Collectively, our data suggest the ARHGAP18 may confer vulnerability to SZ in the Chinese Han population, providing additional evidence for the involvement of neurodevelopmental dysfunction in the pathogenesis of schizophrenia.