Dengtang Liu

Common variants on 8p12 and 1q24.2 confer risk of schizophrenia

Schizophrenia is a severe mental disorder affecting ∼1% of the world population, with heritability of up to 80%. To identify new common genetic risk factors, we performed a genome-wide association study (GWAS) in the Han Chinese population. The discovery sample set consisted of 3,750 individuals with schizophrenia and 6,468 healthy controls (1,578 cases and 1,592 controls from northern Han Chinese, 1,238 cases and 2,856 controls from central Han Chinese, and 934 cases and 2,020 controls from the southern Han Chinese). We further analyzed the strongest association signals in an additional independent cohort of 4,383 cases and 4,539 controls from the Han Chinese population. Meta-analysis identified common SNPs that associated with schizophrenia with genome-wide significance on 8p12 (rs16887244, P = 1.27 × 10−10) and 1q24.2 (rs10489202, P = 9.50 × 10−9). Our findings provide new insights into the pathogenesis of schizophrenia.

Higher white blood cell counts are associated with an increased risk for metabolic syndrome and more severe psychopathology in non-diabetic patients with schizophrenia.

BACKGROUND Unequivocal evidence has emerged linking inflammation to the risk of metabolic problems. Previous research also has suggested a relationship between inflammation and schizophrenia. The present study examined whether white blood cell count (WBC), a marker of systemic inflammation, is associated with metabolic syndrome and psychiatric symptoms in non-diabetic patients with schizophrenia. METHODS Outpatients 19 to 75 years old diagnosed with schizophrenia or schizoaffective disorder participated in a multi-center, cross-sectional study. Vital signs and anthropometric measures were obtained. Fasting blood samples were collected to determine levels of glucose, lipids and WBC. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS In the sample of 199 patients, multiple logistic regression showed that WBC (log transformed) strongly predicted the condition of metabolic syndrome after potential confounding variables including age, gender, race, age of illness onset, family history of diabetes, smoking status and antipsychotic agent used were taken into consideration (odds ratio 47.2, 95% CI 3.4-658.7, p=0.004). On the other hand, significant correlations were found between WBC (log transformed) and BPRS-total score (r=0.18, p=0.014), negative symptom score (r=0.15, p=0.039) as well as anxious depression factor score (r=0.21, p=0.004) after potential confounding variables were taken into consideration. CONCLUSION This study suggested that WBC, a simple, readily available and inexpensive measure, may potentially be a useful marker to predict an increased risk for metabolic syndrome and more severe psychiatric symptoms in non-diabetic patients with schizophrenia.

Prospective memory performance in patients with drug-naïve, first-episode psychosis

Schizophrenia is associated with an impairment of prospective memory (PM) which refers to the ability to remember to carry out an intended action in the future. However, most of these studies were limited to chronic samples. The current study examined the event-based PM and time-based PM using a dual-task paradigm in 22 drug-naïve, first-episode psychosis (FEP) patients and 23 healthy controls. Results indicated that FEP patients performed significantly poorer than healthy controls in both event-based and time-based PM. However, the significant difference in time-based PM disappeared after controlling for working memory. Correlation analysis indicated that both types of PM did not correlate with positive symptoms or negative symptoms, duration of illness, or duration of untreated psychosis. However, time-based PM was correlated with the general psychopathology subscale of the PANSS. Taken together, these findings suggest that PM deficits are present in drug-naïve FEP patients; impairment of event-based PM appears to occur independently, whereas time-based PM impairment may be, in part, a secondary consequence of a working memory deficit.

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.

Both volumetry and functional connectivity of Heschl's gyrus are associated with auditory P300 in first episode schizophrenia

BACKGROUND Reduced gray matter volume in left superior temporal gyrus (STG) is considered to be associated with auditory P300 amplitude in schizophrenia. Little is known about possible pathological circuits regarding sub-regions of STG that contribute to auditory P300 abnormality in schizophrenia. The current study investigated gray matter volume in STG and functional connectivity of Heschls gyrus in first-episode schizophrenia (FESZ), as well as their correlations with P300 amplitude. METHODS Nineteen FESZ patients and 19 healthy controls contributed MRI scans. Eighteen patients and 17 controls underwent auditory P300 test within 1 week after MRI scanning. STG structural abnormalities were analyzed using voxel-based morphometry (VBM) analysis. Bilateral Heschls gyri (HG) were selected as seeds for FC analysis in resting MRI data. Correlations of P300 amplitude with gray matter alterations in STG and HG-based FC were analyzed using Pearson correlation analysis within each group. RESULTS Compared to healthy controls, FESZ patients showed reduced gray matter in left STG and P300 amplitude. Gray matter volume of left Heschls gyrus was positively correlated with P300 amplitude in FESZ patients. HG-based FC of resting fMRI was decreased in the inferior frontal gyrus (IFG), medial frontal gyrus (MFG), anterior cingulate cortex (ACC), and left temporal pole, whereas the same metric was increased in the lingual gyrus, precuneus and cerebellar tonsil among FESZ patients. FC between bilateral HG and precuneus was inversely correlated with P300 amplitude among healthy controls, and was absent among FES patients. CONCLUSIONS The findings point towards both decreased volume of Heschls gyrus and its altered functional pathways may contribute to auditory P300 abnormality in schizophrenia.

Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: a pilot study.

Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-γ agonist, on cognition in clozapine-treated patients with schizophrenia. In an eight-week double-blind, placebo-controlled pilot trial, clozapine-treated patients with schizophrenia were randomized to receive rosiglitazone (4mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence Scale-III (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n=9) and the placebo group (n=10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia.

Association between SREBF2 gene polymorphisms and metabolic syndrome in clozapine-treated patients with schizophrenia

BACKGROUND Patients with schizophrenia using antipsychotics often develop metabolic side effects, especially with clozapine. Previous studies indicated that antipsychotics could activate the pathway of the sterol regulatory element-binding protein (SREBP). The sterol regulatory element binding transcription factor 2 (SREBF2) gene mainly regulates the cholesterol biosynthetic gene. Therefore, we hypothesized that the SREBF2 gene would be a candidate gene for interindividual variation in drug-induced metabolic syndrome (MetS). In this genetic case-control study, we examined the SREBF2 gene polymorphisms in the risk of MetS patients treated with clozapine. METHODS Ten single nucleotide polymorphisms (SNPs) of SREBF2 were genotyped in a CHB (Han Chinese in Beijing, China) population, a sample of 621 schizophrenia patients treated with clozapine. Patients were evaluated for metabolic parameters and screened for the MetS criteria. RESULTS The incidence of MetS among all subjects was 41.8% (260/621). Two markers of SREBF2 were associated with MetS induced by clozapine after False Discovery Rate (FDR) correction (rs1052717, corrected Pallele=0.010, corrected Pgenotype=0.022; and rs2267443, corrected Pgenotype=0.015). Patients who received clozapine and carried the A-allele of rs2267443 or rs1052717 had an increased risk of MetS (rs2267443, odds ratio (OR)=1.67, 95% confidence interval (CI): 1.20-2.34; and rs1052717, OR=1.81, 95% CI: 1.15-1.98), adjusted by logistic regression for clinical characteristics. CONCLUSION The results suggest that the genetic polymorphisms of SREBF2 gene may be associated with MetS in patients treated with clozapine.

Resting-state functional connectivity changes within the default mode network and the salience network after antipsychotic treatment in early-phase schizophrenia

Objective Abnormal resting-state functional connectivity (FC), particularly in the default mode network (DMN) and the salience network (SN), has been reported in schizophrenia, but little is known about the effects of antipsychotics on these networks. The purpose of this study was to examine the effects of atypical antipsychotics on DMN and SN and the relationship between these effects and symptom improvement in patients with schizophrenia. Methods This was a prospective study of 33 patients diagnosed with schizophrenia and treated with antipsychotics at Shanghai Mental Health Center. Thirty-three healthy controls matched for age and gender were recruited. All subjects underwent functional magnetic resonance imaging (fMRI). Healthy controls were scanned only once; patients were scanned before and after 6–8 weeks of treatment. Results In the DMN, the patients exhibited increased FC after treatment in the right superior temporal gyrus, right medial frontal gyrus, and left superior frontal gyrus and decreased FC in the right posterior cingulate/precuneus (P<0.005). In the SN, the patients exhibited decreased FC in the right cerebellum anterior lobe and left insula (P<0.005). The FC in the right posterior cingulate/precuneus in the DMN negatively correlated with the difference between the Clinical Global Impression (CGI) score pre/post-treatment (r=−0.564, P=0.023) and negative trends with the difference in the Positive and Negative Syndrome Scale (PANSS) total score pre/post-treatment (r=−0.475, P=0.063) and the difference in PANSS-positive symptom scores (r=−0.481, P=0.060). Conclusion These findings suggest that atypical antipsychotics could regulate the FC of certain key brain regions within the DMN in early-phase schizophrenia, which might be related to symptom improvement. However, the effects of atypical antipsychotics on SN are less clear.

SOX10 rs139883 Polymorphism Is Associated with the Age of Onset in Schizophrenia

Schizophrenia is a common psychiatric disorder with high heritability. The age of onset is an important phenotype of schizophrenia and may be under considerable genetic control. Our previous study showed that a single nucleotide polymorphism (SNP) rs139887 in sex-determining region Y-box 10 (SOX10) gene was associated with the age of onset in schizophrenia. The aim of this study was to evaluate the effect of another SNP rs139883 in the exon 4 of SOX10 on schizophrenia using an early-onset samples in the Han Chinese population. A total of 309 schizophrenic patients with onset before age 18 and 390 healthy controls were recruited for association study. No significant differences of allele or genotype frequencies were identified between the schizophrenic patients and controls. However, the C allele was significantly associated with an earlier age of onset in total patients and male patients (Kaplan–Meier log rank test P = 0.026; Kaplan–Meier log rank test P = 0.047, respectively), but not in females. In conclusion, the SOX10 rs139883 polymorphism influenced the age of onset of schizophrenia in a gender-specific manner and this may represent a vital genetic clue for the etiology of schizophrenia.

Deficient inhibition of return in chronic but not first-episode patients with schizophrenia

BACKGROUND Inhibition of return (IOR) has been tested in patients with schizophrenia with contradictory results. Some studies indicated that patients with schizophrenia have normal levels of IOR; however, other studies reported delayed or blunted IOR. Inconsistency in findings might be due to differences across studies in relevant aspects associated with disease, such as heterogeneity of the disorder, different medications, onset and severity of the illness. The present study was to explore different patterns of IOR in antipsychotic medication free first-episode schizophrenia and chronic schizophrenia. METHODS Forty two patients with first-episode schizophrenia, 44 patients with chronic schizophrenia, and 38 healthy controls were included in the study. All subjects went through a covert orienting of attention task with seven stimulus onset asynchrony (SOA) intervals (400 ms, 500 ms, 600 ms, 700 ms, 800 ms, 1200 ms and 1500 ms). RESULTS Compared with healthy controls, the magnitude and onset of IOR in first-episode patients with schizophrenia were intact. However, in patients with chronic schizophrenia, there was an attenuated cuing effect especially at SOA 700 ms; in addition, there was a robust IOR until at SOAs 800 ms or above. Moreover, the illness duration and the number of psychotic episodes were significantly correlated with the validity effect at SOAs 400 ms and 600 ms. CONCLUSION Our study suggests that deficient IOR presents in chronic but not in first-episode patients with schizophrenia. IOR deficit in schizophrenia may begin during the course of illness and deteriorate over the course of illness. Our findings are consistent with the neurodegenerative model of schizophrenia.