The cholecystokinin type A receptor (CCKAR) gene has been found to be associated with positive symptoms in patients with schizophrenia but the results reported to date are inconsistent. Considering the involvement of allelic heterogeneity in poor replication of the CCKAR finding, we genotyped five single nucleotide polymorphisms (SNPs) located in the 5′ putative regulatory region of the CCKAR gene in a Chinese case-control sample and then applied the 5-SNP haplotype analysis to extract allelic heterogeneity information. The results showed that three individual haplotypes were strongly associated with increased risk of schizophrenia (corrected P=2.9×10 ^-4 , P=2.5×10 ^-5 , and P=1.4×10 ^-5 , respectively) and their combination gave an odds ratio (OR) of 6.12 with 95% CI 3.67-10.21 (P=6.7×10 ^-15 ). The haplotypes were also associated with some clinical symptoms including hallucination, suspiciousness, and hostility. Our work provided further evidence in support of the CCKAR hypothesis of schizophrenia and also suggested that haplotype-based association analysis may be a powerful approach for identification of allelic heterogeneity of a disease-underlying gene, which is very likely to be attributable to poor replication of an initial finding due to the reduction of sample power and the complexity of genetic architectures. © 2012 Wiley Periodicals, Inc.

Zheng Chunming;Fu Qiang;Shen Yan;Xu Qi

American Journal of Medical Genetics Part B Neuropsychiatric Genetics

2012

Compelling evidence suggests that the glutamatergic system may contribute to the pathophysiology of major depression (MDD). While the D-amino acid oxidase activator (DAOA) gene can affect glutamatergic function, its genetic associations with MDD and abnormal resting-state brain activity have yet to be elucidated. A total of 488 patients with MDD and 480 controls were recruited to examine MDD association for the DAOA gene in a Chinese population, of whom 53 medication-free patients and 46 well-matched controls underwent resting-state functional magnetic resonance imaging for regional homogeneity (ReHo) analysis. The differences in ReHo between genotypes of interest were initially tested by the Student's t test, and the 2×2 (genotypes×disease status) ANOVA was then performed to identify the main effects of genotypes, disease status, and their interactions in MDD. Allelic association of the DAOA gene with MDD was observed for rs2391191, rs3918341, and rs778294 and haplotypic association for 2- and 3-SNP haplotypes. Six clusters in the cerebellum, right middle frontal gyrus and left middle temporal gyrus showed genotypic association between altered ReHo and rs2391191. The main effects of rs2391191 genotypes were found in the right culmen and right middle frontal gyrus. The left uvula and left middle temporal gyrus showed a genotypes×disease status interaction. Our results suggest that the DAOA gene may confer genetic risk of MDD. Genotypic effect of rs2391191 and its interaction with disease status may contribute to the altered ReHo in patients with MDD. Glutamatergic modulation may play an important role in alteration of the resting-state brain activities. © Springer Science+Business Media, LLC 2012.

Chen Jun;Zhang Juan;Shen Yan;Xu Qi;Xu Yong;Liu Zhifen;Zhang Kerang;Xu Cheng

Molecular Neurobiology

2012

While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting-state patients with schizophrenia, a two-stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting-state functional magnetic resonance imaging in 48 first-episode medication-free patients and 43 well-matched controls. The differences in ReHo between genotypes of interest were initially tested by the Student's t-test and the 2×2 (genotypes×disease status) ANOVA was then performed to identify the main effects of genotypes, disease status and their interactions in schizophrenia. The stage-1 study showed association of the DAOA and PSEN2 genes with schizophrenia in a small sample; the stage-2 study with an expanded sample confirmed the disease association for 2-SNP and 3-SNP haplotypes, and the cis-phase interactions between rs2391191 and some other SNPs in the DAOA gene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype×disease status interaction. In conclusion, the DAOA gene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. © 2013 Wiley Periodicals, Inc.

Chen Jun;Zhang Juan;Shen Yan;Xu Qi;Xu Yong;Liu Zhifen;Zhang Kerang;Xu Cheng

American Journal of Medical Genetics Part B Neuropsychiatric Genetics

2013

Objective: To explore the temporal and spatial distribution of growth-associated protein 43 (GAP-43) and phosphorylated growth-associated protein 43 (p-GAP-43) in the dentate gyrus of mesial temporal lobe epilepsy (MTLE) mouse model. Methods: MTLE mouse model was established by using the kainic acid (KA) induction. Immunohistochemistry and Western blotting were applied to detect the expressions of GAP-43 and p-GAP-43 in different stages of epileptogenesis. Results: Both in the epileptic and control mice, high GAP-43 expression level was detected in the dentate gyrus, hilus, and inner molecular layer of hippocampus. Decreased p-GAP-43 expression was detected 5 days, 2 weeks, and 5 weeks after KA-induced seizures. Conclusion: The decreased p-GAP-43 expression in the duration of seizure may play an important role in the synaptic reorganization of the sclerotic hippocampus.

Wu Xiao-Feng;Sha Long-Ze;Sha Zhi-Qiang;Shen Yan;Xu Qi

Acta Academiae Medicinae Sinicae

2013

Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures. © 2013 Springer Science+Business Media.

Sha Longze;Wu Xiaofeng;Sha Zhiqiang;Wang Xueqin;Xing Xiaoliang;Li Wenting;Wang Naili;Shen Yan;Xu Qi;Yao Yuan;Dou Wanchen;Jin Liri;Wu Liwen;Wen Bo;Feng Jing;Wang Jinhui

Molecular Neurobiology

2014

Objective To find the risk loci on cholecystokinin A receptor gene (CCKAR) - a schizophrenia candidate gene by using the deep sequencing and then analyze the variations. Methods In the present study, 8 schizophrenia patients and 8 healthy controls were recruited. After DNA extraction from peripheral blood, we conducted deep sequencing on CCKAR region by HaloPlex Target Enrichment System (Agilent). We used Unphased software to exclude the false positive. Results After deep sequencing, we got 103 loci, a-mong which 30 were located in CCKAR gene. Besides, the SNP rsl91275118 was found to be associated with schizophrenia. Conclusions A new variation that may be associated with schizophrenia was found. The deep sequencing is effective to find genetic variation.

Chen Feng-Ping;Lin Wu;Shen Yan;Xu Qi

Acta Academiae Medicinae Sinicae

2014

© 2015 Elsevier Ireland Ltd. Mesial temporal lobe epilepsy (mTLE) is the main type and most common medically intractable form of epilepsy. Severity of disease-based stratified samples may help identify new disease-associated mutant genes. We analyzed mRNA expression profiles from patient hippocampal tissue. Three of the seven patients had severe mTLE with generalized-onset convulsions and consciousness loss that occurred over many years. We found that compared with other groups, patients with severe mTLE were classified into a distinct group. Whole-exome sequencing and Sanger sequencing validation in all seven patients identified three novel SUN domain-containing ossification factor (. SUCO) mutations in severely affected patients. Furthermore, SUCO knock down significantly reduced dendritic length in vitro. Our results indicate that mTLE defects may affect neuronal development, and suggest that neurons have abnormal development due to lack of SUCO, which may be a generalized-onset epilepsy-related gene.

Sha Zhiqiang;Sha Longze;Li Wenting;Shen Yan;Xu Qi;Dou Wanchen;Wu Liwen

Neuroscience Letters

2015

© 2015 IBRO. Given the detection of aggregated deposits in chronic mental diseases (CMD), the disturbance of proteostasis in those diseases is receiving increasing attention. The study of aggregated proteins can contribute to our understanding of the chronic and progressive condition of such diseases. Dysbindin, encoded by the schizophrenia susceptibility gene DTNBP1, has been reported to co-aggregate with DISC1. However, there has been no evidence to date on the aggregation tendency of dysbindin. Therefore, we investigated the isoform-specific aggregation of dysbindin. We found that dysbindin-1B aggregated into cell-invasive deposits in mice. Because of the efficient propagation of dysbindin-1B, we further studied the mechanism of propagation and identified it as exosome-mediated transmission of the aggregates. In addition, aggregates of dysbindin-1B were toxic. Through exosome-mediated propagation, the deposits of dysbindin-1B exerted toxic effects on recipient neurons a long distance away from the initial aggregation site in mice brain. The rapid long distance propagation of neurotoxic deposits of dysbindin-1B in affected neuronal circuitry indicates a possible mechanism for the progressive deterioration of neurons and cognitive function in CMD.

Zhu C. Y.;Shen Y.;Xu Q.

Neuroscience

2015

© 2015 Elsevier B.V. All rights reserved. Background Major depressive disorder (MDD) is a common, chronic and recurrent mental disease but the precise mechanism behind this disorder remains unknown. FTO is one of the N6-methyladenosine (m6A) modification genes and has recently been found to be associated with depression. N6-methyladenosine (m6A) is the most abundant internal modification on RNA, which is highly enriched within the brain. There are five genes involved in m6A modification including FTO, but whether these m6A modification genes could confer a risk of MDD is still unclear. This study aimed to investigate the genetic influence of the m6A modification genes on risk of MDD. Methods We genotyped 23 SNPs in 5 modification genes among 738 patients with MDD and 1098 controls. The UNPHASED program was applied to analyze the genotyping data for allelic and genotypic association with MDD. Results Of the 23 SNPs selected, rs12936694 from the m6A demethylase gene ALKBH5 showed allelic association (χ²=11.19, p=0.0008, OR=1.491, 95%CI 1.179-1.887) and genotypic association (χ²=12.26, df=2, p=0.0022) with MDD. Limitations Replication and functional study are required to draw a firm conclusion. Conclusions The ALKBH5 gene may play a role in conferring risk of MDD in the Chinese population.

Du Tingfu;Rao Shuquan;Wu Lin;Ye Ning;Liu Zeyue;Hu Huiling;Xiu Jianbo;Shen Yan;Xu Qi

Journal of Affective Disorders

2015

Objective: Diagnosis of schizophrenia is currently dependent on symptom-based criteria and lacks objective indicators. In this study, the authors investigated whether circulating miRNA can serve as a diagnostic biomarker for schizophrenia. Methods: Global plasma miRNAs were profiled in a test cohort of 164 schizophrenia patients and 187 control subjects, using Solexa sequencing, TaqMan Low Density Array, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. The captured miRNAs were then validated byqRT-PCRassays in an independent cohort of400 schizophrenia patients, 213 control subjects, and 162 patients with nonschizophrenia psychiatric disorders; the 400 schizophrenia patients underwent a 12-month follow up study of regular treatment with an atypical antipsychotic (risperidone and aripiprazole). Results: The global plasma miRNA screening revealed eight miRNAs that were up-regulated in schizophrenia, as revealed by both assay platforms. The qRT-PCR analysis showed the up-regulation of miR-130b and miR-193a-3p in schizophrenia but not in nonschizophrenia disorders. Conclusions: The up-regulation of miR-130b and miR-193a-3p is a state-independent biomarker for schizophrenia, and these two miRNAs could be used to develop a diagnostic tool for schizophrenia.

Wei Hui;Yuan Yanbo;Liu Sha;Wang Cheng;Yang Fude;Lu Zheng;Wang Chuanyue;Deng Hong;Zhao Jinping;Shen Yan;Zhang Chenyu;Yu Xin;Xu Qi

American Journal of Psychiatry

2015