© 2015 Elsevier B.V. All rights reserved. The heritability of schizophrenia has been reported to be as high as ~80%, but the contribution of genetic variants identified to this heritability remains to be estimated. Long non-coding RNAs (LncRNAs) are involved in multiple processes critical to normal cellular function and dysfunction of lncRNA MIAT may contribute to the pathophysiology of schizophrenia. However, the genetic evidence of lncRNAs involved in schizophrenia has not been documented. Here, we conducted a two-stage association analysis on 8 tag SNPs that cover the whole MIAT locus in two independent Han Chinese schizophrenia case-control cohorts (discovery sample from Shanxi Province: 1093 patients with paranoid schizophrenia and 1180 control subjects; replication cohort from Jilin Province: 1255 cases and 1209 healthy controls). In discovery stage, significant genetic association with paranoid schizophrenia was observed for rs1894720 (χ ² =74.20, P=7.1E-18), of which minor allele (T) had an OR of 1.70 (95% CI=1.50-1.91). This association was confirmed in the replication cohort (χ ² =22.66, P=1.9E-06, OR=1.32, 95%CI 1.18-1.49). Besides, a weak genotypic association was detected for rs4274 (χ ² =4.96, df=2, P=0.03); the AA carriers showed increased disease risk (OR=1.30, 95%CI=1.03-1.64). No significant association was found between any haplotype and paranoid schizophrenia. The present studies showed that lncRNA MIAT was a novel susceptibility gene for paranoid schizophrenia in the Chinese Han population. Considering that most lncRNAs locate in non-coding regions, our result may explain why most susceptibility loci for schizophrenia identified by genome wide association studies were out of coding regions.

Rao Shu-Quan;Hu Hui-Ling;Ye Ning;Shen Yan;Xu Qi

Schizophrenia Research

2014

© 2016 Wiley Periodicals, Inc. Schizophrenia is one of the most severe psychiatric disorders, with a high heritability of up to 80%. Several studies have reported telomere dysfunction in schizophrenia, and common variants in the telomerase reverse transcriptase (TERT) gene. TERT is a key component of the telomerase complex that maintains telomere length by addition of telomere repeats to telomere ends, and has repeatedly shown association with mean lymphocyte telomere length (LTL). Thus, we hypothesized that TERT may be a novel susceptibility gene for schizophrenia. Using a Taqman protocol, we genotyped eight tag SNPs from the TERT locus in 1,072 patients with paranoid schizophrenia and 1,284 control subjects from a Chinese Han population. We also measured mean LTL in 98 cases and 109 controls using a quantitative PCR-based technique. Chi-square tests showed that two SNPs, rs2075786 (P=0.0009, OR=0.76, 95%CI=0.65-0.90) and rs4975605 (P=0.0026, OR=0.73, 95%CI=0.60-0.90), were associated with a protective effect, while rs10069690 was associated with risk of paranoid schizophrenia (P=0.0044, OR=1.23, 95%CI=1.07-1.42). Additionally, the rs2736118-rs2075786 haplotype showed significant association with paranoid schizophrenia (P=0.0013). Moreover, mean LTL correlated with rs2075786 genotypes was significantly shorter in the patient group than the control group. The present results suggest that the TERT gene may be a novel candidate involved in the development of paranoid schizophrenia.

Rao Shuquan;Ye Ning;Hu Huiling;Shen Yan;Xu Qi

American Journal of Medical Genetics Part B Neuropsychiatric Genetics

2016

© 2016 DTNBP1, which encodes dysbindin-1, is associated with cognitive impairment. Genetic evidence indicates that the C allele of rs117610176 leads to an increase in DTNBP-1b mRNA splicing in patients with paranoid schizophrenia. In addition, dysbindin-1B, rather than dysbindin-1A/C, exhibits a tendency toward toxic aggregation. In postmortem brains, dysbindin-1B not only aggregates with itself, it also co-aggregates with proteins that interact with it. However, the pathogenic mechanism underlying dysbindin-1B toxic aggregation remains unknown. In the brain, dysbindin-1 is primarily found as a subunit of biogenesis of lysosome-related organelles complex 1 (BLOC-1), which plays a role in intracellular vesicle trafficking. Therefore, we hypothesized that dysbindin-1B might impair the cognitive function of schizophrenia patients by co-aggregating with BLOC-1 subunits and disturbing the function of BLOC-1. In this study, we investigated the dominant-negative effect of dysbindin-1B on the BLOC-1 complex. We found that in multiple brain areas in Dys1B ^+/+ mice, the expression levels of soluble functional BLOC-1 subunits were decreased. Meanwhile, BLOC-1 subunits co-aggregated with dysbindin-1B-myc. Functional studies in primary cortical neurons further revealed the malfunction of BLOC-1 in intercellular vesicle trafficking in Dys1B ^+/+ mice. In addition, we used the Morris water maze task to investigate the effects of dysbindin-1B aggregation on cognition. The results demonstrated that Dys1B ^+/+ mice exhibited spatial learning and memory deficits, which were accompanied by the shrinkage of apical and basal dendritic branches and the loss of dendritic spines in hippocampal CA1 neurons, as demonstrated by Golgi staining. Taken together, the results of the present study suggest that dysbindin-1B toxic aggregation might impair cognition through a dominant-negative effect on BLOC-1.

Yang Wei;Zhu Chunyan;Shen Yan;Xu Qi

Neuroscience

2016

© 2016 A genome-wide association study of Han Chinese samples identified three single-nucleotide polymorphisms in the tetraspanin 18 (TSPAN18) gene to be associated with schizophrenia. However, the replication of the TSPAN18 association was inconsistent across studies. To explore the possible reason for poor replication, we conducted a case-control study to validate the TSPAN18 finding in an independent Chinese sample. The frequency of rs11038167 minor allele (A) was significantly higher only in female patients with thought disorder. Our result suggested that the TSPAN18 gene may be involved in the development of psychotic symptoms and contribute to clinical heterogeneity of schizophrenia.

Wu Lin;Chen Fengping;Shen Yan;Xu Qi;Wei Jun

Psychiatry Research

2016

© The Author(s) 2016. Long interspersed nuclear element-1 (LINE-1 or L1) is a type of retrotransposons comprising 17% of the human and mouse genome, and has been found to be associated with several types of neurological disorders. Previous post-mortem brain studies reveal increased L1 copy number in the prefrontal cortex from schizophrenia patients. However, whether L1 retrotransposition occurs similarly in major depressive disorder (MDD) is unknown. Here, L1 copy number was measured by quantitative PCR analysis in peripheral blood of MDD patients (n = 105) and healthy controls (n = 105). The results showed that L1 copy number was increased in MDD patients possibly due to its hypomethylation. Furthermore, L1 copy number in peripheral blood and five brain regions (prefrontal cortex, hippocampus, amygdala, nucleus accumbens and paraventricular hypothalamic nucleus) was measured in the chronic unpredictable mild stress (CUMS) model of depression in mice. Intriguingly, increased L1 copy number in blood and the decreased L1 copy number in the prefrontal cortex were observed in stressed mice, while no change was found in other brain regions. Our results suggest that the changes of L1 may be associated with the pathophysiology of MDD, but the biological mechanism behind dysfunction of L1 retrotransposition in MDD remains to be further investigated.

Liu Shu;Du Tingfu;Liu Zeyue;Shen Yan;Xiu Jianbo;Xu Qi

Scientific Reports

2016

© 2016 Elsevier B.V. Genome-wide association (GWA) studies have identified numerous genetic variants for major depressive disorder (MDD) although most of the genetic variants are intergenic. It has been found that approximately 54% of long non-coding RNAs (lncRNAs) are located in the intergenic regions. We hypothesized that intergenic variants might be involved in the pathogenesis of MDD through regulating the expression of lncRNAs where these variants are located. In this study, several MDD-associated SNPs in three known intergenic lncRNAs were initially genotyped among 978 patients with MDD and 1176 controls, and the real-time PCR assay was performed to quantify the expression of LINC01108 and LINC00578 in peripheral blood cells from 20 MDD patients and 20 controls. The results showed that rs12526133 present in LINC01108 was strongly associated with MDD (χ ²  = 11.68, P = 6.3E − 04), and LINC01108 expression was significantly higher in the patient group than in the control group (FC = 1.90, P < 0.001). The expression of LINC00998 was significantly lower in MDD patients than controls based on microarray analysis (FC = 0.11, P < 0.001), so that its tag SNPs were genotyped and rs2272260 in LINC00998 was found to be associated with MDD (χ ²  = 26.39, P = 2.8E − 07). This work suggests that non-coding variants may play an important role in conferring risk of MDD.

Ye Ning;Rao Shuquan;Du Tingfu;Hu Huiling;Liu Zeyue;Shen Yan;Xu Qi

Gene

2017

© 2017 Sha et al. The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy. Inhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90β recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90β and GLT-1. Using a model of TLE, we demonstrated that long-term systemic administration of 17AAG dramatically suppressed spontaneous recurrent seizures and ameliorated astrogliosis. Overall, these results suggest that up-regulation of GLT-1 by inhibiting Hsp90β in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.

Sha Longze;Wang Xueqin;Li Jing;Shi Xinze;Shen Yan;Xu Qi;Wu Liwen

Journal of Experimental Medicine

2017

© The Author 2017. Background: Prostaglandin (PG) D 2 is the most abundant prostaglandin in the mammalian brain. The physiological and pharmacological actions of PGD 2 in the central nervous system seem to be associated with some of the symptoms exhibited by patients with major depressive disorder. Previous studies have found that PGD 2 synthase was decreased in the cerebrospinal fluid of major depressive disorder patients. We speculated that there may be a dysregulation of PGD 2 levels in major depressive disorder. Methods: Ultra-performance liquid chromatography-tandem mass spectrometry coupled with a stable isotopic-labeled internal standard was used to determine PGD 2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice. A total of 32 drug-free major depressive disorder patients and 30 healthy controls were recruited. An animal model of depression was constructed by exposing mice to 5 weeks of chronic unpredictable mild stress. To explore the role of PGD 2 in major depressive disorder, selenium tetrachloride was administered to simulate the change in PGD 2 levels in mice. Results: Mice exposed to chronic unpredictable mild stress exhibited depression-like behaviors, as indicated by reduced sucrose preference and increased immobility time in the forced swimming test. PGD 2 levels in the plasma of major depressive disorder patients and in the brains of depressive mice were both decreased compared with their corresponding controls. Further inhibiting PGD 2 production in mice resulted in an increased immobility time in the forced swimming test that could be reversed by imipramine. Conclusion: Decreased PGD 2 levels in major depressive disorder are associated with depression-like behaviors.

Chu Cuilin;Wei Hui;Zhu Wanwan;Shen Yan;Xu Qi

International Journal of Neuropsychopharmacology

2017

We report here the two-dimensional protein database of human pancreas. The proteins were analyzed by two-dimensional electrophoresis followed by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Totally, 302 proteins were identified, of which about 27% were enzymes with a broad range of catalytic activities. Several of these are specifically expressed in pancreas, such as pancreatic amylase, pancreatic stone protein, pancreatitis-associated protein, pancreatic lipase, pancreatic elastase, etc. Structural and cytoskeletal proteins are also strongly represented on the gels. Thus, the pancreatic proteome reflects the organ's function. This work paves the way for further studies on pancreatic protein expression in health and disease, such as diabetes and pancreatic cancer.

Liping Hu;Stefan Evers;Zhao Hui Lu;岩 沈;杰 陈

Electrophoresis

2004-2

Incubation of dinoflagellate Crythecodinium cohnii chromosomes in cytoplasmic extracts of unfertilized Xenopus laevis eggs resulted in chromosomes decondensation and recondensation, nuclear envelope assembly, and nuclear reconstitution. Dinoflagellate Crythecodinium cohnii is a kind of primitive eukaryote which possesses numerous permanently condensed chromosomes and discontinuous double-layered nuclear membrane throughout the cell cycle. The assembled nuclei, being surrounded by a continuous double membrane containing nuclear pores and the uniformly dispersed chromatin fibers are morphologically distinguishable from that of Dinoflagellate Crythecodinium cohnii. However, incubation of dinoflagellate Crythecodinium cohnii chromosomes in the extracts from dinoflagellate Crythecodinium cohnii cells does not induce nuclear reconstitution.

Xiao Ling Liu;岩 沈;Er Jie Chen;中和 翟

Cell Research

2000-6