| 1 | J. Neurosci. Res. 2004 Sep 77: 858-66 |
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| PMID | 15334603 |
| 标题 | 精神分裂症患者的死后颞皮层的微阵列分析。 |
| Abstract | 检查与schizophrenia这项研究测量了来自12名受试者的中间回旋中大约12,000个基因的表达schizophreniaand 14 matched normal controls. Among the most consistent changes in genes with robust expression were significant decreases in the expression of myelination-related genes MAG, PLLP (TM4SF11), PLP1, ERBB3 in subjects withschizophrenia。调节神经发育的基因表达也有所改变（TRAF4，NeuroD1，组蛋白脱乙酰基酶3），昼夜节律起搏器（PER1），以及其他几个参与调节染色质功能和信号传导机制的基因。这些发现支持以下假设schizophrenia与少突胶质细胞的异常有关，并提供了最初的证据，这表明表观遗传机制的作用并改变了这种疾病中的昼夜节律。 |
| SCZ Keywords | schizophrenia |
| 2 | 对话Clin Neurosci 2007 -1 9：333-42 |
| PMID | 17969870 |
| 标题 | The role of circadian clock genes in mental disorders. |
| Abstract | 由于数据表明内源性昼夜节律系统与睡眠效果周期之间的不对对准可能导致患有多种精神病患者的临床状况，因此对精神疾病中分子时钟机制的研究引起了人们的兴趣。重度抑郁症（MDD）的睡眠障碍的特征是睡眠潜伏期增加，睡眠效率较低，降低了第一次快速眼动（REM）睡眠发作和早晨觉醒的潜伏期，但很少有数据表明昼夜节律的作用MDD中的时钟基因。关于时钟基因在焦虑中的作用的信息也相对较少。相比之下，在躁郁症（BPD）患者中收集了大量证据表明昼夜节律障碍，即先进的昼夜节律和依赖于状态的REM睡眠潜伏期改变。关于时钟基beplay苹果手机能用吗因在BPD中的作用的大多数研究都集中在时钟的多态性上，但是锂靶GSK3也可能发挥重要作用。理论上还将昼夜节律转移有助于冬季季节性情感障碍（SAD）的病理生理。NPAS2，PER3和BMAL1的某些等位基因组合似乎有助于SAD的风险。在慢性schizophrenia, disturbances of sleep including insomnia and reduced sleep efficiency have been observed. Genetic studies have found associations with CLOCK,PER1，per3和永恒。由于阿尔茨海默氏病引起的睡眠和昼夜节律变化与痴呆症有关，这表明昼夜节律的功能变化是由大脑中时钟基因表达的死后研究支持的。 |
| SCZ Keywords | schizophrenia |
| 3 | Transl Psychiatry 2012 -1 2: e73 |
| PMID | 22832735 |
| 标题 | PER3基因中的启动子多态性与酒精和应激反应有关。 |
| Abstract | The period homolog genesPER1, Per2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response andschizophrenia。我们发现PER3基因座与压力/焦虑特征有关，并且PER3的基础表达也与几种焦虑和成瘾相关的表型相关。酒精治疗导致海马中PER 3的表达增加，这种作用与急性约束应力相互作用。我们的数据提供了有力的证据，表明PER3转录本的变化与压力和酒精有因果关系，并且对压力和酒精有反应。 |
| SCZ Keywords | schizophrenia |
| 4 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| 标题 | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | 母亲需要一个开关在自然回报,whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included:PER1，per2，arc，homer2，creb1，grm3，fosb，gabrb3，adra2a，ntrk2，cry1，penk，penk，cartpt，adcy1，npy1r，htr1a，htr1a，drd1a，gria1，gria1和pdyn。TopPluster分析发现，与尼古丁，氯胺酮和dronabinol的药物作用相关的基因，母体NAC表达谱均显着富集。途径分析表明，产后NAC富含RNA处理，CNS开发/分化和转录调控。加权基因共表达网络分析（WGCNA）确定了转录因子的可能网络，包括NR1D1，PER2，FOSB，EGR1和NR4A1。产后状态涉及增加精神疾病的风险，MSET分析表明，产后NAC富含与抑郁症，躁郁症（BPD）和schizophrenia。与心理健康有关的基因包括：FABP7，GRM3，PENK和NR1D1。我们通过定量PCR NR1D1，PER2，GRM3，PENK，DRD1A和PDYN确认。这项研究首次表明产后NAC涉及与成瘾和奖励有关的大规模基因表达改变。由于产后状态也涉及对药物的反应减少，因此这些发现可以提供有关如何减轻成瘾的见解。 |
| SCZ Keywords | schizophrenia |
| 5 | PLOS ONE 2014 -1 9：E110310 |
| PMID | 25340473 |
| 标题 | Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders. |
| Abstract | Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well asschizophrenia。BHLH转录因子Sharp1/dec2/bhlhe41和Sharp2/dec1/bhlhe40是昼夜节律系统的调节剂，已显示Sharp1/dec2/bhlhe40可以调节人类的体内稳态睡眠驱动器。在这项研究中，我们使用活动物中的在线脑电图记录，行为分析和全球基因表达谱分析表征了Sharp1和Sharp2双突变小鼠（S1/2 - / - ）。脑电图记录显示，睡眠/唤醒幅度减弱和theta振荡的改变。在黑暗相中的睡眠增加与自愿活性减少相似，皮质基因表达特征揭示了与精神病的关联。S1/2 - / - 小鼠在新颖性诱发活性，焦虑和好奇心中的改变。此外，突变小鼠的工作记忆和抑制作用的缺陷表现出类似于精神病症状的抑制作用。网络建模表示神经可塑性和时钟基因之间的联系，特别是对于Sharp1和PER1。Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2. |
| SCZ Keywords | schizophrenia |
| 6 | 神经生物醇。dis。2015年5月77日：228-37 |
| PMID | 25771167 |
| 标题 | The BDNF Val66Met variant affects gene expression through miR-146b. |
| Abstract | 基因表达的变化是对复杂疾病和特征的敏感性的重要机制。单核苷酸多态性（SNP）占基因表达总检测到的遗传变异的很大一部分，但是在反式调节基因表达和疾病易感性中的确切变异仍然在很大程度上未知。BDNF Val66met SNP与许多精神疾病有关，例如抑郁症，焦虑症，schizophreniaand related traits. Using global microRNA expression profiling in hippocampus of humanized BDNF Val66Met knock-in mice we showed that this variant results in dysregulation of at least one microRNA, which in turn affects downstream target genes. Specifically, we show that reduced levels of miR-146b (mir146b), lead to increasedPER1and Npas4 mRNA levels and increased Irak1 protein levels in vitro and are associated with similar changes in the hippocampus of hBDNF(Met/Met) mice. Our findings highlight trans effects of common variants on microRNA-mediated gene expression as an integral part of the genetic architecture of complex disorders and traits. |
| SCZ Keywords | schizophrenia |
| 7 | Mol. Psychiatry 2016 Jun 21: 768-85 |
| PMID | 27046645 |
| 标题 | Towards understanding and predicting suicidality in women: biomarkers and clinical risk assessment. |
| Abstract | 迄今为止，妇女对自杀的研究不足。beplay苹果手机能用吗尽管妇女的自杀率完成率比男性较低，但部分原因是使用不太暴力的方法，她们的自杀企图率较高。我们的小组以前已经确定了男性自杀性的基因组（血液基因表达生物标志物）和临床信息（APP）预测因子。我们现在描述了女性的试点研究。我们使用了强大的参与性发现方法来识别没有自杀念头（无SI）和高自杀构想（高SI）状态（n = 12名参与者）在51名女性精神病参与者中的同伴（n = 12名参与者）之间改变表达的基因（n = 12名参与者）。诊断性躁郁症，抑郁症，精神分裂症和schizophrenia)。然后,我们使用一个收敛的功能基因组学(CFG) approach to prioritize the candidate biomarkers identified in the discovery step by using all the prior evidence in the field. Next, we validated for suicidal behavior the top-ranked biomarkers for SI, in a demographically matched cohort of women suicide completers from the coroner's office (n=6), by assessing which markers were stepwise changed from no SI to high SI to suicide completers. We then tested the 50 biomarkers that survived Bonferroni correction in the validation step, as well as top increased and decreased biomarkers from the discovery and prioritization steps, in a completely independent test cohort of women psychiatric disorder participants for prediction of SI (n=33) and in a future follow-up cohort of psychiatric disorder participants for prediction of psychiatric hospitalizations due to suicidality (n=24). Additionally, we examined how two clinical instruments in the form of apps, Convergent Functional Information for Suicidality (CFI-S) and Simplified Affective State Scale (SASS), previously tested in men, perform in women. The top CFI-S item distinguishing high SI from no SI states was the chronic stress of social isolation. We then showed how the clinical information apps combined with the 50 validated biomarkers into a broad predictor (UP-Suicide), our apriori primary end point, predicts suicidality in women. UP-Suicide had a receiver-operating characteristic (ROC) area under the curve (AUC) of 82% for predicting SI and an AUC of 78% for predicting future hospitalizations for suicidality. Some of the individual components of the UP-Suicide showed even better results. SASS had an AUC of 81% for predicting SI, CFI-S had an AUC of 84% and the combination of the two apps had an AUC of 87%. The top biomarker from our sequential discovery, prioritization and validation steps, BCL2, predicted future hospitalizations due to suicidality with an AUC of 89%, and the panel of 50 validated biomarkers (BioM-50) predicted future hospitalizations due to suicidality with an AUC of 94%. The best overall single blood biomarker for predictions was PIK3C3 with an AUC of 65% for SI and an AUC of 90% for future hospitalizations. Finally, we sought to understand the biology of the biomarkers. BCL2 and GSK3B, the top CFG scoring validated biomarkers, as well as PIK3C3, have anti-apoptotic and neurotrophic effects, are decreased in expression in suicidality and are known targets of the anti-suicidal mood stabilizer drug lithium, which increases their expression and/or activity. Circadian clock genes were overrepresented among the top markers. Notably,PER1自杀性表达的增加，预测未来住院的AUC为84％，而CSNK1A1的表达降低，表达的AUC为96％，用于预测未来的住院治疗。昼夜节律异常与情绪障碍有关，睡眠异常与自杀有关。Docosahexaenoic Acid信号传导是经过验证的生物标志物中高度代表的最佳生物学途径之一，鉴于omega-3脂肪酸的潜在治疗和预防性益处，这一点很感兴趣。当前女性工作中的一些顶级生物标志物显示出与以前的男性作品的表达变化的共同指导性，而其他人则在相反的方向上发生了变化，这是生物学背景的问题和两个性别之间自杀性的差异。通过这项研究，我们开始在女性自杀领域腾出急需的光线，确定有用的客观预测指标，并有助于理解性别的共同点和差异。在研究过程中，一名参与者自杀。回想起来，当分析完成后，她的上自由风险预测评分是所有被测试的参与者的100％。 |
| SCZ Keywords | schizophrenia |
| 8 | 精神分裂。res。2016年4月1日：-1 |
| PMID | 27132483 |
| 标题 | Altered circadian clock gene expression in patients with schizophrenia. |
| Abstract | Impaired circadian rhythmicity has been reported in several psychiatric disorders.schizophreniais commonly associated with aberrant sleep-wake cycles and insomnia. It is not known ifschizophreniais associated with disturbances in molecular rhythmicity. We cultured fibroblasts from skin samples obtained from patients with chronicschizophreniaand from healthy controls, respectively, and analyzed the circadian expression during 48h of the clock genes CLOCK, BMAL1,PER1, PER2, CRY1, CRY2, REV-ERB? and DBP. In fibroblasts obtained from patients with chronicschizophrenia，我们发现与健康对照细胞相比，CRY1和PER2的节奏表达丧失。我们还估计了这些患者的睡眠质量，发现与健康对照相比，大多数患者的睡眠不佳。在另一个患者样本中，我们分析了来自schizophreniaexperiencing their first episode of psychosis, and found decreased expression of CLOCK, PER2 and CRY1 compared to blood cells from healthy controls. These novel findings show disturbances in the molecular clock inschizophrenia并在我们对这种疾病中报道的异常节奏的理解中具有重要意义。 |
| SCZ Keywords | schizophrenia |
| 9 | Psychoneuroendocrinology 2016 Feb 64: 108-16 |
| PMID | 26630391 |
| 标题 | 在第一期精神分裂症患者中暴露于氯氮平后的昼夜神经生物学改变。 |
| Abstract | Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients withschizophrenia。However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment inschizophrenia, but this possibility has not been investigated. 从15个健康的男性对照组和13个男性中收集血液样本schizophreniapatients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1），周期2（PER2），周期3（PER3）和等离子体皮质醇，Orexin和胰岛素的水平。 Compared with healthy controls,schizophrenia患者表达了表达的昼夜节奏PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., inPER1氯氮平治疗8周后，持续存在PER3表达），类似于PER3和NPAS2的24小时表达的降低。氯氮平治疗8周可显着降低24小时的PER2水平，并增加24小时的胰岛素水平。 These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment inschizophrenia。 |
| SCZ Keywords | schizophrenia |