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Exposure to childhood maltreatment is associated with specific epigenetic patterns in sperm 儿童时期遭受虐待与精子的特定表观遗传模式有关
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-03 DOI: 10.1038/s41380-024-02872-3
Jetro J. Tuulari, Matthieu Bourgery, Jo Iversen, Thomas Gade Koefoed, Annukka Ahonen, Ammar Ahmedani, Eeva-Leena Kataja, Linnea Karlsson, Romain Barrès, Hasse Karlsson, Noora Kotaja

Childhood maltreatment exposure (CME) increases the risk of adverse long-term health consequences for the exposed individual. Animal studies suggest that CME may also influence the health and behaviour in the next generation offspring through CME-driven epigenetic changes in the germ line. Here we investigated the associated between early life stress on the epigenome of sperm in humans with history of CME. We measured paternal CME using the Trauma and Distress Scale (TADS) questionnaire and mapped sperm-borne sncRNAs expression by small RNA sequencing (small RNA-seq) and DNA methylation (DNAme) in spermatozoa by reduced-representation bisulfite sequencing (RRBS-seq) in males from the FinnBrain Birth Cohort Study. The study design was a (nested) case-control study, high-TADS (TADS ≥ 39, n = 25 for DNAme and n = 14 for small RNA-seq) and low-TADS (TADS ≤ 10, n = 30 for DNAme and n = 16 for small RNA-seq). We identified 3 genomic regions with differential methylation between low and high-TADS and 68 tRNA-derived small RNAs (tsRNAs) and miRNAs with different levels in males with high CME (False discovery rate, FDR corrected p < 0.05). Of potential interest, we identified differential expression of miRNA hsa-mir-34c-5p and differential methylation levels near the CRTC1 and GBX2 genes, which are documented to control brain development. Our results provide further evidence that early life stress influences the paternal germline epigenome and supports a possible effect in modulating the development of the central nervous system of the next generation.

儿童虐待暴露增加了暴露者长期健康不良后果的风险。动物研究表明,CME还可能通过CME驱动的生殖系表观遗传变化影响下一代后代的健康和行为。在这里,我们研究了早期生活压力对人类精子表观基因组的影响与CME病史之间的关系。我们使用创伤和痛苦量表(TADS)问卷测量了父亲的CME,并通过小RNA测序(small RNA-seq)绘制了精子中sncRNAs的表达,并通过减少代表性亚硫酸氢盐测序(RRBS-seq)绘制了精子中的DNA甲基化(DNAme)。研究设计为(嵌套)病例对照研究,高TADS (TADS≥39,DNAme = 25,小RNA-seq = 14)和低TADS (TADS≤10,DNAme = 30,小RNA-seq = 16)。我们发现了3个基因组区域在低tads和高tads之间存在差异甲基化,68个trna衍生的小rna (tsrna)和miRNAs在高CME男性中具有不同水平(错误发现率,FDR校正p <; 0.05)。潜在的兴趣是,我们鉴定了miRNA hsa-mir-34c-5p的差异表达和CRTC1和GBX2基因附近的差异甲基化水平,这些基因被证明控制大脑发育。我们的研究结果提供了进一步的证据,证明早期生活压力影响父系生殖系表观基因组,并支持在调节下一代中枢神经系统发育方面的可能影响。
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引用次数: 0
Circular reasoning concerning Red flags for predicting rituximab response in OCD. 关于预测强迫症患者利妥昔单抗反应的危险信号的循环推理。
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-01-03 DOI: 10.1038/s41380-024-02885-y
Susanne Bejerot, Albert Max Hietala, Annika Söderbergh, Mats B Humble
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引用次数: 0
Unraveling the associations between voice pitch and major depressive disorder: a multisite genetic study 揭示音高与重度抑郁症之间的联系:一项多位点基因研究
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-31 DOI: 10.1038/s41380-024-02877-y
Yazheng Di, Elior Rahmani, Joel Mefford, Jinhan Wang, Vijay Ravi, Aditya Gorla, Abeer Alwan, Kenneth S. Kendler, Tingshao Zhu, Jonathan Flint

Major depressive disorder (MDD) often goes undiagnosed due to the absence of clear biomarkers. We sought to identify voice biomarkers for MDD and separate biomarkers indicative of MDD predisposition from biomarkers reflecting current depressive symptoms. Using a two-stage meta-analytic design to remove confounds, we tested the association between features representing vocal pitch and MDD in a multisite case-control cohort study of Chinese women with recurrent depression. Sixteen features were replicated in an independent cohort, with absolute association coefficients (beta values) from the combined analysis ranging from 0.24 to 1.07, indicating moderate to large effects. The statistical significance of these associations remained robust, with P values ranging from 7.2 × 10–6 to 6.8 × 10–58. Eleven features were significantly associated with current depressive symptoms. Using genotype data, we found that this association was driven in part by a genetic correlation with MDD. Significant voice features, reflecting a slower pitch change and a lower pitch, achieved an AUC-ROC of 0.90 (sensitivity of 0.85 and specificity of 0.81) in MDD classification. Our results return vocal features to a more central position in clinical and research work on MDD.

由于缺乏明确的生物标志物,重度抑郁症(MDD)经常无法确诊。我们试图确定MDD的语音生物标志物,并将指示MDD易感性的生物标志物与反映当前抑郁症状的生物标志物分开。采用两阶段荟萃分析设计来消除混杂因素,我们在一项中国复发性抑郁症女性的多地点病例对照队列研究中测试了代表音调的特征与重度抑郁症之间的关联。在独立队列中重复了16个特征,联合分析的绝对关联系数(β值)范围为0.24至1.07,表明中等至较大的影响。这些相关性的统计显著性仍然很强,P值在7.2 × 10-6至6.8 × 10-58之间。11项特征与当前抑郁症状显著相关。使用基因型数据,我们发现这种关联部分是由与MDD的遗传相关性驱动的。显著的声音特征,反映较慢的音调变化和较低的音调,在MDD分类中实现了0.90的AUC-ROC(敏感性为0.85,特异性为0.81)。我们的研究结果使声音特征在重度抑郁症的临床和研究工作中处于更加中心的位置。
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引用次数: 0
Assessment and ascertainment in psychiatric molecular genetics: challenges and opportunities for cross-disorder research 精神病学分子遗传学的评估和确定:交叉障碍研究的挑战和机遇
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-27 DOI: 10.1038/s41380-024-02878-x
Na Cai, Brad Verhulst, Ole A. Andreassen, Jan Buitelaar, Howard J. Edenberg, John M. Hettema, Michael Gandal, Andrew Grotzinger, Katherine Jonas, Phil Lee, Travis T. Mallard, Manuel Mattheisen, Michael C. Neale, John I. Nurnberger, Wouter Peyrout, Elliot M. Tucker-Drob, Jordan W. Smoller, Kenneth S. Kendler

Psychiatric disorders are highly comorbid, heritable, and genetically correlated [1,2,3,4]. The primary objective of cross-disorder psychiatric genetics research is to identify and characterize both the shared genetic factors that contribute to convergent disease etiologies and the unique genetic factors that distinguish between disorders [4, 5]. This information can illuminate the biological mechanisms underlying comorbid presentations of psychopathology, improve nosology and prediction of illness risk and trajectories, and aid the development of more effective and targeted interventions. In this review we discuss how estimates of comorbidity and identification of shared genetic loci between disorders can be influenced by how disorders are measured (phenotypic assessment) and the inclusion or exclusion criteria in individual genetic studies (sample ascertainment). Specifically, the depth of measurement, source of diagnosis, and time frame of disease trajectory have major implications for the clinical validity of the assessed phenotypes. Further, biases introduced in the ascertainment of both cases and controls can inflate or reduce estimates of genetic correlations. The impact of these design choices may have important implications for large meta-analyses of cohorts from diverse populations that use different forms of assessment and inclusion criteria, and subsequent cross-disorder analyses thereof. We review how assessment and ascertainment affect genetic findings in both univariate and multivariate analyses and conclude with recommendations for addressing them in future research.

精神疾病是高度共病、可遗传和遗传相关的[1,2,3,4]。交叉障碍精神病学遗传学研究的主要目标是识别和表征导致疾病趋同病因的共同遗传因素和区分疾病的独特遗传因素[4,5]。这些信息可以阐明精神病理学共病表现的生物学机制,改善疾病分类学和疾病风险和轨迹的预测,并有助于开发更有效和有针对性的干预措施。在这篇综述中,我们讨论了疾病之间共病的估计和共享遗传位点的识别如何受到疾病测量方式(表型评估)和个体遗传研究中的纳入或排除标准(样本确定)的影响。具体而言,测量深度、诊断来源和疾病轨迹的时间框架对评估表型的临床有效性具有重要影响。此外,在确定病例和对照时引入的偏差可以夸大或降低遗传相关性的估计。这些设计选择的影响可能对使用不同形式的评估和纳入标准的来自不同人群的队列的大型荟萃分析以及随后的交叉障碍分析具有重要意义。我们回顾了在单变量和多变量分析中评估和确定如何影响遗传发现,并总结了在未来研究中解决这些问题的建议。
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引用次数: 0
Genetic risk for treatment resistant schizophrenia and corresponding variation in dopamine synthesis capacity and D2/3 receptor availability in healthy individuals 治疗难治性精神分裂症的遗传风险及健康个体多巴胺合成能力和D2/3受体可用性的相应变异
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-27 DOI: 10.1038/s41380-024-02873-2
Daniel Paul Eisenberg, Rachael Keir Blackman, Maria G. Tietcheu, Philip D. Kohn, Jasmin S. Bettina, Bhaskar Kolachana, Michael D. Gregory, Karen F. Berman

Dysfunction of dopamine systems has long been considered a hallmark of schizophrenia, and nearly all current first-line medication treatments block dopamine D2 receptors. However, approximately a quarter of patients will not adequately respond to these agents and are considered treatment-resistant. Whereas abnormally high striatal presynaptic dopamine synthesis capacity has been observed in people with schizophrenia, studies of treatment-resistant patients have not shown this pattern and have even found the opposite – i.e., reductions in striatal presynaptic dopamine synthesis capacity. Whether such reductions in fact represent clinical epiphenomena such as medication or other treatment effects or whether they rather represent neurobiological differences related to etiology has been unclear. To understand the dopaminergic implications of genetic liability for treatment-resistant schizophrenia without the confound of clinical epiphenomena, we studied a cohort of healthy individuals without neuropsychiatric illness using [18F]-FDOPA positron emission tomography (PET) and found that striatal presynaptic dopamine synthesis capacity showed an expected direct association with cumulative genetic risk burden for general schizophrenia but an inverse association with specific polygenic risk for treatment-resistant schizophrenia. Subsequent evaluation of D2/3 dopamine receptor availability in an overlapping cohort using [18F]-fallypride PET did not identify any effects of genetic risk in the striatum but found an association with treatment-resistant schizophrenia polygenic risk in the thalamus. Overall, these results align with prior PET studies in patients and implicate, at least with respect to the dopamine system, fundamentally distinct molecular mechanisms in the unique genetic liability for treatment-resistant schizophrenia.

长期以来,多巴胺系统功能障碍一直被认为是精神分裂症的一个标志,目前几乎所有的一线药物治疗都会阻断多巴胺D2受体。然而,大约四分之一的患者对这些药物没有充分的反应,被认为是治疗耐药。虽然在精神分裂症患者中观察到异常高的纹状体突触前多巴胺合成能力,但对治疗抵抗患者的研究并未显示出这种模式,甚至发现了相反的情况-即纹状体突触前多巴胺合成能力降低。这种减少实际上是否代表临床现象,如药物或其他治疗效果,或者它们是否代表与病因相关的神经生物学差异,目前尚不清楚。为了在不混淆临床现象的情况下理解难治性精神分裂症遗传倾向的多巴胺能含义,我们使用[18F]-FDOPA正电子发射断层扫描(PET)研究了一组没有神经精神疾病的健康个体,发现纹状体突触前多巴胺合成能力与一般精神分裂症的累积遗传风险负担有预期的直接关联,但与治疗抵抗性精神分裂症的特定多基因风险呈负相关。随后使用[18F]-fallypride PET对重叠队列中D2/3多巴胺受体可用性进行评估,未发现纹状体中遗传风险的任何影响,但发现丘脑与治疗抵抗性精神分裂症多基因风险相关。总的来说,这些结果与之前对患者的PET研究一致,至少在多巴胺系统方面,从根本上不同的分子机制在治疗难治性精神分裂症的独特遗传责任中。
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引用次数: 0
Clinical response to neurofeedback in major depression relates to subtypes of whole-brain activation patterns during training 重度抑郁症患者对神经反馈的临床反应与训练期间全脑激活模式的亚型有关
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-26 DOI: 10.1038/s41380-024-02880-3
Masaya Misaki, Kymberly D. Young, Aki Tsuchiyagaito, Jonathan Savitz, Salvador M. Guinjoan

Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t = −4.404, d = −0.704, p < 0.001) but not in the control group (t = −1.609, d = −0.430, p = 0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype: F = 8.735, p = 0.005; feedback response subtype: F = 5.326, p = 0.008; subtypes’ interaction: F = 3.471, p = 0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.

重度抑郁症(MDD)发病率高,给个人和医疗保健系统带来沉重负担,是一项重大的公共卫生挑战。实时功能磁共振成像神经反馈(rtfMRI-NF)有望治疗这种疾病,但其作用机制仍不清楚。本研究调查了 rtfMRI-NF 训练期间的全脑反应模式,以解释 MDD 临床疗效的个体差异。我们分析了 95 名 MDD 患者(67 名活动期患者,28 名对照组患者)的数据,这些数据来自之前的 rtfMRI-NF 研究,这些研究旨在通过积极的自传体记忆回忆来增加左侧杏仁核的激活。在活动组(t = -4.404,d = -0.704,p <0.001)观察到症状明显减轻,而在对照组(t = -1.609,d = -0.430,p = 0.111)则没有。然而,左侧杏仁核激活并不能解释临床疗效的变化。为了阐明临床疗效背后的大脑训练过程,我们研究了神经反馈过程中两个关键阶段的全脑激活模式:自我调节期间的激活和对反馈信号呈现的瞬时反应。通过系统的特征选择、流形提取、聚类和交叉验证,我们确定了两种调节激活亚型和三种大脑对反馈信号的反应亚型。这些亚型与临床效果明显相关(调节亚型:F = 8.735,p = 0.005;反馈反应亚型:F = 5.326,p = 0.008;亚型交互作用:F = 3.471,p = 0.039)。与症状明显减轻相关的亚型的特点是控制区域(包括外侧前额叶区域)的选择性增加,而与自我推理思维相关的区域(如默认模式区域)的选择性减少。这些研究结果表明,与神经反馈目标区域本身的激活水平相比,训练期间的大规模大脑活动对临床疗效的影响更为关键。结合这些模式对神经反馈训练进行定制,可以显著提高其疗效。
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引用次数: 0
ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation ADNP通过雄性未折叠蛋白反应和雌性线粒体基因调控对性别依赖性海马神经发生至关重要
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-23 DOI: 10.1038/s41380-024-02879-w
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman, Maram Ganaiem, Shula Shazman, Paschalis Theotokis, Nikolaos Grigoriadis, Noam Shomron, Illana Gozes

Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer’s disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer’s disease. While autism is more prevalent in boys and Alzheimer’s disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/−) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.

活动依赖性神经保护蛋白(activity-dependent neuroprotective protein, ADNP)对脑的形成和防止牛头病至关重要,在调节类固醇激素生物发生的同时,对神经发生和认知功能至关重要。因此,ADNP的新生突变导致综合征性自闭症,而体细胞ADNP突变与阿尔茨海默病的进展相似。此外,ADNP片段NAP(研究药物达文尼肽)的临床试验显示,对患有tau病进行性核上性麻痹的女性有效,并在男性(空间)和女性(言语)中不同程度地增强了记忆,表现出前驱阿尔茨海默病。虽然自闭症在男孩中更为普遍,阿尔茨海默病在女性中更为普遍,但两者都涉及神经发生受损。在这里,我们询问ADNP是否依赖性别调节神经发生。使用溴脱氧尿苷(BrdU)作为神经发生的标记物,我们发现在adnp完整的雄性小鼠海马脑室下区标记比雌性小鼠高两倍。Adnp单倍体不足(Adnp+/−)小鼠或CRSIPR/ cas9编辑小鼠呈现最普遍的神经发育Adnp综合征突变p.Tyr718* (Tyr)显示雄性BrdU掺入显著减少,导致突变的雌性比雄性表现出更高的标记。NAP治疗补偿了男性BrdU标记的减少。机制上,海马RNAseq揭示了男性特异性Tyr下调内质网未折叠蛋白反应基因,这对性别依赖性器官发生至关重要。新发现的线粒体ADNP可及性被Tyr718*突变抑制,进一步揭示了女性特异性的Tyr下调线粒体ATP6。NAP可抑制p.Tyr718*引起的差异表达,并伴有神经毒性、促炎和促凋亡基因的下调。因此,ADNP是性别依赖性神经发生的关键调节因子,通过控制规范通路起作用,NAP补偿基本的ADNP缺陷,朝着针对ADNP综合征和相关神经发育/神经退行性疾病的临床发展迈进。
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引用次数: 0
Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations 精神病生物型的遗传分析:共同祖先调整的多基因风险和独特的基因组关联
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-21 DOI: 10.1038/s41380-024-02876-z
Cuihua Xia, Ney Alliey-Rodriguez, Carol A. Tamminga, Matcheri S. Keshavan, Godfrey D. Pearlson, Sarah K. Keedy, Brett Clementz, Jennifer E. McDowell, David Parker, Rebekka Lencer, S. Kristian Hill, Jeffrey R. Bishop, Elena I. Ivleva, Cindy Wen, Rujia Dai, Chao Chen, Chunyu Liu, Elliot S. Gershon

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.

双相精神分裂症中间表型网络(B-SNIP)基于多祖先样本的神经生物学测量创建了精神病生物型。这些生物型与DSM诊断的精神分裂症、分裂情感性障碍和双相情感障碍相吻合。最近发展的两种多基因风险评分(PRSs)的事后祖先调整方法产生了祖先调整的PRSs (AAPRSs),它允许对多祖先样本进行PRS分析。应用于精神分裂症PRS,我们发现Khera AAPRS方法与Ge方法相比具有优越的可移植性和相当的预测精度。精神障碍的三种生物型具有相似的AAPRSs。在生物型的基因组分析中,在成人大脑和胎儿大脑中遗传调控表达(GReX)的转录组全关联研究(TWAS)中,12个基因和同种异构体显示出与特定生物型的显著基因组关联。通过在关联分析中纳入基因型主成分来解决TWAS膨胀问题。这12个基因/同型异构体中有7个满足孟德尔随机化(MR)的假定因果关系标准,包括4个基因TMEM140、ARTN、C1orf115、CYREN,以及3个转录本ENSG00000272941、ENSG00000257176、ENSG00000287733。这些基因在转染(RET)信号传导、神经细胞粘附分子1 (NCAM1)相互作用和神经突起生长的NCAM信号传导过程中的重排生物学途径中富集。与生物型的特殊关联表明,分别分析生物型可能有利于药理学临床试验和生物学研究。
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引用次数: 0
OXTR-mediated signaling in astrocytes contributes to anxiolysis 星形胶质细胞中oxtr介导的信号有助于焦虑缓解
IF 11 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-19 DOI: 10.1038/s41380-024-02870-5
Carl-Philipp Meinung, Laura Boi, Sareh Pandamooz, David Mazaud, Grégory Ghézali, Nathalie Rouach, Inga D. Neumann

Astrocytes are an indispensable part of signal processing within the mammalian brain. Thus, the mode of action of a neuropeptide such as oxytocin (OXT) can only be fully understood considering this integral part of the CNS. Here, we show that OXT regulates astrocytic gene expression, intracellular signaling and specific proteins both in vitro and in vivo. This translates into rapid regulation of astroglial structural and functional properties including cytoskeletal plasticity, coverage of synapses and gap-junction coupling. At the molecular level, we identify the previously undescribed Sp1-Gem signaling cascade as the key driver for these cell type-specific OXT effects. Finally at the behavioral level, we found in vivo that OXT requires astrocytes to exert its well described anxiolytic properties within the hypothalamic paraventricular nucleus. Thus, our study points to OXT receptor-expressing astrocytes as a critical component of the brain OXT system.

星形胶质细胞是哺乳动物大脑信号处理不可或缺的一部分。因此,只有考虑到中枢神经系统的这一组成部分,才能充分理解催产素(OXT)等神经肽的作用模式。在这里,我们发现 OXT 在体外和体内都能调节星形胶质细胞的基因表达、细胞内信号传导和特定蛋白质。这将转化为对星形胶质细胞结构和功能特性的快速调控,包括细胞骨架的可塑性、突触的覆盖范围和间隙连接。在分子水平上,我们发现之前未曾描述过的 Sp1-Gem 信号级联是这些细胞类型特异性 OXT 效应的关键驱动因素。最后,在行为学层面,我们在体内发现,OXT 需要星形胶质细胞才能在下丘脑室旁核发挥其广为描述的抗焦虑特性。因此,我们的研究表明,表达 OXT 受体的星形胶质细胞是大脑 OXT 系统的重要组成部分。
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引用次数: 0
Efficacy and acceptability of pharmacological interventions for tardive dyskinesia in people with schizophrenia or mood disorders: a systematic review and network meta-analysis 精神分裂症或心境障碍患者迟发性运动障碍的药物干预的疗效和可接受性:一项系统综述和网络荟萃分析
IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-18 DOI: 10.1038/s41380-024-02733-z
Marco Solmi, Michele Fornaro, Stefano Caiolo, Marialaura Lussignoli, Claudio Caiazza, Michele De Prisco, Niccolo Solini, Andrea de Bartolomeis, Felice Iasevoli, Giorgio Pigato, Cinzia Del Giovane, Andrea Cipriani, Christoph U. Correll
Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register (22/05/2023, pre-defined protocol https://osf.io/b52ae/ ), for randomized controlled trials (RCTs) of pharmacological/brain stimulation interventions for DRA-induced TD in adults with schizophrenia or mood disorders. Primary outcomes were TD symptom change (standardized mean difference/SMD) and all-cause discontinuation (acceptability-risk ratio/RR). Sensitivity analyses were conducted. Global, local inconsistencies, risk of bias (RoB-2 tool), and confidence in evidence (CINeMA) were measured. We included 46 trials (n = 2844, age = 52.89 ± 9.94 years, males = 59.8%, schizophrenia = 84.6%, mood disorders = 15.4%), all testing pharmacological interventions versus placebo. We identified three subnetworks. In network 1, several treatments outperformed placebo on TD symptoms with large effect sizes (k = 34, n = 2269), encompassing 22 interventions versus placebo, but 18 had 1 RCTs only, and 15 had n ≤ 20. High heterogeneity (I2 = 57.1%; tau2 = 0.0797), and global inconsistency (Q = 32.64; df = 14; p = 0.0032) emerged. No significant differences emerged in acceptability. When restricting analyses to treatments with trials with n > 20 and >1 RCT, only valbenazine (k = 5, SMD = −0.69; 95% CI = −1.00, −0.37) and vitamin E (k = 7, SMD = −0.49; 95% CI = −0.87, −0.11) were superior to placebo. Deutetrabenazine outperformed placebo considering AIMS score and in low risk of bias trials only and with a moderate effect size for 24/36 mg (k = 2, SMD = −0.57/−0.60). Confidence in findings was low for deutetrabenazine and valbenazine, very low for all others. In network 2 (k = 2, n = 63), switch to molindone (k = 1, n = 9) versus switch to haloperidol worsened TD (SMD = 1.68; 95% CI = 0.61,2.76). In network 3 (k = 3, n = 194), antipsychotic wash-out+placebo (k = 1, n = 25) versus TAU+placebo (k = 1, n = 27) worsened TD (SMD = 1.30; 95% CI = 0.36,2.23). Despite large effect sizes for some treatments with very low quality/confidence, when considering higher quality evidence only valbenazine or deutetrabenazine are evidence-based first-line treatments for TD, and potentially vitamin E as second-line. Switching to molindone and antipsychotic washout should be avoided. More treatment options and higher-quality trials are needed.
接触多巴胺受体拮抗剂(DRAs)的人可能会出现迟发性运动障碍(TD)。其临床治疗仍具有挑战性。我们通过搜索 PubMed/MEDLINE/PsycINFO/ClinicalTrials.gov/Cochrane Central Register(2023 年 5 月 22 日,预定义方案 https://osf.io/b52ae/)进行了一项系统性综述/随机效应网络荟萃分析(NMA),以了解针对精神分裂症或情绪障碍成人患者中 DRA 引起的 TD 的药物/脑刺激干预的随机对照试验(RCT)。主要结果为TD症状变化(标准化平均差/SMD)和全因停药(可接受性风险比/RR)。进行了敏感性分析。对整体、局部不一致性、偏倚风险(RoB-2 工具)和证据置信度(CINeMA)进行了测量。我们纳入了 46 项试验(n = 2844,年龄 = 52.89 ± 9.94 岁,男性 = 59.8%,精神分裂症 = 84.6%,心境障碍 = 15.4%),所有试验均为药物干预与安慰剂对比试验。我们发现了三个子网络。在网络1中,几种治疗方法对TD症状的疗效优于安慰剂,且具有较大的效应量(k = 34,n = 2269),包括22项干预措施与安慰剂的比较,但18项仅有1项RCT,15项的n≤20。出现了高度异质性(I2 = 57.1%;tau2 = 0.0797)和总体不一致性(Q = 32.64;df = 14;p = 0.0032)。在可接受性方面没有出现明显差异。如果将分析范围限制在具有 n > 20 项试验和 > 1 项 RCT 的治疗方法,则只有戊苯那嗪(k = 5,SMD = -0.69;95% CI = -1.00, -0.37)和维生素 E(k = 7,SMD = -0.49;95% CI = -0.87, -0.11)优于安慰剂。考虑到AIMS评分,仅在偏倚风险较低的试验中,24/36毫克(k = 2,SMD = -0.57/-0.60)的去甲替拉嗪的疗效优于安慰剂。去甲替拉嗪和戊苯那嗪的研究结果可信度较低,所有其他药物的可信度都很低。在网络 2(k = 2,n = 63)中,改用莫林酮(k = 1,n = 9)与改用氟哌啶醇相比,TD 会恶化(SMD = 1.68;95% CI = 0.61,2.76)。在网络3(k = 3,n = 194)中,抗精神病药物洗脱+安慰剂(k = 1,n = 25)与TAU+安慰剂(k = 1,n = 27)相比,TD恶化(SMD = 1.30;95% CI = 0.36,2.23)。尽管一些质量/置信度很低的治疗方法的效应大小很大,但如果考虑到质量较高的证据,只有戊苯那嗪或去甲替拉嗪是循证的TD一线治疗方法,维生素E可能是二线治疗方法。应避免转用吗丁啉酮和抗精神病药物冲洗。我们需要更多的治疗方案和更高质量的试验。
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Molecular Psychiatry
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