Biological Characterization of Genetic Mechanisms in Neuropsychiatric Disorders

神经精神疾病遗传机制的生物学特征

• 批准号: 7735222
• 负责人: Daniel Weinberger
• 金额: $ 183.08万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7735222
• 关键词: AKT1 gene; Accounting; Adhesions; Adolescence; Adolescent; Affect; Agonist; Alleles; Anhedonia; Animals; Autopsy; Behavior; Behavioral; Binding; Biological; Biological Assay; Biology; Body Weight decreased; Brain; Brain Diseases; COMT gene; Callithrix; Callithrix jacchus jacchus; Catechol O-Methyltransferase; Cell Adhesion; Cell Line; Cell model; Cells; Childhood; Chromosome Mapping; Chromosome Pairing; Clinical; Cognition; Cognitive; Collaborations; Complement; Complement component C1s; Complement component C4; Complex; Computer information processing; Condition; Corpus striatum structure; DLG4 gene; DRD2 gene; Daily; Data; Data Set; Development; Developmental Process; Diagnosis; Disease; Dopamine; Dopamine D1 Receptor; Emotional; Emotions; Enuresis; Environment; ErbB4 gene; Europe; Evolution; Exhibits; FGF20 gene; Family; Functional disorder; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Growth; Hippocampus (Brain); Human; Image; Impairment; Individual; Institutes; Interview; Knockout Mice; Lead; Learning; Lectin; Life; Link; Magnetic Resonance Imaging; Measures; Mediating; Memory; Mental disorders; Minor; Mission; Molecular; Molecular Biology; Molecular Target; Monkeys; Mood Disorders; NRG1 gene; Neuregulin 1; Neuronal Plasticity; Neurosciences; Outcome; PLAB Protein; Pathway interactions; Patients; Phenotype; Play; Positron-Emission Tomography; Precursor B-Lymphoblast; Predisposition; Prevention; Process; Protein Overexpression; Proteins; Psychiatric therapeutic procedure; Psychotic Disorders; Range; Rate; Reporting; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Schizophrenia; Scientist; Siblings; Stress; Structure; Susceptibility Gene; Synapses; System; Testing; Therapeutic; Time; Transcript; Transgenic Mice; Translating; United States National Institutes of Health; Up-Regulation; Variant; Ventricular; Vision; Weight; Work; base; brain size; case control; cell motility; clinical Diagnosis; cohort; depressive symptoms; deprivation; disorder risk; gene environment interaction; gene function; genetic association; genetic variant; gray matter; human FGF20 protein; immunoregulation; infancy; lymphoblast; molecular pathology; neurobiological mechanism; neurogenesis; neuroimaging; neuropsychiatry; neuropsychological; novel; programs; radiotracer; receptor; response; stressor; synaptic function; tool; transmission process; trend; valylvaline

Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. To date, we have evidence of association with schizophrenia in our family datasets of at least the following genes: COMT, DTNBP1, MUTED, EAA1, MRDS1, GAD1, DISC1, FEZ1, CITRON, NDE1, NRG1, PIK3d, ErbB4, DLG4, LIS1, MHTFR, DRD2, CAPON, PPP1R1B, DAARP, GRM3, CHRNA7, KCNH2, SREB2, PRODH, CAMKIIa, AKT1, FGF20, RELN1, and RCCX. Our dataset consists of individuals from over 750 families and case/control datasets of over 650. The unique aspects of our dataset, which may explain the strength of the genetic associations that have emerged, is that every subject, both cases and controls, are evaluated extensively with structured on sight interviews by the same clinicians who have worked together on this project for over ten years. As characterization of single genetic variant rapidly proceeds, research increasingly turns to dissecting gene-gene and gene-environment interactions. Our strategy for characterizing and mapping gene effects in brain with cognitive and neuroimaging assays enables us to better define intermediate phenotypes. Here we outline recent advances of linking genes to structural and functional variation in brain systems related to cognition and emotion. One study looked at a common polymorphism, COMT val158met, which has been shown to affect dopamine tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with PET radiotracer NNC112. We compared NNC112 binding in val/val normal controls versus met allele carriers. Val/val subjects had significantly higher cortical NNC112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of NNC112 as a marker for low DA tone as previously suggested by studies in schizophrenia. For the first time we have shown in the human brain that the val158met polymorphism is a genetic factor accounting for variability across individuals in D1 receptor availability. An example of structural impact is the G protein-coupled receptor (GPCR) which is highly diversified and involved in many forms of information processing. SREB2 (superconserved receptor expressed in brain) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, such as hippocampal dendate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to SCZ. Mild overexpression of SEB2 caused significant brain weight reduction and ventricular enlargement in transgenic mice as well as behavioral abnormalities mirroring psychiatric disorders. SREB2 knockout mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavior abnormalities. Because of phenotypic overlap between SREB2 transgenic mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 variants were over-transmitted to the schizophrenia family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy. Our present data warrant further studies investigating brain disorders. Toward this end, specific agonists and antagonist for SREB2 should be powerful tools and may eventually lead directly to development of therapeutics for neuropsychiatric disorders. Our findings on the neurobiological mechanism of the NRG1 schizophrenia susceptibility gene demonstrated impairment in NRG1-mediated cell migration. Using a B lymphoblast cell model we examined cell adhesion, an essential component process of cell motility. NRG1 induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. In cell lines from patients and controls, patients showed significant deficiency in the range of NRG1 induced adhesion. We also found a COMT val158met genotype effect showing a strong trend towards predicting the range of the NRG1-induced adhesion response with val/val having decreased variation in cell adhesion even in controls. Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion. This year we also investigated the impact of environment on risk for disease. We investigated how an early stressor, like parental separation, is a vulnerability factor in mood disorder. In common marmoset monkeys, daily deprivation during infancy produces a pro-depressive state of increased basal activity and reactivity in stress systems and mild anhedonia that persists at least to adolescence. We examined genes implicated in neural plasticity and in the pathophysiology of mood disorder, in the hippocampus of these same adolescent marmosets. We found effects on hippocampal gene expression, suggestive of changes in synaptic functioning and plasticity. The data suggest that hippocampal involvement in the disorder begins prior to the first episode of illness, and may reflect the role that early developmental adversity plays in its origins. We also looked to see if a preexisting condition, like childhood enuresis, could be a premorbid marker for neurodevelopmental abnormalities related to schizophrenia and found that there were higher rates of childhood enuresis (21%) compared with sibling (11%) or controls (7%). Patients with enuresis performed worse on cognitive tests as compared with non-enuresis patients. Recent findings, implicate complement in neurogenesis, synapse remodeling and pruning during brain developmental processes contribute to schizophrenia susceptibility. The role of complement, has been examined. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by other groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergoes dynamic changes, depending on the illness course and the state of neuroimmune crosstalk. It is plausible that the multicomponent complement system has an association with schizophrenia susceptibility, pathopsychology and illness course. For which understanding may bring a new perspective for possible immunomodulation and immunocorrection of the disease. The complex organization of connectivity in the human brain is incompletely understood. Here we show using anatomical networks derived from analysis of inter-regional covariation of gray matter volume in MRI data on controls, that classical divisions of cortex (multimodal, unimodal, and transmodal) have some distinct topological attributes. We found the multimodal network had a hierarchical organization dominated by frontal hubs with low clustering, transmodal netmodal as assortative. We propose that the topological differences between divisions of normal cortex may represent the outcome of different growth processes for multimodal and transmodal networks and that neurodevelopmental abnormalities in schizophrenia specifically impact multimodal cortical organization.

基因是许多精神疾病的主要原因，但其作用机制长期以来似乎难以捉摸。迄今为止，我们的家庭数据集中至少有以下基因与精神分裂症相关的证据：COMT、DTNBP1、MUTED、EAA1、MRDS1、GAD1、DISC1、FEZ1、CITRON、NDE1、NRG1、PIK3d、ErbB4、DLG4、LIS1、MHTFR、DRD2、CAPON、PPP1R1B、DAARP、 GRM3、CHRNA7、KCNH2、SREB2、PRODH、CAMKIIa、AKT1、FGF20、RELN1 和 RCCX。我们的数据集由来自 750 多个家庭的个体和超过 650 个病例/对照数据集组成。我们数据集的独特之处在于，每个受试者（包括病例和对照）均由在该项目上合作了十多年的同一临床医生通过结构化的现场访谈进行了广泛的评估，这可以解释已出现的遗传关联的强度。随着单一遗传变异特征的快速进展，研究越来越多地转向剖析基因-基因和基因-环境相互作用。我们通过认知和神经影像分析来表征和绘制大脑中基因效应的策略使我们能够更好地定义中间表型。在这里，我们概述了将基因与认知和情感相关的大脑系统的结构和功能变异联系起来的最新进展。一项研究着眼于一种常见的多态性 COMT val158met，它已被证明会影响皮质中的多巴胺张力和皮质功能。 D1 受体是皮质中主要的 DA 受体，研究表明，根据 PET 放射性示踪剂 NNC112 的测量，皮质 DA 水平的降低与 D1 受体可用性的上调有关。我们比较了 val/val 正常对照与 met 等位基因携带者中的 NNC112 结合。与 Met 携带者相比，Val/val 受试者的皮质 NNC112 结合显着更高，但纹状体结合没有差异。这些结果证实了 COMT 在调节皮层而非纹状体中 DA 传输中的突出作用，以及 NNC112 作为低 DA 音调标记物的可靠性，正如先前精神分裂症研究所表明的那样。我们首次在人脑中证明 val158met 多态性是一个遗传因素，可解释 D1 受体可用性的个体差异。 结构影响的一个例子是 G 蛋白偶联受体 (GPCR)，它高度多样化并参与多种形式的信息处理。 SREB2（大脑中表达的超级保守受体）是整个脊椎动物进化过程中最保守的 GPCR，在表现出高水平可塑性的大脑结构中大量表达，例如海马齿状回。在这里，我们证明 SREB2 参与确定大脑大小、调节不同的行为，并可能与 SCZ 的脆弱性有关。 SEB2的轻度过度表达导致转基因小鼠脑重量显着减轻、脑室扩大以及反映精神疾病的行为异常。 SREB2 基因敲除小鼠表现出相反的表型，即大脑重量显着增加，伴随着记忆力增强的趋势，而没有明显的其他行为异常。由于 SREB2 转基因小鼠和精神分裂症之间的表型重叠，我们寻找两者之间可能的联系。两个 SREB2 变体的次要等位基因过度传播到基于精神分裂症家族的样本中，并显示出等位基因负载与患者海马灰质体积减少相关。我们的数据表明 SREB2 是精神疾病的潜在危险因素，其途径可作为精神治疗的目标。我们目前的数据值得进一步研究调查脑部疾病。为此，SREB2 的特异性激动剂和拮抗剂应该成为强大的工具，并可能最终直接导致神经精神疾病治疗方法的开发。 我们对 NRG1 精神分裂症易感基因的神经生物学机制的研究结果表明，NRG1 介导的细胞迁移受到损害。使用 B 淋巴母细胞模型，我们检查了细胞粘附，这是细胞运动的重要组成过程。 NRG1 诱导淋巴母细胞呈现不同水平的粘附，其特征是粘附牢固度随时间变化。 在来自患者和对照的细胞系中，患者在 NRG1 诱导的粘附范围内表现出显着缺陷。我们还发现 COMT val158met 基因型效应显示出预测 NRG1 诱导的粘附反应范围的强烈趋势，即使在对照组中，val/val 的细胞粘附变化也减少。我们的研究结果表明，NRG1 与精神分裂症遗传相关的机制可能涉及细胞粘附的分子生物学。 今年我们还调查了环境对疾病风险的影响。我们调查了早期压力源（例如父母分离）如何成为情绪障碍的脆弱因素。在普通狨猴中，婴儿期每天的剥夺会产生一种促抑郁状态，即应激系统的基础活动和反应性增加，以及至少持续到青春期的轻度快感缺失。我们在这些青春期狨猴的海马体中检查了与神经可塑性和情绪障碍的病理生理学有关的基因。我们发现对海马基因表达的影响，表明突触功能和可塑性的变化。数据表明，海马体在疾病首次发作之前就开始参与这种疾病，并且可能反映了早期发育逆境在其起源中所起的作用。 我们还研究了先前存在的疾病，如儿童遗尿症，是否可能是与精神分裂症相关的神经发育异常的病前标志，并发现与兄弟姐妹（11%）或对照组（7%）相比，儿童遗尿症的发生率（21%）更高。与非遗尿症患者相比，遗尿症患者在认知测试中表现较差。 最近的研究结果表明，大脑发育过程中的神经发生、突触重塑和修剪中的补体会导致精神分裂症的易感性。补体的作用已被检查。其他研究小组也报道了精神分裂症中 C1、C3、C4 补体成分的活性增加。针对不同受试者队列的两项研究显示 MBL-MASP-2 活性增加，该疾病很可能伴随着补体经典途径和凝集素途径的改变，这些途径会根据病程和神经免疫串扰的状态而发生动态变化。多组分补体系统可能与精神分裂症易感性、病理心理学和病程有关。对于这一点的理解可能会为该疾病的可能的免疫调节和免疫纠正带来新的视角。 人脑中复杂的连接组织尚不完全清楚。在这里，我们使用从对照 MRI 数据中灰质体积的区域间协变分析得出的解剖网络来证明，皮层的经典划分（多模态、单模态和跨模态）具有一些独特的拓扑属性。我们发现多模式网络具有以低聚类、跨模式网络模式作为分类的前端中心主导的分层组织。我们提出，正常皮质分区之间的拓扑差异可能代表多模式和跨模式网络不同生长过程的结果，并且精神分裂症的神经发育异常特别影响多模式皮质组织。