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.

基因是许多精神病疾病的主要因素，但它们的作用机理长期以来似乎难以捉摸。 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，PODH，CAMKIIA，AKT1，FGF20，RERN1和RCCX。我们的数据集由来自750多个家庭的个体以及650多个案例/控制数据集组成。我们数据集的独特方面可以解释出现了已经出现的遗传关联的强度，是，每个受试者（包括病例和对照）的每个受试者都经过与十多年来在此项目中共同进行的临床访谈的结构进行广泛评估。随着单个遗传变异的表征，迅速进行，研究越来越多地转化为基因 - 基因和基因环境相互作用。我们用认知和神经影像学测定的大脑中表征和映射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与认知和情感有关的大脑系统中的结构和功能变化联系起来的最新进展。一项研究研究了一种常见的多态性COMT Val158met，已显示出会影响皮质和皮质功能中多巴胺的张力。 D1受体是皮层中的主要DA受体，研究表明，皮质DA的水平降低与D1受体可用性的上调有关，如PET radiotracer NNC112测量。我们比较了Val/Val正常对照中的NNC112结合与MET等位基因载体。与MET载体相比，VAL/VAL受试者具有明显更高的皮质NNC112结合，但纹状体结合没有差异。这些结果证实了COMT在调节DA传播中的重要作用，而不是纹状体，以及NNC112作为低DA张力标记的可靠性，如先前在精神分裂症研究中所建议的那样。我们在人脑中首次表明，val158met多态性是遗传因素，该因素构成了D1受体可用性中个体的变异性。 结构性影响的一个例子是G蛋白偶联受体（GPCR），它具有高度多样化，并参与了多种形式的信息处理。 SREB2（在大脑中表达的超保守受体）是整个脊椎动物进化中最保守的GPCR，并且在表现出高水平可塑性的大脑结构中表达了丰富的GPCR，例如海马甲状酸酯回。在这里，我们表明SREB2参与了确定大脑大小，调节各种行为，并有可能在SCZ脆弱性中。 SEB2的轻度过表达导致转基因小鼠的大脑体重减轻和心室肿大以及反映精神疾病的行为异常。 SREB2敲除小鼠表现出相互的表型，伴随着增强记忆的趋势而没有明显其他行为异常的趋势，大脑体重的显着增加。由于SREB2转基因小鼠和精神分裂症之间的表型重叠，我们寻求两者之间的可能联系。两个SREB2变体的次要等位基因过度转移到基于精神分裂症的家庭样本中，并显示出患者海马灰质体积减少的等位基因负载相关性。我们的数据暗示SREB2是精神疾病的潜在危险因素及其途径作为精神疗法的靶标。我们目前的数据需要进一步研究脑疾病的研究。为此，SREB2的特定激动剂和对手应该是强大的工具，并最终可能直接导致神经精神疾病的治疗疗法。 我们关于NRG1精神分裂症易感性基因的神经生物学机制的发现表明NRG1介导的细胞迁移受损。使用B淋巴细胞模型，我们检查了细胞粘附，这是细胞运动的重要组成过程。 NRG1诱导淋巴细胞假设具有不同水平的粘附水平，其特征是依赖于时间依赖的固定性。 在患者和对照组的细胞系中，患者在NRG1诱导的粘附范围内表现出明显的缺乏。我们还发现COMT Val158mET基因型效应显示，即使对照组中，Val/Val的粘附响应的范围也有很强的趋势，即VAL/Val的粘附响应的范围减少。我们的发现表明，NRG1遗传与精神分裂症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）如何是情绪障碍的脆弱性因素。在常见的marmoset猴子中，婴儿期的每日剥夺会产生抑郁的状态，即压力系统和轻度抗反感的基础活性和反应性的增加，至少至少持续到青春期。我们检查了与这些青少年果酱的海马中有关神经可塑性和情绪障碍的病理生理学的基因。我们发现对海马基因表达的影响，提示突触功能和可塑性的变化。数据表明，海马参与该疾病是在疾病第一集之前开始的，并且可能反映了早期发育逆境在其起源中发挥的作用。 我们还研究了像童年遗尿一样的先前存在状况是否可能是与精神分裂症相关的神经发育异常的病前标记，并发现与同胞（11％）或对照组（7％）相比，儿童期遗尿所（21％）的率更高。与非富甲酸盐患者相比，遗传患者在认知测试方面的表现较差。 最近的发现暗示了脑发育过程中神经发生，突触重塑和修剪的补体，这有助于精神分裂症的敏感性。补体的作用已被检查。其他群体已经报道了精神分裂症中C1，C3，C4补体成分的活性增加。两项对不同受试者队列的研究表明，MBL-MASP-2活性增加，可能伴随着补体经典和凝集素途径的改变，这会根据疾病病程和神经免疫串扰的状态而发生动态变化。多组分补体系统与精神分裂症的易感性，病理心理学和疾病课程有关联是合理的。对此，可能会带来对疾病的免疫调节和免疫纠正的新观点。 人脑中连通性的复杂组织尚不完全理解。在这里，我们使用的是从MRI数据中灰质体积的区域间协调得出的解剖网络，在对照组中，Cortex的经典划分（多模式，单峰和跨模式）具有一些不同的拓扑属性。我们发现，多模式网络的层次结构组织由额叶枢纽主导，其聚类低，跨模式Netmodal作为分类。我们建议，正常皮质分裂之间的拓扑差异可能代表了多模式和跨模式网络的不同生长过程的结果，而精神分裂症的神经发育异常特别影响了多模式皮质组织。