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诱因，但其作用机制长期以来似乎难以捉摸。迄今为止，我们在我们的家族数据集中至少有以下基因与精神分裂症相关的证据：COMT、DTNBP1、mud1、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。我们的数据集包括来自750多个家庭的个体和650多个病例/对照数据集。我们数据集的独特之处在于，每个受试者，包括病例和对照组，都是由在这个项目上合作了十多年的同一位临床医生通过结构化的现场访谈进行广泛评估的，这可能解释了已经出现的遗传关联的强度。随着单基因变异特征的快速发展，研究日益转向剖析基因-基因和基因-环境的相互作用。我们的策略是用认知和神经成像分析来表征和绘制大脑中的基因效应，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层和皮质功能中的多巴胺张力。D1受体是皮层中主要的DA受体，研究表明，通过PET放射性示踪剂NNC112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NNC112在val/val正常对照和met等位基因携带者中的结合情况。与Met携带者相比，Val/ Val受试者的皮层NNC112结合水平显著高于Met携带者，但纹状体结合水平无显著差异。这些结果证实了COMT在皮质而非纹状体中调节DA传递的突出作用，以及NNC112作为低DA音调标记物的可靠性，正如之前在精神分裂症研究中提出的那样。我们首次在人脑中证明，val158met多态性是D1受体可用性个体差异的遗传因素。结构影响的一个例子是G蛋白偶联受体（GPCR），它高度多样化，参与多种形式的信息处理。SREB2（大脑中表达的超保守受体）是脊椎动物进化过程中最保守的GPCR，在具有高可塑性的大脑结构中大量表达，如海马树突回。在这里，我们发现SREB2参与决定大脑大小，调节多种行为，并可能对SCZ易损性有影响。SEB2轻度过表达导致转基因小鼠脑重量明显减轻和心室增大，以及反映精神疾病的行为异常。SREB2基因敲除小鼠表现出互惠表型，脑重量显著增加，记忆力增强，但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。两种SREB2变异的次要等位基因被过度传递到精神分裂症家族样本中，并显示等位基因负荷与患者海马灰质体积减少有关。我们的数据表明SREB2是精神疾病的潜在危险因素，其途径是精神治疗的靶点。我们目前的数据为进一步研究脑部疾病提供了依据。为此，针对SREB2的特异性激动剂和拮抗剂应该是强有力的工具，并可能最终直接导致神经精神疾病治疗方法的发展。