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: 7594625
• 负责人: Daniel Weinberger
• 金额: $ 75.45万
• 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/7594625
• 关键词: AKT1 gene; Accounting; Adult; Affect; Alleles; Animals; Antipsychotic Agents; Attention; Autopsy; Behavior; Biological; Biological Assay; Biology; Bipolar Disorder; Brain; Brain region; Catechols; Cell Differentiation process; Cell Line; Cell model; Cells; Chromosome Mapping; Clinical; Cognition; Cognitive; Collaborations; Complex; Coupling; DARPP 32; DISC1 protein; DLG4 gene; DNA; DNA biosynthesis; DRD2 gene; Data; Data Set; Development; Diagnosis; Disease; Dopamine; Emotional; Emotions; Environment; Equilibrium; ErbB4 gene; Europe; Event; Exons; FGF20 gene; Family; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Haplotypes; Hereditary Disease; Hippocampus (Brain); Human; Image; Incidence; Individual; Individual Differences; Institutes; Interview; Learning; Life; Link; Major Depressive Disorder; Malignant Neoplasms; Mammary Neoplasms; Mediating; Memory; Mental disorders; Methyltransferase; Mission; Modification; Molecular; Molecular Target; Motor Activity; Mus; Mutation; NRG1 gene; Neuregulin 1; Neurobiology; Neuroblastoma; Neurons; Neuropeptides; Neurosciences; Neurotransmitters; PLAB Protein; Pathogenesis; Pathway interactions; Patients; Pattern; Performance; Phenotype; Play; Prefrontal Cortex; Prevention; Process; Property; Protein Isoforms; Protein Overexpression; Proteins; Psychotic Disorders; RNA Splicing; Regulation; Relative (related person); Research; Research Personnel; Resources; Risk; Role; Schizophrenia; Scientist; Short-Term Memory; Signal Pathway; Signal Transduction; Site; Specificity; Staging; Stimulus; Stress; Structure; Susceptibility Gene; System; Testing; Therapeutic; Tissues; Transcript; Transcriptional Regulation; Translating; United States National Institutes of Health; Variant; Vision; Work; age group; base; brain morphology; case control; cell type; clinical Diagnosis; dopamine system; enzyme activity; fetal; gene environment interaction; gene function; gene interaction; genetic association; genetic variant; human FGF20 protein; mRNA Expression; memory recognition; methionylmethionine; migration; molecular pathology; neonate; neurobiological mechanism; neurogenesis; neuroimaging; neuropsychiatry; neuropsychological; neurotransmission; novel; pituitary adenylate cyclase activating polypeptide; postnatal; programs; promoter; protein expression; receptor; synaptogenesis; trait; tumorigenesis

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 variants 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 examined genotype effect of catechol-o-methyltransferase (COMT) Val158Met on corticolimbic circuitry and functional connectivity. We found that Met/Met subjects had the ability to focus attention on relevant stimuli while inhibiting interference from other stimuli. This may be of great advantage during working memory (WM) task, but may have deleterious effects in environments with multiple stimuli requiring rapid and flexible processing. Another study evaluated COMT and GRM3 and examined their combined effects on dissociable components of the WM network. We found an epistatic interaction of these genes on the engagement of prefrontal cortex. GRM3 genotype was associated with inefficiency and altered prefrontal coupling on the background of COMT Val. As we know, abnormalities in dopamine (DA) neurotransmission contribute to psychiatric disorders. It has been shown that a network of brain regions is involved in performance of declarative and recognition memory tasks and this network, hippocampus and VLPFC, is modulated by DA. Regulation of DA signaling and neurotransmission is critically affected by COMT. We examined the effect of COMT Val158Met on function and coupling during recognition memory. There is compelling evidence that DA is an important modulator of hippocampal and prefrontal cortical interaction. This suggests that individual differences in responsivity and connectivity related to genetic modulation of DA, is a mechanism accounting for some individual differences in recognition memory performance. We also examined the effects of the PACAP gene on neurobiological traits related to risk for schizophrenia (SCZ). PACAP is a neuropeptide with neurotransmission modulating activity. We found an allele is overexpressed in patients showing an association with reduced hippocampal volume and poorer memory performance. We generated mice lacking the PACAP gene and observed abnormal behaviors, like elevated locomotor activity, which were reversed by treatment with an antipsychotic. These data suggest that alterations in PACAP signaling may contribute to the pathogenesis of SCZ. Our examination of transcripts, protein processing and expression has resulted in several findings. One study of DA- and cAMP-regulated phosphoprotein (DARPP-32) we identified a common haplotype, which predicts mRNA expression in postmortem human brain. This haplotype is associated with enhanced performance on several cognitive tests and imaging revealed an impact on neostriatal volume, activation, and functional connectivity of PFC. We use postmortem brain to focus on postnatal developmental changes. We examined COMT enzyme activity and protein expression in the PFC in 6 age groups of normals. We found a significant increase in COMT enzyme activity from neonate to adulthood which is paralleled by increases in protein expression. COMT protein expression is related to the Val158Met genotype. These increases may reflect changes in the PFC dopamine system and stresses the importance of COMT for PFC dopamine regulation during maturation. We also examined the DISC1 gene. DISC1 is the result of a balanced molecular translocation, which segregates with major mental disorders like SCZ, bipolar disorder and major depressive disorder (MDD). Our association study of DISC1 with MDD and SCZ found the risk allele, Cys704 associated with increased risk of developing MDD. Ser704Cys variation impacts brain morphology in normals and in primary neuronal culture, knockdown of cellular DISC1 protein resulted in suppression of ERK and Akt modification, whose signaling pathways are implicated in MDD. A possible biological mechanism of MDD is associated with lower biological activity on ERK signaling. Many human genes are known to produce more than one protein isoform through various molecular events. The use of multiple DNA replication start sites (promoters) is a frequent mechanism for generation of isoforms that provide tissue/cell type specificity, developmental-stage specificity, and allows for diverse functional properties of a gene. Neuregulin 1 (Nrg1) has nine alternative promoters. Genetic variations in promoters can contribute to genetic diseases by creating entirely new transcripts from any given gene. Such mechanisms may underlie the pathogenesis of complex diseases like SCZ. Recently, altered expression of a novel isoform (type 4) in the brain has been associated with schizo-related genetic variants. We isolated and characterized NRG1 type 4 DNA from adult and fetal human brain and identified a novel splice variant. We found a NRG1 protein representing a putative type 4 proprotein which is exclusively expressed in adult and fetal brain. Nrg1 type 4 expression is higher in the fetal brain and may have an important functional role during early brain development mediated through NRG1s effects on neurogenesis, neuronal migration, cell differentiation and synapse formation, and the regulation of neurotransmitter function. The fact that expression is brain-specific may be valuable in terms of possible therapeutics of NRG1 type 4 in SCZ. Nrg1 plays an important role in oncogenesis, and is overexpressed in various cancer tissues. However, we did not detect NRG1 type 4 in breast tumor and neuroblastoma cell lines. This absence, when juxtaposed to increased NRG1 type 4 associated with risk for SCZ, may contribute to the reduced incidence of cancer in patients SCZ and their relatives. This convergent pattern suggests that genetic regulation of type 4 may have a dual effect of protecting against cancer while increasing risk for SCZ. We have shown that type 4 represents a novel, translated, developmentally regulated, brain-specific isoform. We also show that a NRG1 promoter mutation, which impacts risk, is functional and selectively affects transcriptional levels of the type 4 isoform, providing a mechanism for the functional associations. Lastly, recent identification of NRG1 receptor, ErbB4 as a candidate SCZ risk gene, suggests that other molecules in the NRG1 pathway may also be involved. It has been shown that a molecular mechanism contributing to the genetic association of NRG1 with SCZ involves altered transcriptional regulation of a novel variant of the gene. We examined ErbB4 splice variant gene expression in hippocampus and DLPFC. ErbB4 splice patterns remain unaltered in hippocampus of SCZ, however we show an increase in expression of only the splice variant containing exons 16 and 26 in DLPFC in SCZ, suggesting that an ErbB4 receptor with exons 16 and 26 domains is preferentially upregulated in the disea

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。随着对单基因变异特征的快速研究，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。一项研究检测了儿茶酚-o-甲基转移酶（COMT） Val158Met基因型对皮质边缘回路和功能连接的影响。我们发现Met/Met受试者有能力将注意力集中在相关刺激上，同时抑制其他刺激的干扰。这可能在工作记忆（WM）任务中具有很大的优势，但在需要快速灵活处理的多重刺激环境中可能会产生有害的影响。另一项研究评估了COMT和GRM3，并检查了它们对WM网络可分离成分的综合影响。我们发现这些基因在前额皮质的参与上有上位性的相互作用。在COMT Val的背景下，GRM3基因型与效率低下和前额叶耦合改变有关。我们知道，多巴胺（DA）神经传递异常与精神疾病有关。研究表明，陈述性和识别性记忆任务的执行涉及一个大脑区域网络，海马体和VLPFC，该网络由DA调节。COMT对DA信号和神经传递的调节有重要影响。我们研究了COMT Val158Met在识别记忆过程中对功能和耦合的影响。有令人信服的证据表明，DA是海马和前额叶皮层相互作用的重要调节剂。这表明个体在响应性和连通性上的差异与DA的遗传调节有关，是个体识别记忆表现差异的一种机制。我们还研究了PACAP基因对与精神分裂症（SCZ）风险相关的神经生物学特征的影响。PACAP是一种具有神经传递调节活性的神经肽。我们发现一个等位基因在患者中过度表达，与海马体积减少和记忆力下降有关。我们制造了缺乏PACAP基因的小鼠，观察到异常行为，如运动活动的增加，通过抗精神病药物治疗可以逆转。这些数据表明，PACAP信号的改变可能与SCZ的发病机制有关。