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Neurobiological relevance of 9p24.1 CNVs for bipolar disorder and schizophrenia

9p24.1 CNV 与双相情感障碍和精神分裂症的神经生物学相关性

基本信息

批准号：
8754996
负责人：
Uwe Rudolph
金额：
$ 19.75万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8754996
关键词：
9p24.1 Affect Agonist Alleles Anxiety Apoptosis Apoptotic Attention Behavior Behavioral Biochemical Biochemical Reaction Biological Bipolar Disorder Boxing Brain Breeding Chromosomes Chronic Circadian Rhythms Complex Copy Number Polymorphism Development Diagnosis Disease E2F Transcription Factor 1 E2F1 gene Engineering FDA approved Family Frequencies Future Gene Deletion Gene Dosage Gene Expression Gene Targeting Genes Genetic Genetic Recombination Genetic Risk Genomic Segment Glutamates Glycine Glycine decarboxylase High Pressure Liquid Chromatography Hippocampus (Brain)Hospitals Housing Human Individual Interneurons Investigation Knock-out Lead Light Link Lithium Measures Mediating Mediator of activation protein Memory impairment Mental Depression Messenger RNA MicroRNAs Molecular Monitor Mood Disorders Morphology Motor Activity Mus Mutation N-Methyl-D-Aspartate Receptors Neurobiology Neurodevelopmental Disorder Neuroglia Odds Ratio PAX5 gene Parvalbumins Pathway interactions Patients Phenotype Play Process Research Personnel Rett Syndrome Reverse Transcriptase Polymerase Chain Reaction Risk Risk-Taking Role Schizoaffective Disorders Schizophrenia Serine Short-Term Memory Site Somatosensory Cortex Somatostatin Son Staging Stress Sucrose Swimming Techniques Testing Time Variant Vertebral column base bipolar mania conditioned fear developmental disease disorder risk feeding genetic risk factor hippocampal subregions in vivo interest mouse model neurobiological mechanism neuropsychiatry novel novel therapeutic intervention novel therapeutics preference public health relevance rare variant receptor function structural genomics transmission process ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The genetics of developmental disorders like bipolar disorder and schizophrenia are complex, and an overlap in the genetic factors contributing to these two disorders has been found. While common variants are typically associated with small effect sizes, individually rare variants in particular copy number variants (CNVs), i.e., deletions or duplications of genomic segments, have been associated with large effect sizes, even up to an odds ratio of 63. Potentially, the relatively large effect size of CNVs could result from severa genes in the CNVs contributing to the phenotypic changes, potentially in converging pathways. We have used chromosome engineering techniques (gene targeting and cre-loxP-mediated trans-allelic recombination in vivo) to develop mice modeling a 9p24.1 duplication/triplication found in a family affected by bipolar disorder and schizoaffective disorder. As overlapping deletions have been found in other families affected by schizophrenia, we propose to study mice with 1 (deletion), 2 (wt), 3 (duplication) and 4 (triplication) copies of the 15 9p24.1 genes (collectively called 9p24.1 CNV mice). The basic hypothesis is that changes in 9p24.1 copy number, in particular increases, are sufficient to elicit phenotypic changes reminiscent of major neuropsychiatric disorders. The CNV region includes GLDC, UHRF2 and the micro RNA miR-4665. GLDC is a "smoking gun". Increased expression of GLDC could result in increased degradation of glycine, a co-agonist at the NMDA receptor. NMDA receptor hypofunction has been shown to result in schizophrenia-related phenotypes in mice. We will investigate the level of glycine and D-serine, another co-agonist at the NMDA receptor at the same site, and schizophrenia-like behavior in the 9p24.1 CNV mice to test the hypothesis that duplication or triplication of GLDC may contribute to neuropsychiatric phenotypes. UHRF2, which is expressed in hippocampus and subcortical plate, encodes an ubiquitine modifier (SUMO) E3 ligase which is an important mediator of E2F1-mediated apoptosis. As increased expression of apoptotic genes has been found in bipolar disorder, an increase in UHRF2 copy number could result in increased apoptosis. miR-4665, specifically miR-4665-5p is poorly characterized so far, but has computationally predicted target genes (MECP2, ANK3, PAX5) that have been linked to neurodevelopmental disorders: MECP2 to Rett Syndrome, and ANK3 and PAX5 actually to bipolar disorder. By monitoring changes in gene expression globally, we will examine whether changes in 9p24.1 copy number will lead to changes in the expression of genes outside of this region which may be mediated by miR-4665-5p. In summary, we propose to determine copy number effects in the 9p24.1 region with specific hypotheses concerning how they may contribute to neuropsychiatric-related phenotypes. The studies form the basis for even more targeted interrogation of the role of individual genetic factors in the 9p24.1 region in the development and expression of major neuropsychiatric disorders.

描述（由申请人提供）：发育障碍如双相情感障碍和精神分裂症的遗传学是复杂的，并且已经发现导致这两种障碍的遗传因素的重叠。虽然常见的变异通常与小的效应量相关，但个别罕见的变异，特别是拷贝数变异（CNV），即，缺失或基因组片段的重复，与大的效应量相关，甚至高达63的比值比。潜在地，CNVs的相对大的效应量可能是由于CNVs中的几个基因促成表型变化，潜在地在会聚途径中。我们已经使用染色体工程技术（基因靶向和cre-loxP介导的体内反式等位基因重组）来开发小鼠模型，在双相情感障碍和双相情感障碍的家庭中发现9p24.1重复/三重。由于在其他受精神分裂症影响的家族中发现了重叠缺失，我们建议研究具有15个9p24.1基因的1（缺失）、2（wt）、3（重复）和4（三重）拷贝的小鼠（统称为9p24.1 CNV小鼠）。基本假设是9p24.1拷贝数的变化，特别是增加，足以引起主要神经精神疾病的表型变化。CNV区域包括GLDC、UHRF 2和微小RNA miR-4665。GLDC是一把“冒烟的枪”。GLDC表达增加可导致甘氨酸降解增加，甘氨酸是NMDA受体的共激动剂。NMDA受体功能减退已显示导致小鼠中精神分裂症相关的表型。我们将研究甘氨酸和D-丝氨酸（NMDA受体同一位点的另一种共激动剂）的水平以及9p24.1 CNV小鼠的精神分裂症样行为，以检验GLDC重复或三倍可能导致神经精神表型的假设。UHRF 2在海马和皮层下板中表达，编码泛素修饰剂（SUMO）E3连接酶，E3连接酶是E2 F1介导的细胞凋亡的重要介质。由于在双相情感障碍中发现凋亡基因表达增加，因此UHRF 2拷贝数增加可能导致凋亡增加。到目前为止，miR-4665，特别是miR-4665- 5 p的特征很差，但计算预测的靶基因（MECP 2，ANK 3，PAX 5）与神经发育障碍有关：MECP 2与Rett综合征有关，ANK 3和PAX 5实际上与双相情感障碍有关。通过监测基因表达的变化，我们将研究9p24.1拷贝数的变化是否会导致该区域以外的基因表达的变化，这可能是由miR-4665- 5 p介导的。总之，我们建议确定在9p24.1区域的拷贝数效应与具体的假设，关于它们如何可能有助于神经精神相关的表型。这些研究为更有针对性地询问9p24.1区域中个体遗传因素在主要神经精神疾病的发展和表达中的作用奠定了基础。