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）：双相情感障碍和精神分裂症等发育障碍的遗传学很复杂，并且已经发现导致这两种疾病的遗传因素有重叠。虽然常见变异通常与较小的效应量相关，但个别罕见的变异尤其是特定拷贝数变异 (CNV)，即缺失或基因组片段的重复，与较大的效应大小相关，甚至高达 63 的比值比。CNV 相对较大的效应大小可能是由于 CNV 中的多个基因导致表型变化，可能在聚合途径中。我们使用染色体工程技术（基因打靶和 cre-loxP 介导的体内反等位基因重组）来开发小鼠模型，对在受双相情感障碍和分裂情感障碍影响的家庭中发现的 9p24.1 重复/三重进行建模。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（统称为 9p24）的 1 个（缺失）、2 个（wt）、3 个（重复）和 4 个（三倍）拷贝的小鼠。 .1 CNV 小鼠）。基本假设是 9p24.1 拷贝数的变化，特别是增加，足以引起表型变化，让人想起主要的神经精神疾病。 CNV 区域包括 GLDC、UHRF2 和微小 RNA miR-4665。 GLDC是一个“铁证”。 GLDC 表达增加可能导致甘氨酸（NMDA 受体的共激动剂）降解增加。 NMDA 受体功能低下已被证明会导致小鼠出现精神分裂症相关表型。我们将研究甘氨酸和 D-丝氨酸（同一位点 NMDA 受体的另一种共激动剂）的水平，以及 9p24.1 CNV 小鼠的精神分裂症样行为，以检验 GLDC 的重复或三倍可能导致的假设神经精神表型。 UHRF2 在海马和皮质下板中表达，编码泛素修饰剂 (SUMO) E3 连接酶，是 E2F1 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 UHRF2 拷贝数的增加可能导致细胞凋亡增加。到目前为止，miR-4665，特别是 miR-4665-5p 的特征还很不清楚，但通过计算预测了与神经发育障碍相关的靶基因（MECP2、ANK3、PAX5）：MECP2 与雷特综合征有关，而 ANK3 和 PAX5 实际上与双相情感障碍有关。通过监测全球基因表达的变化，我们将检查 9p24.1 拷贝数的变化是否会导致该区域之外的基因表达发生变化，而这可能是由 miR-4665-5p 介导的。总之，我们建议确定 9p24.1 区域的拷贝数效应，并提出关于它们如何促进神经精神相关表型的具体假设。这些研究为更有针对性地探究 9p24.1 区域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。