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）：躁郁症和精神分裂症等发育障碍的遗传学很复杂，并且发现了导致这两种疾病的遗传因素的重叠。虽然常见变体通常与小效应大小相关，但在特定拷贝数变体（CNV）的单独稀有变体（即删除）或基因组片段的重复，即使效应大小也很大，甚至几率为63。可能是，CNV的相对较大的CNV效应大小可能是由于CNV中的Severa基因造成了有助于表型变化的CNV中的Severa基因，并有可能在收敛途径中。我们已经使用染色体工程技术（基因靶向和Cre-loxp介导的体内跨皮肤重组）来开发在受双相情感障碍和SCHIZACTARCTACTARCTACTARCTACTARCEDRIAS的家庭中发现的9p24.1重复/三次建模的小鼠。由于在受精神分裂症影响的其他家族中发现了重叠的缺失，因此我们建议用1（删除），2（WT），3（重复）和4（三分之一）和4（三分之一）副本研究小鼠的15 9p24.1基因（集体称为9p24.1 CNV小鼠）。基本的假设是，9p24.1拷贝数的变化，特别是增加，足以引起表型变化，让人联想到主要神经精神疾病。 CNV区域包括GLDC，UHRF2和微RNA miR-4665。 GLDC是“吸烟枪”。 GLDC的表达增加可能导致NMDA受体的共同受体甘氨酸的降解增加。 NMDA受体功能障碍已显示出可导致小鼠与精神分裂症相关的表型。我们将研究同一部位的NMDA受体的另一位共同受体的甘氨酸和D丝氨酸的水平，以及9p24.1 CNV小鼠中类似精神分裂症的行为，以检验GLDC重复或一式一式一式一式三位一体的假设可能对神经心理现象有助于。在海马和皮层下板中表达的UHRF2编码泛素修饰剂（SUMO）E3连接酶，这是E2F1介导的凋亡的重要介体。由于在躁郁症中发现了凋亡基因的表达增加，因此UHRF2拷贝数的增加可能导致凋亡增加。到目前为止，miR-4665，特别是miR-4665-5p的特征很差，但是在计算上预测的靶基因（MECP2，ANK3，PAX5）与神经发育障碍有关：MECP2与RETT综合征和ANK3和PAX5的MECP2实际上与双极疾病有关。通过监测全球基因表达的变化，我们将检查9P24.1拷贝数中的变化是否会导致该区域以外的基因表达变化，而该区域以外的基因表达可能会由miR-4665-5p介导。总而言之，我们建议确定9P24.1区域中的拷贝数效应，并具有有关它们如何有助于神经精神病相关的表型的特定假设。该研究构成了对9p24.1区域中单个遗传因素在主要神经精神疾病的发展和表达中的作用更具针对性的质疑的基础。