Understanding the genomic risk architecture of schizophrenia using gene expressio

利用基因表达了解精神分裂症的基因组风险结构

基本信息

批准号：
7940987
负责人：
JOSEPH A GOGOS
金额：
$ 50万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7940987
关键词：
22q11.2 Accounting Address Affect Alleles Animal Model Architecture Behavioral Biological Process Biology Brain Brain region Brain-Derived Neurotrophic Factor Chromosomal translocation Chromosomes Cognitive Development Disease Environmental Risk Factor Etiology Evaluation Excitatory Synapse Financial compensation Future Gene Expression Gene Expression Process Gene Expression Profile Genes Genetic Genetic Heterogeneity Genetic Models Genetic Risk Genetic Structures Genetic Variation Genomics Goals Hippocampus (Brain)Human Genetics Inherited Knowledge Mental disorders MicroRNAs Modeling Molecular Molecular Profiling Mus Mutation Neurobehavioral Manifestations Neurobiology Pathway interactions Patients Pattern Penetrance Performance Pharmacotherapy Phenotype Play Prefrontal Cortex Process Reporting Research Risk Role Schizophrenia Short-Term Memory Single Nucleotide Polymorphism Structure Syndrome Testing Time Uncertainty Variant Work chromosome mutation clinical phenotype critical developmental period design disorder risk genetic variant insight microdeletion mouse model mutant neurochemistry neurodevelopment neuron development neuropsychiatry novel patient population programs synaptogenesis trait

项目摘要

Description (provided by applicant): This proposal represents a move from genomics to biology designed to identify the patterns of gene expression induced by disease-associated mutations and help frame our understanding and elucidate the structure of the still elusive genetic interactions underlying disease risk ("Schizophrenia interactome"). Recent studies have unequivocally demonstrated an important contribution of rare structural mutations to the genetic architecture of numerous psychiatric disorders, including schizophrenia. Determining how such mutations act in concert with modifiers to cause and influence the clinical phenotype is an important question that remains to be addressed. We contend that common genetic variation (including single nucleotide polymorphisms, SNPs) plays a key role in determining the penetrance or the expressivity of rare mutations. This hypothesis has not been directly tested and given the difficulties and uncertainties associated with testing common variation in patient populations it may be impossible to test it unequivocally using human genetic approaches. However, availability of animal models could offer important insights into how rare and common variation interact to affect key neurobiological processes and the gene expression networks underlying such processes. To accomplish this goal, we propose to utilize four "key" mouse lines generated in our lab: i. Two lines that faithfully model two rare mutations that unequivocally predispose to schizophrenia: a truncation of the DISC1 (short for Disrupted-In-Schizophrenia 1) gene and a microdeletion on chromosome 22q11.2; ii. Two lines that faithfully model two alleles of a common variant (BDNF Val66Met) associated with a number of psychiatric diseases and related traits, which undoubtedly modulates neurotrophic action in the developing brain. We propose to analyze the transcriptional profile in the hippocampus and prefrontal cortex across critical developmental periods to obtain an unbiased evaluation of the transcriptional programs affected by the combined effect of rare and common disease-associated variation, reflecting downstream effects of the mutation and/or adaptive/compensatory changes. Our work promises to advance our current genetic knowledge, identify novel disease-related genes or genetic pathways that could be tested in future human genetic studies of SCZ, as well as provide targets for novel pharmacotherapy approaches

描述（由申请人提供）：该提案代表了从基因组学到生物学的转变，旨在识别疾病相关突变诱导的基因表达模式，并帮助我们理解和阐明疾病风险背后仍然难以捉摸的遗传相互作用的结构（“精神分裂症相互作用组”）。最近的研究明确证明了罕见的结构突变对包括精神分裂症在内的多种精神疾病的遗传结构的重要贡献。确定此类突变如何与修饰因子协同作用以引起和影响临床表型是一个有待解决的重要问题。我们认为，常见的遗传变异（包括单核苷酸多态性，SNP）在决定罕见突变的外显率或表达性方面发挥着关键作用。该假设尚未经过直接检验，并且考虑到与测试患者群体中的常见变异相关的困难和不确定性，可能不可能使用人类遗传方法明确地检验它。然而，动物模型的可用性可以提供重要的见解，了解罕见和常见的变异如何相互作用，影响关键的神经生物学过程以及这些过程背后的基因表达网络。为了实现这一目标，我们建议利用我们实验室生成的四个“关键”小鼠品系：两条细胞系忠实地模拟了两种明显易患精神分裂症的罕见突变：DISC1（Disrupted-In-Schizophrenia 1 的缩写）基因的截短和染色体 22q11.2 上的微缺失；二.两条细胞系忠实地模拟了与许多精神疾病和相关特征相关的常见变体（BDNF Val66Met）的两个等位基因，这无疑调节了发育中大脑的神经营养作用。我们建议分析关键发育时期海马和前额叶皮层的转录谱，以获得对受罕见和常见疾病相关变异综合效应影响的转录程序的公正评估，反映突变和/或适应性的下游影响/补偿性改变。我们的工作有望推进我们当前的遗传知识，识别可在未来 SCZ 人类遗传学研究中进行测试的新的疾病相关基因或遗传途径，并为新的药物治疗方法提供靶点