3/5-Genetics of Transcriptional Endophenotypes for Schizophrenia

3/5-精神分裂症转录内表型的遗传学

• 批准号: 8237585
• 负责人: Ruben C. Gur
• 金额: $ 8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237585
• 关键词: Affect; African American; Alabama; Biological Assay; Biological Process; Biology; Biomedical Research; California; Cell Line; Chromosome Mapping; DNA; DNA Methylation; Data; Data Collection; Data Set; Diagnosis; Diagnostic; Disease; Emotions; Etiology; Face; Family; Family Study; Family member; Freezing; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome Scan; Genomics; Genotype; Goals; Gur; Individual; Investigation; Joints; Measures; Memory; Methods; Molecular Genetics; National Institute of Mental Health; Neurocognition; Neurocognitive; Neurons; Parents; Pennsylvania; Phenotype; Prevention; Process; Psyche structure; Psychiatry; RNA; Research Institute; Research Personnel; Risk; Risk Factors; Role; Sampling; Schizophrenia; Signal Transduction; Site; Testing; Texas; Transcript; Universities; Variant; base; brain tissue; cognitive function; cost; database of Genotypes and Phenotypes; design; endophenotype; flexibility; genetic analysis; genetic pedigree; genome wide association study; genome-wide; innovation; interest; lymphoblastoid cell line; neurocognitive test; novel; proband; psychogenetics; repository; trait; transcriptomics

DESCRIPTION (provided by applicant): Schizophrenia is a common and debilitating condition with high personal costs to affected individuals and their families as well as high societal costs. Relatively little is known about the pathophysiology of schizophrenia. Although there is strong evidence for a genetic component to risk of schizophrenia, few specific genes involved in its etiology have been identified. In this set of coordinated R01s, we propose to take an alternative approach to localizing genes influencing risk of schizophrenia, combining established intermediate risk factors for schizophrenia with identification of novel transcriptional endophenotypes and combining standard GWAS gene localization approaches with innovative methods utilizing joint analysis of association and linkage and joint analysis of genomic and transcriptomic evidence. We will utilize existing samples and data from three ongoing studies: the Consortium on the Genetics of Schizophrenia (COGS); the Multiplex Multigenerational Investigation of Schizophrenia (MGI); and the Project among African Americans to Explore Risks for Schizophrenia (PAARTNERS). These three family studies were designed to investigate genetic influences on schizophrenia using neurocognitive phenotypes associated with schizophrenia risk. We hypothesize that alterations in gene regulation are responsible for some portion of the genetic liability to schizophrenia. Thus, we will use RNA expression levels both as potential endophenotypes for schizophrenia and as an alternative method of genome scanning. Identification of transcriptional correlates of schizophrenia will be facilitated by use of a novel Endophenotype Ranking Value (ERV) that combines the strength of the genetic signal on a potential endophenotype with the strength of its correlation with the disease of interest (i.e. schizophrenia) in a single measure. We will conduct a conventional genome-wide association study (GWAS) for schizophrenia, for newly identified transcriptional endophenotypes, and for classical neurocognitive risk factors. We will also take advantage of the large families in these samples to conduct joint linkage and association. Finally we will combine genomic and transcriptomic lines of evidence in a joint test to identify genes influencing schizophrenia and associated neurocognitive risk factors. All data generated in the course of the project will be shared through dbGaP and the NIMH Genetics Repository. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify genes influencing risk of schizophrenia utilizing information from intermediate traits, including levels of gene expression and measures of cognitive function, in families from three genetic consortia. Integration of information from the proposed association and gene expression studies, along with information from ongoing studies of DNA methylation and structural variants in these same families, will contribute to our understanding of the basic biological processes underlying schizophrenia, has the potential to aid in diagnosis and prevention, and may suggest new avenues of treatment.

描述（由申请人提供）：精神分裂症是一种常见且令人衰弱的状况，对受影响的个人及其家人以及高昂的社会成本具有很高的个人费用。关于精神分裂症的病理生理学知之甚少。尽管有强有力的证据表明遗传成分有精神分裂症的风险，但鉴定出参与其病因的特定基因很少。在这组协调的R01中，我们建议采用一种替代方法来定位基因，影响精神分裂症的风险，将精神分裂症的既定中间风险因素与鉴定的新型转录式内部型和鉴定，并将标准GWAS基因本地化方法结合到使用创新迹象和链接分析的共同分析和基因分析的共同分析。我们将利用三项正在进行的研究的现有样本和数据：精神分裂症遗传学的财团（COGS）；精神分裂症（MGI）的多元二苯二型研究；以及非裔美国人中的项目，以探索精神分裂症的风险（Paartners）。这三项家庭研究旨在研究与精神分裂症风险相关的神经认知表型对精神分裂症的遗传影响。我们假设基因调节的改变是导致精神分裂症遗传责任的一部分。因此，我们将使用RNA表达水平作为精神分裂症的潜在内表型，也是基因组扫描的另一种方法。通过使用一种新型的内表型排名值（ERV）来促进精神分裂症的转录相关性的鉴定，该排名值（ERV）将遗传信号的强度与潜在的内型型的强度与其与利益疾病（即精神分裂症）相关的强度（即单一度量）。我们将针对精神分裂症，新确定的转录内表型和经典神经认知危险因素进行一项常规全基因组关联研究（GWAS）。我们还将利用这些样本中的大家庭进行联合联系和关联。最后，我们将在关节测试中结合基因组和转录组证据线，以鉴定影响精神分裂症和相关神经认知危险因素的基因。项目过程中生成的所有数据将通过DBGAP和NIMH遗传库共享。 公共卫生相关性：该项目的目的是确定利用来自中间性状的信息的基因，包括来自三个遗传联盟的家庭中中间性状的信息，包括基因表达和认知功能的度量水平。来自拟议关联和基因表达研究的信息的整合，以及这些家族中DNA甲基化和结构变异的持续研究的信息将有助于我们对精神分裂症基本的基本生物学过程的理解，具有帮助诊断和预防的潜力，并可能提出新的治疗途径。