5/5 Genetics of Transcriptional Endophenotypes for Schizophrenia

描述（由申请人提供）：精神分裂症是一种常见的和衰弱的条件与高的个人成本，受影响的个人和他们的家庭，以及高的社会成本。对精神分裂症的病理生理学知之甚少。虽然有强有力的证据表明精神分裂症的风险的遗传成分，很少有特定的基因参与其病因已被确定。在这一组协调R 01，我们建议采取另一种方法来定位影响精神分裂症风险的基因，结合建立的精神分裂症的中间风险因素与识别新的转录内表型，并结合标准的GWAS基因定位方法与创新的方法，利用联合分析的关联和连锁和联合分析的基因组和转录证据。我们将利用现有的样本和数据，从三个正在进行的研究：精神分裂症遗传学联盟（COGS）;精神分裂症的多重多代调查（MGI）;和非裔美国人中的项目，以探索精神分裂症的风险（PAARTNERS）。这三个家庭研究的目的是调查精神分裂症的遗传影响，使用神经认知表型与精神分裂症的风险。我们假设基因调控的改变是精神分裂症遗传易感性的一部分。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和作为基因组扫描的替代方法。精神分裂症的转录相关物的鉴定将通过使用新的内表型排序值（ERV）来促进，所述内表型排序值在单一测量中将潜在内表型上的遗传信号的强度与其与感兴趣的疾病（即精神分裂症）的相关性的强度组合。我们将对精神分裂症、新发现的转录内表型和经典的神经认知危险因素进行常规的全基因组关联研究（GWAS）。我们也会利用这些样本中的大家庭，进行联合联动和关联。最后，我们将结合联合收割机的基因组和转录组学的证据，在一个联合测试，以确定基因影响精神分裂症和相关的神经认知危险因素。在项目过程中产生的所有数据将通过dbGaP和NIMH遗传学知识库共享。 公共卫生相关性：该项目的目标是确定基因影响精神分裂症的风险，利用中间性状的信息，包括基因表达水平和认知功能的措施，在三个遗传财团的家庭。整合信息，从拟议的关联和基因表达研究，沿着的信息，从正在进行的研究DNA甲基化和结构变异在这些相同的家庭，将有助于我们了解的基本生物学过程的精神分裂症，有可能有助于诊断和预防，并可能提出新的治疗途径。

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.