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、使人虚弱的疾病，对受影响的个人及其家人来说，个人成本很高，社会成本也很高。人们对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因素与精神分裂症的风险有关，但与其病因学相关的特定基因却很少被识别出来。在这组协调的R01中，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，将已确定的精神分裂症中间风险因素与新的转录内表型鉴定相结合，并将标准的Gwas基因定位方法与利用联合关联和连锁分析以及基因组和转录证据的联合分析的创新方法相结合。我们将利用来自三项正在进行的研究的现有样本和数据：精神分裂症遗传学联合会(COGS)；精神分裂症多代多代调查(MGI)；以及在非裔美国人中探索精神分裂症风险的项目(PAARTNERS)。这三项家庭研究旨在利用与精神分裂症风险相关的神经认知表型来调查遗传对精神分裂症的影响。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原因。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。通过使用一种新的内表型排名值(ERV)，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)的相关性的强度结合在一起，将有助于识别精神分裂症的转录相关性。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。我们还将利用这些样本中的大家庭进行联合联动和关联。最后，我们将在一项联合测试中结合基因组和转录组证据，以确定影响精神分裂症的基因和相关的神经认知风险因素。在项目过程中产生的所有数据将通过DBGaP和NIMH基因库共享。 公共卫生相关性：该项目的目标是利用来自三个基因联盟的家庭的中间特征信息，包括基因表达水平和认知功能测量，确定影响精神分裂症风险的基因。整合来自拟议的关联和基因表达研究的信息，以及正在进行的DNA甲基化和结构变异研究的信息，将有助于我们了解精神分裂症潜在的基本生物学过程，有可能帮助诊断和预防，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.