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衰弱的疾病，对受影响的个人及其家庭来说，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精神分裂症的风险与遗传因素有关，但很少有特定的基因被确定为其病因。在这组协调的R01s中，我们建议采用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危险因素与鉴定新的转录内表型相结合，将标准的GWAS基因定位方法与利用关联和连锁联合分析以及基因组和转录组学证据联合分析的创新方法相结合。我们将利用三项正在进行的研究的现有样本和数据：精神分裂症遗传学联合会（COGS）；精神分裂症多代调查（MGI）；以及非裔美国人探索精神分裂症风险项目（伙伴）。这三个家庭研究旨在通过与精神分裂症风险相关的神经认知表型来研究遗传对精神分裂症的影响。我们假设基因调控的改变在一定程度上导致了精神分裂症的遗传倾向。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基因组扫描的替代方法。通过使用一种新的内表型排序值（ERV），将潜在内表型上的遗传信号强度与其与感兴趣的疾病（即精神分裂症）的相关性强度在单一测量中结合起来，将有助于鉴定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风险因素进行传统的全基因组关联研究（GWAS）。我们还将利用这些样本中的大家庭进行联合联动和关联。最后，我们将在联合测试中结合基因组和转录组学的证据，以确定影响精神分裂症和相关神经认知风险因素的基因。项目过程中产生的所有数据将通过dbGaP和NIMH基因库共享。

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.