An integrated approach to study GPCR variants associated with complex diseases

 描述(由申请人提供)：美国国立卫生研究院在获取大量个体的基因组数据方面投入了大量资金。现在的挑战是利用基因变异的数据来改善医疗保健和临床实践。研究与特定疾病相关的基因变异的功能后果可以告诉我们该疾病的机制基础和潜在的未来治疗靶点。G蛋白偶联受体(GPCRs)组成了一个大的基因家族，代表了基因组中最“可下药”的部分。虽然已经发现了大量的GPCR变异体，但大多数GPCR变异体的功能后果和潜在的临床影响尚未确定。我们建议结合基于表型和功能的方法来识别临床上最重要的GPCR变异体。盖辛格健康系统是电子健康记录系统的先驱之一，这证明了其合理性和可行性。近二十年来，我们收集了约300,000,000名患者的详细临床数据，包括关于&GT；750,000名患者的丰富、机密信息(例如，ICD9代码、实验室值、药物、保险索赔)，这些信息已输入高度标准化、可搜索和可输出的数据库。此外，我们已经对这个群体中的大约18,000名患者进行了基因分型，并收集了另外大约20,000名受试者的DNA样本，以进行基因分型工作。在这些资源的基础上，我们将与宾夕法尼亚州立大学合作，实施表型全关联(Phewas)方法，以确定存在于1%人口中的与GPCR变异体相关的主要临床表型。然后，我们将使用快速但全面的方法来测试每个GPCR变异体的功能后果，以确定是否存在可能导致相关表型的病理生物学的功能缺陷。最后，我们将使用盖辛格独特的同意程序重新联系研究参与者，目的是从那些携带功能障碍的GPCR变体的人身上收集额外的血液。这些血液将被用来提取可诱导的多能干细胞，供科学界用于进一步的派生和功能分析。

 DESCRIPTION (provided by applicant): The NIH has invested heavily in obtaining genomic data on a large number of individuals. The challenge now is to use the data on genetic variations to improve health care and clinical practice. Investigating functional consequences of genetic variants associated with a given disorder can inform us of the mechanistic basis of the disorder and potential future therapeutic targets. G protein coupled receptors (GPCRs) comprise a large gene family that represents the most "druggable" portion of the genome. Although a large number of GPCR variants have been identified, the functional consequence and potential clinical impact of most of these GPCR variants have not been determined. We propose to combine phenome- and function-based approaches to identify the most clinically important GPCR variants. Attesting to both rationale and feasibility, the Geisinger Health System is one of the pioneers of the electronic health record system. For nearly two decades, we have collected detailed clinical data on ~3,000,000 patients, including rich, categorical information (eg, ICD9 codes, lab values, medications, insurance claims) on >750,000 individuals that has been entered into a highly standardized, searchable, and exportable database. Moreover, we have genotyped ~18,000 patients in this group and have collected DNA samples on another ~20,000 subjects for on-going genotyping efforts. Building on these resources, we will collaborate with Penn State University to perform a phenome-wide association (PheWAS) approach to identify major clinical phenotypes associated with GPCR variants that are present in >1% of the population. We will then use rapid but comprehensive approaches to test the functional consequence of each GPCR variant to determine whether functional defects exist that could contribute to the pathobiology of the associated phenotype. Finally, we will use Geisinger's unique consent process to re- contact study participants for the purpose of collecting additional blood from those carrying dysfunctional GPCR variants. This blood will be used to derive inducible pluripotent stem cells that will be made available to the scientific community for further derivation and functional analysis.