From GWAS to PheWAS: Scanning the EMR Phenome for Gene-disease Associations

描述(由申请人提供)：基因组医学为改进诊断方法和更有效的、针对患者的治疗提供了希望。全基因组相关研究(GWAS)阐明了遗传标记，这些标记改善了临床对许多疾病和疾病的风险和机制的理解，并最终可能指导根据患者的具体情况进行诊断和治疗。该项目将在现有工作的基础上，跨基因组和表型组确定基因-表型关联，部署新的表型全基因组关联研究(Phewas)方法，深入研究整个基因组中常见和罕见变异的电子医疗记录(EMR)派生的表型。该项目是由大型DNA生物库与未识别的EMR副本连接起来的。这个项目有三个具体目标。首先，我们将扩展Phewas表型库，包括二进制性状和连续变量，其中包含来自自然语言处理、实验室数据和报告数据的约7000个表型。第二个目标是使用现有的全基因组和外显子组变异数据以及目标1中导出的更广泛的表型集，对常见和罕见的变异进行Phewas。我们将使用单一变异和多变异聚合方法分析关联。我们将通过与已知关联的比较来验证我们在目标2中的方法的有效性。第三个目标是开发一个以标准为基础的基础设施，以共享Phewas成果，并开发工具，使其他人能够执行Phewas。该项目产生的工具不仅将扩展当前Phewas方法学的能力，而且还将广泛地使临床研究和后续的基因研究成为可能。

DESCRIPTION (provided by applicant): Genomic medicine offers hope for improved diagnostic methods and for more effective, patient-specific therapies. Genome-wide associated studies (GWAS) elucidate genetic markers that improve clinical understanding of risks and mechanisms for many diseases and conditions and that may ultimately guide diagnosis and therapy on a patient-specific basis. This project will expand on existing work to identify gene-phenotype associations across the genome and phenome, deploying new phenome-wide associations study (PheWAS) methods to deeply investigate electronic medical record (EMR)-derived phenotypes across common and rare variants across the genome. The project is enabled by large DNA biobanks coupled to de-identified copies of EMR. This project has three specific aims. First, we will expand the PheWAS phenotype library to include both binary traits and continuous variables incorporating about 7000 phenotypes derived from natural language processing, laboratory data, and report data. The second aim is to perform a PheWAS for common and rare variants using extant genome-wide and exome variant data and the broader set of phenotypes derived in Aim 1. We will analyze associations using single variant and multi-variant aggregation methods. We will validate the efficacy of our methods in Aim 2 by comparing to known associations. The third aim is to develop a standards-based infrastructure to share PheWAS results and develop tools to enable others to perform PheWAS. The tools generated from this project will not only expand the capabilities of the current PheWAS methodology, but will also broadly enable clinical research and subsequent genetic studies.