Investigating the clinical ontologies of loss-of-function and gain-of-function human gene variants

项目摘要/摘要 此建议是为MD/博士生的个人博士前奖学金申请。约瑟夫·帕克 正在考虑的申请人，提出了一个研究培训计划，其长期目标是发展成为一个 研究心脏代谢和其他疾病的遗传机制的独立医生-科学家 复杂的疾病，使用计算，实验和翻译的方法。全基因组关联 GWAS研究已经成功地描述了常见遗传变异对人类疾病的作用， 分析具有共同疾病特征的大量人群，但许多基因的临床本体仍然存在， 通过这些基于表型的方法学描述不完全。此外，一个基本问题是， 遗传关联研究仍然是描述疾病的功能后果的困难- 相关变体与其各自的基因产物（即功能丧失与功能获得）。Penn Medicine Biobank，一个基于医疗系统的基因型、全外显子组测序和电子健康数据库 记录（EHR）数据，允许一个公正的，基因型优先的方法来描述之间的关系， 功能失调的基因和人类疾病特征在临床环境中通过全表型 关联研究（PheWAS）。通过基因负荷PheWAS测试，拟议的研究旨在表征 由基因组上每个基因的罕见的功能丧失突变引起的疾病的临床表现- 大规模我们的分析将使临床医生能够更有效地识别遗传疾病， 临床环境中的患者。此外，除了我们对功能丧失突变的询问外， 拟议的项目有可能确定已知的功能获得性突变在人类疾病中的作用 并确定与疾病相关的新的功能获得性变体，为研究人员设计 基础科学的后续实验研究以及促进更有效治疗的平台 发现。重要的是，在进行拟议的研究时，约瑟夫将接受严格的培训， 计算生物学和统计遗传学在资助期间，促进他的成熟， 成功的，独立的医生，科学家彻底准备的临床职业生涯，包括分析 “组学”和“大数据”。这些目标将通过广泛的研究金培训计划共同实现 由他和他的赞助人丹尼尔雷德共同开发。在众多高级调查员的指导下， 定期出席研讨会、会议和其他机会，与 宾夕法尼亚大学的著名科学家，以及合作研究环境， 雷德实验室及其周围的物理组织的推动下，约瑟夫是装备精良，以实现他的 职业目标，通过他的发展保证在拟议的培训。

PROJECT SUMMARY/ABSTRACT This proposal is for an MD/PhD student’s individual pre-doctoral fellowship application. Joseph Park, the applicant under consideration, proposes a research training plan with the long-term goal of developing into an independent physician-scientist studying the genetic mechanisms underlying cardiometabolic and other complex diseases using computational, experimental, and translational approaches. Genome-wide association studies (GWAS) have successfully described the roles of common genetic variation on human diseases by analyzing large populations with shared disease traits, but the clinical ontologies of numerous genes remain incompletely described through these phenotype-based methodologies. Additionally, a fundamental problem of genetic association studies remains to be the difficulty of describing the functional consequences of disease- associated variants to their respective gene products (i.e. loss- vs. gain-of-function). The Penn Medicine Biobank, a healthcare system-based database of genotype, whole-exome sequencing, and electronic health record (EHR) data, allows for an unbiased, genotype-first approach to describing the relationships between dysfunctional genes and human disease traits captured in the clinical setting through phenome-wide association studies (PheWAS). Through gene-burden PheWAS tests, the proposed study aims to characterize the clinical manifestations of disease caused by rare, loss-of-function mutations in each gene on a genome- wide scale. Our analyses will enable clinicians to more effectively identify genetic diseases among their patients in the clinical setting. Furthermore, in addition to our interrogation of loss-of-function mutations, our proposed project has the potential to define the roles of known gain-of-function mutations in human disease and identify novel gain-of-function variants relevant to disease, offering a direction for investigators to design follow-up experimental studies in the basic sciences as well as a platform promoting more efficient therapeutic discoveries. And importantly, while conducting the proposed study, Joseph will receive rigorous training in computational biology and statistical genetics during the funding period, promoting his maturation into a successful, independent physician-scientist thoroughly prepared for a clinical career involving the analysis of “omics” and “big data”. These goals will be accomplished through the extensive fellowship training plan jointly developed by him and his sponsor, Daniel Rader. Through the mentorship of numerous senior investigators, regular attendance at seminars, conferences, and other opportunities for presentation and interaction with renowned scientists at the University of Pennsylvania, and the collaborative research environment that the Rader laboratory and its physically surrounding organizations promote, Joseph is well-equipped to achieve his career goals through his guaranteed development during the proposed training.