Development and Application of Phenome-wide Scan of Heritability (PheSH)

描述(由申请人提供)：了解常见和罕见疾病的遗传病因学，对于遗传学在“个性化医学”中的应用至关重要。所有疾病都是环境和/或遗传因素共同作用的结果。疾病/性状中因遗传因素而产生的变异量称为“遗传力”。如果没有通过遗传力测量证明有很强的遗传成分的证据，进行遗传/基因组研究是困难的。遗传力可以用双胞胎或其他家庭结构来衡量，但 面临着收集有限的可用家庭和适当的表型数据所需的资源的挑战。此外，即使确定了这些家系，遗传力测量通常也仅限于一种疾病。这项拟议的研究通过以新颖的方式应用成熟的统计方法来解决这些挑战，利用电子病历(EMR)中的数据同时计算许多疾病的遗传率。这项拟议的项目将检验这一假设，即数千种临床表型(由家庭中的患者病历定义)可用于测量遗传力，以指导进一步的遗传/基因组研究。我们称这种新的生物信息学方法为全基因组遗传性扫描(PheSH)。PheSH的概念源于我在NLM支持的指导培训期间进行的Phenome-Wide Association Study(PheWAS)的工作。Phewas和PheSH都是与表型无关的方法，允许同时对许多临床疾病或性状进行遗传研究。在我职业生涯的独立阶段，我计划继续开发表型无关的技术，包括PheSH，以研究人类疾病的遗传病因学。

DESCRIPTION (provided by applicant): Understanding the genetic etiology of diseases, both common and rare, is paramount to the application of genetics in "personalized medicine." All diseases are the result of a combination of environmental and/or genetic factors. The amount of variation in a disease/trait that is due to a genetic contribution is called "heritability." Conducing genetic/genomic studies is difficult without evidence of a strong genetic component by heritability measurements. Heritability can be measured in twins or other family structures, but is challenged by the resources required to collect the limited available families with appropriate phenotypic data. Moreover, even when these families are identified, heritability measurements are typically restricted to a single disease. The proposed research addresses these challenges by applying well-developed statistical methods in novel ways to simultaneously calculate heritability for many diseases using data available in the electronic medical record (EMR). The proposed project will test the hypothesis that thousands of clinical phenotypes, defined by patient medical records in families, can be used to measure heritability to direct further genetic/genomic studies. We call this novel bioinformatic method Phenome-wide Scan of Heritability (PheSH). The PheSH concept resulted from my work on Phenome-Wide Association Studies (PheWAS) conducted during my NLM-supported mentored training. Both PheWAS and PheSH are phenotype- independent approaches that allow for the genetic study of many clinical diseases or traits simultaneously. In the independent phase of my career, I plan to continue developing phenotype-independent techniques, including PheSH, to study the genetic etiology of human disease.