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，对于遗传学在“个性化医疗”中的应用至关重要。“所有疾病都是环境和/或遗传因素综合作用的结果。由于遗传贡献而引起的疾病/性状的变异量称为“遗传力”。“如果没有遗传性测量的强有力的遗传成分的证据，进行遗传/基因组研究是困难的。遗传性可以在双胞胎或其他家庭结构中测量，但 由于收集具有适当表型数据的有限可用家族所需的资源而受到挑战。此外，即使这些家庭被确定，遗传力的测量通常仅限于一种疾病。这项研究通过以新的方式应用发达的统计方法来解决这些挑战，使用电子病历（EMR）中的可用数据同时计算许多疾病的遗传性。拟议的项目将测试的假设，数以千计的临床表型，由患者的医疗记录在家庭中定义，可用于测量遗传性，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表型遗传性扫描（PheSH）。PheSH概念源于我在NLM支持的指导培训期间进行的全表型关联研究（PheWAS）工作。PheWAS和PheSH都是不依赖表型的方法，其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独立技术，包括PheSH，以研究人类疾病的遗传病因。

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.