Polygenic Risk of Disease in Populations of Diverse Ancestry

项目总结 在本应用程序中，我们建议在我们之前关于多基因风险评分(PRSS)的工作基础上，将其扩展到 不同的祖先群体。通过改进风险分层，常见疾病的PRSS有可能 转变临床实践。然而，这样的PRSS必须为不同的祖先群体提供，以确保 公平实施基因组医学，减少#年健康差距的潜在恶化 基因组医学的背景。我们的应用程序旨在满足为不同领域开发PRSS的迫切需求 并将重点关注冠心病(CHD)及其危险因素：高血压、糖尿病、 肥胖和高胆固醇血症，在全世界范围内共同构成巨大的健康负担。先心病是典型的 用于复杂疾病的PRSS给出了可用验证的风险预测方程，将个体绑定到 风险类别，并通过PRS大幅重新分类这些类别，从而实现治疗 这意味着什么。作为PRS分集联盟(PRS-DC)的一部分，我们将开发生成PRS的方法 使用具有CHD基因组和表型数据的现有数据集和新数据集的不同血统人群 及其风险因素。我们将协调这些数据集中的数据元素。我们开发的方法将是 适用于为不同人群的一系列常见疾病制定PRS。 调查小组是Mayo Emerge IV应用程序的一部分，将成为 PrS-DC和Emerge。为了为不同的祖先生成PRS，我们将使用Emerge中的数据 联盟、百万退伍军人计划(MVP)、全美计划(AOU)、DBGaP、PRS-DC Sites，英国 生物库，以及与代表中东、南亚的几个国际组织的合作 和东亚的同龄人。我们的应用程序包括几项创新，以支持使用PRSS来应对风险 不同血统人群中冠心病的分层与预防。我们的具体目标是： 具体目标1.整合和协调来自不同来源表型数据，以实现跨平台 不同血统群体中常见疾病的表型和PRSS的产生。具体目标2.发展 人群中冠心病及其主要危险因素(高血压、糖尿病、肥胖、高胆固醇血症)的危险因素 有着不同血统的人。具体目标3.开发新的统计和计算方法，以说明 不同的遗传祖先和多基因风险模型中的混合。具体目标4.发展“临床就绪”的PRSS 通过创建PRSCHD的参考分布并将其与临床相结合，为不同的祖先群体提供参考 用于计算绝对风险估计的信息。

PROJECT SUMMARY In this application we propose to build on our prior work on polygenic risk scores (PRSs) to extend these to diverse ancestry groups. By improving risk stratification, PRSs for common diseases have the potential to transform clinical practice. However, such PRSs must be available for diverse ancestry groups to ensure equitable implementation of genomic medicine and reduce the potential exacerbation of health disparities in the context of genomic medicine. Our application aims to address the critical need to develop PRSs for diverse ancestry groups and will focus on coronary heart disease (CHD) and its risk factors: hypertension, diabetes, obesity and hypercholesterolemia, collectively an enormous health burden world-wide. CHD is the prototypical complex disease for the use of PRSs given available validated risk prediction equations that bin individuals into risk categories and substantial reclassification across these categories by a PRS with consequent therapeutic implications. As part of the PRS Diversity Consortium (PRS-DC), we will develop methods to generate PRSs for populations of diverse ancestry using existing and new datasets with genomic and phenotype data for CHD and its risk factors. We will harmonize data elements across these data sets. The methods we develop will be applicable towards the generation of PRSs for a broad range of common diseases across diverse populations. The investigative team is part of the Mayo eMERGE IV application and will serve as a bridge between the PRS-DC and eMERGE. To generate PRSs for diverse ancestries, we will use data from the eMERGE consortium, Million Veteran’s Program (MVP), the All of US (AoU) program, dbGAP, PRS-DC sites, UK Biobank, and collaborations with several international groups representing the Middle Eastern, South Asian and East Asian cohorts. Our application includes several innovations to enable the use of PRSs for risk stratification and prevention of CHD in individuals belonging to diverse ancestries. Our specific aims are: Specific aim 1. Integrate and harmonize phenotype data from heterogeneous sources to enable cross platform phenotyping and generation of PRSs for common diseases in diverse ancestry groups. Specific aim 2. Develop PRSs for CHD and its major risk factors (hypertension, diabetes, obesity, hypercholesterolemia) in populations of diverse ancestry. Specific aim 3. Develop novel statistical and computational methods to account for diverse genetic ancestry and admixture in models of polygenic risk. Specific aim 4. Develop ‘clinic ready’ PRSs for diverse ancestry groups by creating reference distributions of a PRSCHD and integrate it with clinical information to compute absolute risk estimates.