Polygenic Risk of Disease in Populations of Diverse Ancestry

项目摘要 在本申请中，我们建议建立在我们先前的多基因风险评分（PRS）工作的基础上，将其扩展到 不同的祖先群体。通过改善风险分层，常见疾病的PRS有可能 改变临床实践。然而，必须向不同的祖先群体提供这种减贫战略，以确保 公平实施基因组医学，减少健康差距的潜在加剧， 基因组医学的背景。我们的应用程序旨在解决迫切需要制定不同的PRS 祖先群体，并将重点放在冠心病（CHD）及其危险因素：高血压，糖尿病， 肥胖症和高胆固醇血症，在世界范围内共同构成巨大的健康负担。冠心病是典型的 考虑到可用的经验证的风险预测方程， 风险类别和PRS对这些类别的实质性重新分类， 影响作为PRS多样性联盟（PRS-DC）的一部分，我们将开发生成PRS的方法 使用现有和新的CHD基因组和表型数据集， 及其风险因素。我们将协调这些数据集的数据元素。我们开发的方法将是 适用于为不同人群的广泛常见疾病生成减贫战略。 该调查小组是马约eMERGE IV应用程序的一部分，将作为 PRS-DC和eMERGE。为了生成不同血统的PRS，我们将使用eMERGE的数据 联盟、百万退伍军人计划（MVP）、全美（AoU）计划、dbGAP、PRS-DC站点、英国 生物库，并与代表中东、南亚和非洲的几个国际组织合作， 和东亚的同伙。我们的应用程序包括几个创新，使使用的PRS的风险 分层和预防属于不同祖先的个体的CHD。我们的具体目标是： 具体目标1.整合和协调来自不同来源的表型数据，以实现跨平台 表型和不同祖先群体常见疾病的PRS生成。具体目标2。发展 人群中CHD及其主要危险因素（高血压、糖尿病、肥胖、高胆固醇血症）的PRS 不同的祖先。具体目标3。开发新的统计和计算方法， 多基因风险模型中的不同遗传祖先和混合物。具体目标4。制定"临床就绪" PRS 通过创建PRSCHD的参考分布，并将其与临床 计算绝对风险估计。

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.