Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care

摘要 心血管疾病（CVD）及其危险因素造成了重大的社会负担，是心血管疾病的主要原因。 发病率、死亡率和残疾率。精准医疗在解决心血管疾病及其风险因素方面具有独特的优势， 数十年的调查和数十亿美元的投资使他们能够建立强大的 潜在的遗传基础。多基因风险评分（PRS），将风险变异聚合为单一评分， 提供了一个这样的例子。心血管病患者的PRS研究已从估计转向检查临床 效用;即，确定何时以及如何采用PRS，以及 环境/生活方式风险评分（ERS）可以与PRS一起在临床上使用。但大多数 大规模CVD研究中的参与者都是欧洲血统（EA），这限制了全球范围内的研究。 将遗传关联转化为与所有人群相关的临床和公共卫生应用。 PAGE协会和其他人已经证明，EA派生的PRS不能直接翻译为 种族/民族多样化的人口。用于PRS估计和解释的统计工具基于 在人口结构的背景下， 种族/民族多样化的人口。这些研究差距将加剧长期存在的种族/族裔 心血管疾病及其危险因素的差异，强调需要进行研究，使所有群体都能获得 PRS-enabled个性化预防的好处。 在此修订后的应用程序中，我们通过利用 来自队列和生物库网络的高质量、统一和集中可用的数据， 电子健康记录，捕捉心血管疾病及其危险因素。通过这一努力，我们将包括超过150万非- 欧洲血统参与者在种族/民族方面开发并验证CVD相关特征的PRS 不同的人群。我们将为临床和公共卫生创造方法，资源和最佳实践 社区.这项研究将允许采用和应用PRS进行检测，干预， CVD危险因素的治疗。我们的最终目标是减少和预防所有人群的CVD负担。 我们的具体目标是：（1）创建无偏倚的PRS：结合ERS开发和评估CVD PRS 在大型和种族/民族多样化的PAGE研究中;和（2）验证、校准和传播： 外部验证和改进生物库中的风险评分模型，并将风险评分模型转化为改进的 医学界的接触和理解。 我们将构建下一代方法、资源和最佳实践， PRS的发展以及随后的CVD预测和临床询问。专注于非EA 人类将确保他们不是最后一个从基因组医学新时代受益的人。

Abstract Cardiovascular disease (CVD) and its risk factors impose major societal burdens and are leading causes of morbidity, mortality, and disability. Precision medicine is uniquely positioned to address CVD and its risk factors, enabled by decades of investigation and billions of dollars of investment that have established their strong underlying genetic basis. Polygenic risk scores (PRS), the aggregation of risk variants into a single score, provides one such example. Research on PRS in CVD has transitioned from estimation to examining the clinical utility; i.e., determining when and how PRS adoption will occur and how similarly conceived environmental/lifestyle risk scores (ERS) can be used clinically in concert with PRS. However, the majority of participants included in large-scale CVD research have been of European ancestry (EA), limiting the global translation of genetic associations into clinical and public health applications relevant for all populations. The PAGE consortium and others have demonstrated that EA-derived PRS are not directly translatable to racially/ethnically diverse populations. Statistical tools for PRS estimation and interpretation are founded on strong assumptions that are violated, and create bias, in the context of population structure that characterizes racially/ethnically diverse populations. These research gaps will exacerbate long-standing racial/ethnic disparities in CVD and its risk factors, underscoring the need for research that enables all groups to reap the benefits of PRS-enabled personalized prevention. In this revised application, we address the limitations previously identified in our original application by leveraging high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked electronic health records, capturing CVD and its risk factors. Through this effort, we will include over 1.5M non- European ancestry participants to develop and validate PRS for CVD-associated traits in racially/ethnically diverse populations. We will create the methods, resources, and best practices for the clinical and public health communities. This research will permit adoption and application of PRS for the detection, intervention, and treatment of CVD risk factors. Our ultimate goal is to reduce and prevent the burden of CVD in all populations. Our Specific Aims are (1) Creation of unbiased PRS: Develop and evaluate CVD PRS in combination with ERS in the large and racially/ethnically diverse PAGE study; and (2) Validation, calibration and dissemination: Externally validate and improve upon risk score models in biobanks and translate risk score models for improved access and understanding for the medical community. We will build the next generation of methods, resources, and best-practices to empower appropriate development of PRS and subsequent prediction and clinical interrogation in CVD. Deliberate focus on non-EA populations will ensure that they are not the last to benefit in the new era of genomic medicine.