Polygenic Risk Score (PRS) Methods and Analysis for Populations of Diverse Ancestry - Study Sites

摘要/摘要 在全球范围内，非传染性疾病(NCDs)的公共卫生负担超过了传染病。 心脏代谢性疾病(CMD)，如心脏病和中风，是全球主要的死亡原因。 在这项应用中，我们将探索常见CMD的基因组风险，包括高血压、中风、糖尿病、 肥胖、血脂异常和肾脏疾病及相关特征(包括体重指数、血压、血脂、血糖、胰岛素 和肌酸)在具有非洲血统(AA)的人口中。有证据表明，多基因风险 分数(PRS)从一个祖先群体(例如，欧洲裔美国人)的发现研究转化为 目标人群(例如撒哈拉以南非洲人)，特别是当他们因巨大的遗传差异而分离时。 然而，这还没有用功能强大的大型AA数据集进行评估。此外，高遗传性 需要调查非欧洲血统(EA)种群的多样性和种群结构 了解具有不同基因组背景的人居住的其他地区的PRS的表现。 我们汇集了非洲人类遗传与健康联盟(H3Africa)、其他非洲人、牙买加人和 非洲裔美国人核心队列，开发具有相关表型的50,000多名参与者的联合资源 和基因组学数据，称为非洲血统人群的心脏代谢紊乱 (红衣主教)研究地点。此外，Cardinal研究站点将包括5个重复队列，&>100,000 参与者来自不同血统的人群。我们的主要目标是建立一个研究点 针对AA群体的方法和分析，以及为其他群体协作生成和提炼PR 通过将现有数据集与基因组学和表型数据相结合来实现不同血统的人群 一系列复杂的疾病和特征。我们的第一个目标是整合表型和基因组数据 来自七项个人队列研究的约50,000名非洲人。随后，我们将评估PRSS和 开发一种新的方法，考虑祖先特定的基因组区域，以改进预测 以遗传亚结构为特征的群体中PRSS的数量。最后，我们将开发一个交互式仪表板 用于传播来自不同血统人口的与减贫有关的数据。红衣主教研究地点是理想的 产生对复杂疾病病因学的新的生物学见解，并在全球人口中应用。 红衣主教团队的成员已经成功地合作了大约十年，产生和 通过影响较大的出版物传播科学知识。通过在伦敦建立一个学习地点 多基因风险评分多样性联盟，Cardinal带来最大的非洲血统队列 与会人员，探讨基因组学对常见慢性精神疾病和其他非传染性疾病的贡献。

Abstract/Summary Globally, non-communicable diseases (NCDs) outrank infectious diseases in terms of public health burden. Cardiometabolic diseases (CMD) such as heart disease and stroke are the leading causes of death worldwide. In this application we will explore the genomic risk for common CMD, including hypertension, stroke, diabetes, obesity, dyslipidemia and kidney disease, and related traits (including BMI, blood pressure, lipid, glucose, insulin and creatine) across populations with African ancestry (AA). There is evidence to suggest that polygenic risk scores (PRSs) translate poorly from a discovery study in one ancestral population (e.g. European Americans) to a target population (e.g. sub-Saharan Africans), especially when they are separated by large genetic differences. However, this has not been evaluated with large, well-powered AA datasets. Furthermore, the high genetic diversity and population structure among non-European Ancestry (EA) populations need to be investigated to understand the performance of PRSs in other regions populated by people with diverse genomic backgrounds. We bring together the Human Heredity and Health in Africa Consortium (H3Africa), other African, Jamaican and African American core cohorts, to develop a joint resource of over 50,000 participants with relevant phenotype and genomics data, referred to as the CARdiometabolic Disorders IN African-ancestry PopuLations (CARDINAL) Study Site. In addition, the CARDINAL Study Site will include 5 replication cohorts with >100,000 participants from diverse ancestry populations. Our main objective is to establish a Study Site for PRS Methods and Analysis for AA Populations and to collaboratively generate and refine PRS for other populations of diverse ancestry by integrating existing datasets with genomics and phenotype data for a range of complex diseases and traits. Our first aim is to integrate phenotype and genomic datasets from ~50,000 African individuals from seven individual cohort studies. Subsequently, we will evaluate PRSs and develop a novel method that takes into consideration, ancestry-specific genomic regions to improve prediction of PRSs in populations characterised by genetic sub-structure. Finally, we will develop an interactive dashboard for dissemination of PRS-related data from diverse ancestry populations. CARDINAL Study Site is ideal for generating novel biologic insights into complex disease etiology, with applications in global populations. Members of the CARDINAL team have successfully worked together for about a decade, generating and disseminating scientific knowledge through high impact publications. By establishing a Study Site in the Polygenic Risk Score Diversity Consortium, CARDINAL brings the largest cohort of African-ancestry participants to the table, to explore the genomics contribution to common CMDs and other NCDs.