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

摘要/概要 在全球范围内，非传染性疾病在公共卫生负担方面超过传染病。 心脏病和中风等心脏代谢疾病是全球主要的死亡原因。 在本申请中，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，以及相关性状（包括BMI、血压、血脂、血糖、胰岛素 和肌酸）在具有非洲血统（AA）的人群中的分布。有证据表明，多基因风险 从一个祖先群体（如欧洲裔美国人）的发现研究到 目标人群（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开时。 然而，这还没有用大型的、功效良好的AA数据集进行评估。此外，高基因 需要调查非欧洲野生动物种群的多样性和种群结构， 了解PRS在其他地区的表现，这些地区的人口具有不同的基因组背景。 我们汇集了非洲人类遗传和健康联合会（H3 Africa），其他非洲人，牙买加人和 非洲裔美国人核心队列，以开发超过50 000名具有相关表型的参与者的联合资源 和基因组学数据，被称为非洲血统人群的心脏代谢障碍， （CARDINAL）研究中心。此外，CARDINAL研究中心将包括5个重复队列， 来自不同祖先群体的参与者。我们的主要目标是为PRS建立一个研究中心 AA人群的方法和分析，并协作生成和完善其他患者的PRS 通过整合现有数据集与基因组学和表型数据， 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集， 来自7项个体队列研究的约50，000名非洲个体。随后，我们将评估生产者责任计划， 开发一种新的方法，考虑到祖先特定的基因组区域，以提高预测 以遗传子结构为特征的群体中的PRS。最后，我们将开发一个交互式仪表板 用于传播来自不同祖先人群的与PRS相关的数据。Cardinal研究中心是理想的 对复杂的疾病病因产生新的生物学见解，并在全球人群中应用。 CARDINAL团队的成员已经成功地合作了大约十年，产生和 通过影响力大的出版物传播科学知识。通过建立一个研究中心， 多基因风险评分多样性联盟，CARDINAL带来了非洲血统的最大队列 与会者讨论，探讨基因组学对常见CMD和其他NCD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.