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.

Narrative Cardiometabolic diseases are on the increase worldwide, contributing to high levels of morbidity and mortality, with limited resources among lower-resource populations in North America and Africa to prevent disease, make diagnosis and clinically manage patients. In this study we bring together ~50,000 African-ancestry participants (African American, Jamaicans and continental African) to form the CARDINAL study to assess and develop polygenic risk scores for cardiometabolic diseases and traits, and to develop analytic approaches for multi-ethnic cohorts leveraging the increased genetic diversity and lower linkage disequilibrium in African genomes. This research will lead to a better understanding of the transferability of polygenic risk scores from discovery to target populations of different ethnicities, informing prevention and diagnostic strategies that could contribute to the development of effective public health policies.