Addressing Disparities in Polygenic Risk Score for Coronary Heart Diseases in Diverse Populations

PROJECT SUMMARY/ABSTRACT Coronary heart disease (CHD) remains a leading cause of death worldwide, and accurate risk prediction is crucial for early intervention. While clinical risk scores (CRS) based on traditional risk factors are commonly used, polygenic risk scores (PRS) have emerged as a promising tool, particularly when combined with CRS. However,

current CHD PRSs have limited predictive value, especially for populations with diverse ancestries. Additionally, CRS fails to account for environmental and social factors that contribute to CHD disparities in minority groups. To achieve health equity and improve CHD health for all, it is crucial to tailor CHD risk prediction approaches

to individuals based on their genetic background, susceptibility to traditional risk factors, as well as their social and environmental context. Dr. Tcheandjieu's career goal is to leverage these factors to develop an inclusive risk prediction strategy that mitigates disparities. In the current project, she will focus on understanding the genetic

architecture of CHD across populations. She hypothesizes that the limited predictive value of current CHD PRS in diverse populations is due to the Eurocentric bias in their development, the exclusion of low-frequency genetic variants, and inadequate representation of the genetic contribution of CHD risk factors, especially since the

prevalence of CHD risk factors varies across populations. To test these hypotheses, she will analyze genetic data from 2.1 million individuals with European, African, Indigenous American, and Asian ancestries from large biobanks. In Aim 1, she will explore population-specific differences in haplotype structures, allele frequencies,

and effect sizes of variants in CHD and PRS. In Aim 2, she will study the association between CHD and rare variants within each ancestry, quantify CHD heritability due to rare variants, and assess their PRS predictive value. In Aim 3, Dr. Tcheandjieu will develop population-specific CHD PRSs with enhanced predictive value by

incorporating the genetic risk for CHD and its risk factors, considering variations between ancestries and enriching the PRS with rare variants. To achieve these aims and strive toward her career goal, Dr. Tcheandjieu will strengthen her knowledge with training in statistical and population genetics, functional genomics, and

cardiovascular social epidemiology. Dr. Tcheandjieu will be mentored by a team of scientists with extensive experience and expertise in various aspects of her proposed research and training. Additionally, The Gladstone Institutes and the University of California, San Francisco are world-leading biomedical research centers. Dr.

Tcheandjieu will take advantage of the rich resources within these research environments to complete the program. Overall, the research, training, and institutional environment described in this proposal will aid Dr. Tcheandjieu in her long-term career goals of (1) addressing disparities of CHD susceptibility across diverse

populations and (2) becoming a successful independent investigator. Overall, the proposed research has significant potential to address the limited applicability of current PRS to diverse populations and develop novel and innovative CHD PRSs that improve risk prediction in diverse populations, reducing health disparities.