Genetic Architecture of Coronary Atherosclerosis Across European, African, and Admixed American Populations Using All of Us Research Program Data

Moultrie, GA

Introduction:

Coronary atherosclerosis, the underlying pathology of most coronary artery disease, is characterized by the accumulation of lipid-rich plaques within the coronary arteries, leading to increased cardiovascular risk. Established genes such as LDLR highlight the importance of lipid metabolism in disease pathogenesis, yet population-specific genetic contributors in African and Admixed American populations remain poorly understood. Identifying additional genetic contributors may improve our understanding of disease mechanisms and support more equitable cardiovascular risk prediction tools.

Methods:

We analyzed Genome Wide Association Study (GWAS) summary statistics from the All of Us Research Program using the All-by-All Research Browser to identify genetic variants associated with coronary atherosclerosis. We reviewed the results for coronary atherosclerosis (phenoname: CV_404.2) across European, African, and Admixed American populations. We extracted and organized variant-level meta-analysis tables and summary statistics in Python using a Jupyter Notebook to examine p-values, effect sizes (betas), and allele information. We utilized Manhattan plots to visualize genome-wide signals, applying a genome-wide significance threshold of p < 5 × 10⁻⁸ to identify significant loci.

Results:

Examination of genome-wide association summary statistics revealed ancestry-specific association signals related to coronary atherosclerosis. In the European (EUR) population, the strongest signal occurred on chromosome 9 at the 9p21 locus near CDKN2B-AS1, with extremely significant p-values, consistent with a well-established coronary artery disease susceptibility region. Additional genome-wide significant loci were observed near SLC22A3, PHACTR1, and the CELSR2/PSRC1 region. In the Admixed American (AMR) population, the strongest association signal occurred near ADCY2 on chromosome 5 (p = 3.18 × 10⁻⁸), exceeding the conventional genome-wide significance threshold. The African (AFR) population revealed several suggestive association signals, but no variants exceeded genome-wide significance. We observed suggestive loci on chromosome 15 near IQCH/AAGAB and chromosome 22 near OSBP2. These loci have not been widely reported in prior coronary atherosclerosis GWAS in African ancestry populations and may warrant further investigation.

Conclusion:

Our analysis highlighted several genetic loci associated with coronary atherosclerosis across multiple populations. Well-known loci, such as the 9p21 region near CDKN2B-AS1, were identified in the European population, and we also observed additional population-specific signals in admixed American and African ancestry groups. Understanding these genetic contributors may improve insight into the biological mechanisms of coronary atherosclerosis and support the development of improved risk prediction and targeted therapies.