Ancestry-Specific Risk Factors and Genetic Contributions in the Pathophysiology of Coronary Artery Disease

Understanding the genetic pathophysiology of coronary artery disease (CAD) across diverse ancestry populations is critical for elucidating disease mechanisms and informing equitable global prevention strategies. This research used data from genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses to investigate the utility and feasibility of multi-ancestry genetic research in improving understanding of CAD pathophysiology.

Two systematic reviews were conducted to map the landscape of CAD genetic research. The first identified major gaps in representation, with only 39% percent of GWAS including non-European populations and no representation from continental African or admixed American ancestries. The second review synthesized MR studies investigating CAD risk factors across multiple populations, revealing broad consistency in the direction of effects but notable variation in effect sizes, particularly for blood pressure.

Building on these findings, bi-directional and two-sample MR analyses were conducted across African, East Asian, European and South Asian populations. These analyses revealed ancestry-specific variation in the strength and direction of causal effects for key modifiable risk factors of CAD. They also highlighted key methodological challenges, including limited statistical power in non-European datasets, phenotypic heterogeneity, and difficulties integrating data sources across ancestries using existing tools. These limitations have important implications for the interpretation and generalisability of MR findings across global populations.

Collectively, these findings emphasise the urgent need for more inclusive genetic research to advance understanding of CAD pathophysiology. The identification of ancestry-specific risk loci and variation in causal pathways, alongside the limited quality and availability of GWAS in non-European populations, underscores critical gaps in the current evidence base. Prioritising the inclusion of diverse populations is essential for developing context-specific prevention strategies capable of reducing CAD risk more effectively and equitably worldwide.