Causal Relationships Between Major Depressive Disorder and Coronary Artery Disease Across Diverse Populations: A...

Coronary artery disease remains the leading cause of cardiovascular mortality worldwide, with a disproportionate burden in low- and middle-income countries. Although observational studies have established a bidirectional relationship between depression and coronary artery disease, the underlying genetic basis of this association remains unclear, particularly in underrepresented diverse-ancestry populations. Establishing whether this relationship is causal and whether it differs by ancestry is critical for informing targeted and equitable prevention strategies.

This study employed a bidirectional two-sample Mendelian randomisation framework to investigate the causal relationship between major depressive disorder and coronary artery disease across East Asian, European and African populations. Using summary statistics from large-scale genome-wide association studies, we assessed both the direction and strength of genetic associations between major depressive disorder and coronary artery disease. Sensitivity analyses were conducted to test the robustness of the findings.

Genetically predicted major depressive disorder was associated with increased coronary artery disease risk in European populations, confirming a causal effect consistent with prior evidence. In East Asians, we found a potentially false-positive result suggesting an inverse association between genetic liability to coronary artery disease and major depressive disorder (IVW OR = 0.942; p = 0.040), which was not supported across Mendelian randomisation sensitivity analyses and did not hold true after Bonferroni correction. In African ancestry populations, no significant causal effects were detected in either direction, due to wide confidence intervals resulting from limited sample sizes.

Our findings provide evidence for a causal relationship between depression and coronary artery disease in Europeans and suggest potential ancestry-specific variation in this relationship, with a novel inverse association between coronary artery disease and major depressive disorder observed in East Asians requiring further replication and validation. These results highlight how limited data availability in underrepresented populations constrains causal inference, underscoring the need for more inclusive genetic research to inform equitable, population-relevant public health strategies.