Coronary artery disease (CAD) has been shown to be associated with stroke risk. However, the causal genetic overlap and shared genetic architecture underlying CAD and stroke remain unknown. Here, we aim to identify shared genetic relationships between CAD and stroke, focusing on causal genetic overlap, causal directions, and novel risk loci. Using MiXeR, we identified substantial causal variants (~900) shared between CAD and stroke. LD score regression analysis showed a significant positive genetic correlation (rG = 0.49, P = 1.4 x 10^-48) between CAD and stroke. We conducted Mendelian randomization analyses to estimate the potential causal association between CAD and stroke. We observed the significant causal association of CAD with the risk of stroke, independent from its common confounding factors, including type 2 diabetes, atrial fibrillation, BMI, smoking, and educational attainment. Multi-traits GWAS meta-analysis identified novel SNPs, while Summary-based Mendelian randomization analysis (SMR) was performed to identify causal risk genes linked to CAD and stroke. We identified 14 overlapping novel independent loci. SMR analysis further identified putative causal genes shared between CAD and stroke. This study advances our understanding of the shared genetic architecture and causal association between CAD and stroke risk, potentially indicating a common molecular mechanism underlying both conditions.

The authors have declared no competing interest.

This study did not receive any funding

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