Abstract Body (Do not enter title and authors here): Background: Major depressive disorder (MDD) has been hypothesized to have a causal relationship with various cardiovascular diseases, including coronary artery disease (CAD), atrial fibrillation (AF), and heart failure (HF). Our meta-analysis of Mendelian Randomization (MR) studies aims to identify these associations by using genetic variants as instrumental variables and minimizing confounding factors and reverse causation.

Methods: We systematically reviewed the Pubmed, Embase, and Scopus databases to find studies through May 2024 evaluating the association of MDD with the occurrence of Coronary Artery Disease (CAD), Heart Failure (HF), and Atrial Fibrillation (AF). Data sources included multiple genome-wide association studies (GWAS) involving European and mixed ancestries, the IEU Open GWAS Project, the Psychiatric Genomics Consortium (PGC), and combined data from 23andMe, PGC, and the UK Biobank. Random effects models and I² statistics were used for pooled odds ratios (OR) and heterogeneity assessments, respectively. The impact of individual studies on the overall estimate was assessed with Leave one-out sensitivity analysis.

Results:
MDD and CAD: Seven studies were included in the analysis. The overall Inverse Variance Weighted (IVW) estimate indicated odds of developing CAD were 17% higher in those with MDD than without (OR: 1.17, 95% CI: 1.08-1.28, P < 0.01), with substantial heterogeneity (I² = 89.89%, P < 0.01). Leave-one-out analysis confirmed equal results as the pooled estimate remained significant across all iterations (OR range: 1.14 to 1.20).
MDD and AF: Three studies were included in the analysis. No significant association between MDD and AF was observed in the pooled IVW estimate (OR: 1.03, 95% CI: 0.98-1.08, P = 0.35). The heterogeneity was low (I² = 5.22%, P = 0.35).
MDD and HF: Three studies were included in this analysis. MDD was associated with a significant risk of developing heart failure (OR: 1.11, 95% CI: 1.05-1.18, P < 0.01), with no observed heterogeneity (I² = 0%, P = 0.49).

Conclusion: MDD increases the risk of CAD by 17% and the risk of HF by 11% with no significant association between MDD and AF. The substantial heterogeneity in the MDD-CAD association suggests that further studies are warranted to explore potential sources of this variability. These findings highlight the importance of managing depressive symptoms as part of cardiovascular disease prevention strategies.