Mendelian randomization and transcriptome analysis reveal depression-driven regulatory patterns of the immune microenvironment in myocardial infarction and heart failure

Background Major depressive disorder (MDD) and cardiovascular diseases (CVD) are mutually amplifying global health burdens, yet the causal directions and immune-determined molecular substructures that link MDD to myocardial infarction (MI) and heart failure (HF) remain poorly resolved. Methods Bidirectional two-sample Mendelian randomization (MR) was applied to large-scale GWAS (1.35 million MDD; 361 K MI; 977 K HF) followed by replication in 11,004 NHANES 2005–2020 participants using restricted cubic splines and multivariable logistic regression. Multi-cohort transcriptomics (peripheral blood microarray n = 447; in-house RNA-seq n = 14; left-ventricular tissue from dilated cardiomyopathy (DCM) patients (n = 332) were integrated to identify MDD-driven expression signatures. LASSO regression, CIBERSORT, ssGSEA, consensus clustering and GSVA were employed to derive diagnostic gene panels and immune endotypes. Results MR analyses provided genetic evidence consistent with a directional effect of MDD on MI (IVW β = 0.01, P = 4.6 × 10⁻ 6 ) and HF (IVW β = 0.19, P = 1.3 × 10⁻ 6 ) without reverse causation. Depression (PHQ-9 ≥ 10) has a dose-dependent nonlinear association with MI and HF (P