Genetic association and potential mediators between subjective well-being and cardiovascular events: A bidirectional two-sample, two-step Mendelian randomization study

Observational evidence suggests that subjective well-being (SWB) is inversely associated with cardiovascular (CV) events, yet whether this link is causal and through which pathways remains unclear. To test this, we performed a two-sample bidirectional Mendelian randomization (MR) analysis using genetic instruments for SWB (N = 2370,390) and major adverse cardiovascular events (MACE; N = 500,348). All the data were from the largest available genome-wide association studies in populations of European descent. In univariable MR, each 1-standard-deviation increase in genetically predicted SWB reduced the odds of MACE by 39% (odds ratio = 0.61; 95% confidence interval, 0.50-0.74; P = 5.82 × 10⁻⁷). This association remained after multivariable MR adjustment for general medical conditions - Alzheimer disease, hypothyroidism, hyperthyroidism, multiple sclerosis, Addison disease, Cushing syndrome, Parkinson disease, systemic lupus erythematosus, and epilepsy - which often co-occur with mood symptoms and may also influence CV risk. Two-step MR analysis identified 3 out of 46 candidates as mediators between SWB and MACE: body mass index, diastolic blood pressure and triglycerides, accounting for 13.97% (95% confidence interval, 6.34%-21.60%), 6.05% (95% confidence interval, 0.00%-12.10%) and 10.53% (95% confidence interval, 4.45%-16.60%) of the total effect of SWB on MACE, respectively. Sensitivity analyses were directionally consistent, whereas MR-Egger did not reach statistical significance. Taken together, these results suggest that higher SWB may be associated with a lower risk of CV events, partly through metabolic and hemodynamic pathways. Targeting SWB may therefore complement conventional risk-factor management in CV prevention.