ObjectiveObservational studies have shown a correlation between unpleasant emotions and coronary atherosclerosis, but the underlying causal linkages are still uncertain. We conducted a Mendelian randomization (MR) investigation on two samples for this purpose.MethodsIn genome-wide association studies in the UK Biobank (total = 459,561), we selected 40 distinct single-nucleotide polymorphisms (SNPs) related to unpleasant emotions as genome-wide statistically significant instrumental variables. FinnGen consortium provided summary-level data on coronary atherosclerosis for 211,203 individuals of Finnish descent. MR-Egger regression, the inverse variance weighted technique (IVW), and the weighted median method were used in the process of conducting data analysis.ResultsThere was sufficient evidence to establish a causal connection between unpleasant emotions and coronary atherosclerosis risk. For each unit increase in the log-odds ratio of unpleasant feelings, the odds ratios were 3.61 (95% CI: 1.64–7.95;P= 0.001). The outcomes of sensitivity analyses were comparable. There was no indication of heterogeneity or directional pleiotropy.ConclusionOur findings provide causal evidence for the effects of unpleasant emotions on coronary atherosclerosis.