Neuroticism as a protective factor for cardiomyopathy: A mediation Mendelian randomization study.

The relationship between Neuroticism and cardiomyopathy (CM) remains underexplored, despite links to other cardiovascular conditions. To investigate the causal effect of genetically predicted neuroticism on cardiomyopathy risk and to identify circulating protein mediators of this association using a two-step, proteome-wide mediation Mendelian randomization (MR) framework. We performed a two-sample MR study using GWAS data from UK Biobank (neuroticism: n = 393,411-374,323) and FinnGen (cardiomyopathy: n = 159,811-218,792). Causal estimates were derived using inverse-variance weighted MR, with sensitivity, multivariable MR, reverse-direction MR, and proteome-wide two-step mediation MR to identify circulating protein mediators. Genetically predicted higher neuroticism was causally associated with reduced cardiomyopathy risk (IVW OR = 0.85-0.88, P < 0.05), consistent across two UK Biobank instruments and FinnGen phenotypes. A proteome-wide mediation analysis identified 13 circulating proteins that significantly mediated this protective effect (P < 0.05), with KLRC4 (10.89%), THPO (9.49%), and PRLH (9.25%) accounting for the largest proportions. For all mediators, higher neuroticism was associated with elevated protein levels, which in turn were associated with lower cardiomyopathy risk. Sensitivity analyses showed no evidence of heterogeneity or horizontal pleiotropy (P > 0.05), thereby supporting the robustness of the findings. Our findings provide genetic evidence that higher neuroticism is causally linked to a lower risk of primary (nonischemic) cardiomyopathy, partially mediated by circulating proteins involved in immune, hematopoietic, and neuroendocrine pathways.