Exploring Causal Association between Neuroticism Subclusters and Risk of Coronary Atherosclerosis: A Mendelian Randomization Analysis based on Genome-Wide Association Studies

BackgroundUnderstanding the risk factors associated with coronary atherosclerosis (CA)--an evident cardiovascular disease--is vital. This study aimed to explore the causal relationship between neuroticism subclusters and CA, focusing on lipids as mediators, using genome-wide association studies and Mendelian randomization (MR). Methods and ResultsInstrumental variables were selected based on their genetic associations with neuroticism subclusters and CA. Causal effects were primarily assessed using inverse variance-weighted (IVW) methods. Sensitivity analyses and colocalization analyses were conducted, and possible confounders were determined using multivariable MR analysis. IVW modeling revealed that neuroticism subclusters significantly affect CA risk (ebi-a-GCST006475 odds ratio [OR]: 1.02, 95% confidence interval [95%CI]: 1.01-1.03, P = 1.52E-05; ebi-a-GCST006478 OR: 1.01, 95%CI: 1.00-1.02, P = 0.026; ebi-a-GCST006950 OR: 1.01, 95%CI: 1.00-1.02, P = 0.036). Cochrans Q test demonstrated moderate heterogeneity (ebi-a-GCST006475, P < 0.05, I{superscript 2} = 28%). The Steiger test confirmed the correct causal direction (P < 0.05). Multivariable MR remained significant after adjusting for confounders (P < 0.05). Mediation analyses suggested that lipids partially mediated the neuroticism-CA effect. ConclusionsOverall, our findings indicated a causal link between neuroticism subclusters and CA, with lipids partially mediating this relationship, emphasizing the role of psychosocial factors in cardiovascular risk assessment and intervention strategies.