Association between specific neuroticism symptoms and cardiovascular disease: insights from genetic analysis

Although neuroticism has been linked to cardiovascular disease (CVD), the etiological relevance of individual neuroticism symptoms remains poorly understood. In this study, we employed Linkage disequilibrium score regression (LDSC) and systematic Mendelian randomization (MR) analyses to examine the potential causal effects of specific neuroticism symptoms on CVD. We obtained summary-level data on 13 specific neuroticism symptoms from the UK Biobank (ranging from 366,726-380,506 participants). Summary statistics for CVD originated from three European-descent GWASs with a total of 799,534 participants. LDSC was performed to investigate the genetic associations between specific neuroticism symptoms and CVD. The inversevariance weighted approach was applied to test the causality for the studied associations, together with extensive validation and sensitivity analyses to verify the main results. LDSC revealed significant genetic correlations between most neuroticism symptoms and CVD ri(r_g range: 0.0837-0.2041), except for "feeling tense" and "worrying after embarrassment". Furthermore, MR analyses indicated that genetically predicted neuroticism sum-score was causally associated with increased risk of ischemic stroke (IS) (OR = 1.23; 95% CI = 1.05-1.44) and myocardial infarction (MI) (OR = 1.20; 95% CI = 1.02-1.41). Among individual symptoms, irritableness was associated with intracerebral hemorrhage (OR = 4.15; 95% CI = 1.17-14.68), mood swings was associated with IS (OR = 1.30; 95% CI = 1.01-1.68), coronary artery disease (OR = 1.72; 95% CI = 1.35-2.20), and MI (OR = 1.74; 95% CI = 1.29-2.35), and feeling fed up was associated with IS (OR = 1.32; 95% CI = 1.02-1.71). These results remained robust across multiple sensitivity analyses. Overall, our study provided genetic and causal evidence supporting the role of neuroticism sum-score, irritableness, mood swings, and feeling fed up as risk factors for CVD, highlighting potential targets for early intervention and prevention.