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Background <p>This study employed two-sample Mendelian randomization (MR) to investigate the potential causal associations between neuroticism, schizophrenia, and various cardiovascular diseases (CVDs), including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), stroke, hemorrhagic stroke, and ischemic stroke, along with its subtypes.</p> Methods <p>We identified independent genetic variants associated with neuroticism and schizophrenia, along with summary statistics for the instrument–outcome relationship, from the largest available genome-wide association study (GWAS) of European ancestry. The inverse variance-weighted (IVW) method was utilized as the primary analytical approach.</p> Results <p>The IVW analysis indicated that genetically determined neuroticism was associated with an increased risk of small-vessel stroke (SVS: odds ratio [95% confidence interval] = 1.42 [1.19–1.68], <i>P</i> &lt; 0.001) and MI (1.13 [1.03–1.25], <i>P</i> = 0.013). Furthermore, a significant association was observed between schizophrenia and HF (1.13 [1.00–1.06], <i>P</i> = 0.026). These associations remained significant after performing multivariable MR to adjust for sleep duration and body mass index. Specifically, the associations between genetic liability to neuroticism and both SVS and MI were statistically significant, with odds ratios of 1.26 (95% CI 1.02–1.58, <i>P</i> = 0.036) and 1.17 (95% CI 1.05–1.32, <i>P</i> = 0.006), respectively. Furthermore, the associations between schizophrenia and HF remained significant, with an odds ratio of 1.05 (95% CI 1.01–1.09, <i>P</i> = 0.007). These results were consistent across extensive sensitivity analyses.</p> Conclusion <p>Our preliminary genetic evidence suggests that neuroticism may increase the risk of SVS and MI, while schizophrenia may elevate the risk of HF. These findings could inform the identification of patient populations that would benefit from CVD prevention strategies that emphasize mental health improvement.</p>

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Investigating the causal associations between neuroticism, schizophrenia, and cardiovascular diseases using Mendelian randomization

  • 期刊论文

  • 发表日期：

    2025年11月25日

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  • Liyuan Pu,
  • Ruijie Zhang,
  • Lifang Pan,
  • Yiwan Li,
  • Supei Hu,
  • Yi Huang

摘要

Background

This study employed two-sample Mendelian randomization (MR) to investigate the potential causal associations between neuroticism, schizophrenia, and various cardiovascular diseases (CVDs), including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), stroke, hemorrhagic stroke, and ischemic stroke, along with its subtypes.

Methods

We identified independent genetic variants associated with neuroticism and schizophrenia, along with summary statistics for the instrument–outcome relationship, from the largest available genome-wide association study (GWAS) of European ancestry. The inverse variance-weighted (IVW) method was utilized as the primary analytical approach.

Results

The IVW analysis indicated that genetically determined neuroticism was associated with an increased risk of small-vessel stroke (SVS: odds ratio [95% confidence interval] = 1.42 [1.19–1.68], P < 0.001) and MI (1.13 [1.03–1.25], P = 0.013). Furthermore, a significant association was observed between schizophrenia and HF (1.13 [1.00–1.06], P = 0.026). These associations remained significant after performing multivariable MR to adjust for sleep duration and body mass index. Specifically, the associations between genetic liability to neuroticism and both SVS and MI were statistically significant, with odds ratios of 1.26 (95% CI 1.02–1.58, P = 0.036) and 1.17 (95% CI 1.05–1.32, P = 0.006), respectively. Furthermore, the associations between schizophrenia and HF remained significant, with an odds ratio of 1.05 (95% CI 1.01–1.09, P = 0.007). These results were consistent across extensive sensitivity analyses.

Conclusion

Our preliminary genetic evidence suggests that neuroticism may increase the risk of SVS and MI, while schizophrenia may elevate the risk of HF. These findings could inform the identification of patient populations that would benefit from CVD prevention strategies that emphasize mental health improvement.