The causal mediating effect of smoking on the relationship between irritability and bipolar disorder: A two-step Mendelian randomization study.

INTRODUCTION: Bipolar disorder is a periodic episode of extreme fluctuations in emotion that has been shown to be associated with smoking and irritability, but the relationship between the three has not been studied, especially in terms of genetic causality. This study aimed to obtain potential causal estimates of the association between irritability and bipolar disorder while quantifying the mediating effects of the modifiable risk factor, smoking. METHODS: This study used a two-step Mendelian randomization (MR) method and employed the inverse variance weighted method for the two-sample MR, utilizing SNPs as genetic instruments. Sensitivity analyses were conducted to detect heterogeneity and horizontal pleiotropy. RESULTS: Irritability (OR=3.13; 95% CI: 1.23-7.93; p=0.016) and smoking (OR=2.00; 95% CI: 1.47-2.37; p<0.001) were significantly associated with bipolar disorder from a genetic perspective. Irritability was associated with a higher risk of smoking (OR=1.21; 95% CI: 1.07-1.37; p=0.002). Sensitivity analyses confirmed the robustness of these results. Mediation analysis indicated that smoking partially mediated the potential pathway from irritability and bipolar disorder, with the proportion of the effect of irritability on bipolar disorder mediated by smoking being 11.76% (95% CI: 2-21; p=0.012). CONCLUSIONS: Smoking plays a mediating role in the potential causal pathway linking irritability and bipolar disorder, suggesting that smoking cessation interventions may possibly help mitigate the risk of bipolar disorder among individuals with heightened irritability.