What comes first: Heart rate variability changes or insomnia? A causal investigation using Mendelian randomization.

Background: Heart rate variability (HRV), a vital indicator of autonomic nervous system function, is frequently altered in patients with insomnia. While substantial evidence suggests a link between HRV changes and insomnia, previous studies have been limited by small sample sizes and cross-sectional designs, making it impossible to determine whether HRV changes are a cause or consequence of insomnia. Understanding this causal relationship is crucial for developing targeted interventions for sleep disorders. Objective: To investigate the potential bidirectional causal relationship between HRV and insomnia using two-sample Mendelian randomization (MR) analysis. Method: We obtained genome-wide association study (GWAS) summary statistics for three HRV traits (pvRSA/HF, RMSSD, and SDNN) from IEU Open GWAS database and insomnia data from FinnGen database (5763 cases and 445,483 controls). Bidirectional MR analyses were performed using multiple methods including inverse variance weighted (IVW), MR-Egger, weighted median, and mode-based approaches. Sensitivity analyses were conducted to assess heterogeneity and horizontal pleiotropy. Results: MR analysis of HRV on insomnia revealed significant causal effects, specifically for pvRSA/HF (OR = 1.437, 95 % CI: 1.147-1.801, Conclusions: This study provides genetic evidence that altered HRV may causally increase insomnia risk, while insomnia does not appear to causally affect HRV. These findings suggest that regulating HRV might help alleviate insomnia symptoms and improve sleep quality, and highlight the potential of HRV as a therapeutic target in sleep disorders.