Causal relationship between subhealth status and pan-cancer risk: A Mendelian randomization study

Subhealth status (SHS), an intermediate state between health and disease, is increasingly prevalent, yet its potential causal role in cancer remains unclear. Leveraging publicly available genome-wide association data from the Integrative Epidemiology Unit, we conducted a two-sample Mendelian randomization (MR) study to estimate the causal effects of 4 SHS proxies - heart rate variability (HRV), health satisfaction, irritability, and mood swings - on risk of lung, breast, colorectal, prostate, cervical, pancreatic, and basal-cell carcinoma. Inverse variance-weighted (IVW) regression was the primary analysis, supplemented by sensitivity analyses (weighted median, MR-Egger, radial IVW, maximum likelihood). Genetically predicted higher HRV (standard deviation of normal-to-normal interbeat intervals and peak-to-valley respiratory sinus arrhythmia or high-frequency power) was associated with lower colorectal cancer risk. Higher irritability was causally linked to increased lung cancer risk. Mood swings showed a modest positive association with basal-cell carcinoma. Greater health satisfaction was associated with higher risks of cervical and pancreatic cancer. No directional pleiotropy or heterogeneity was detected for these associations. These findings suggest that selected SHS indicators may causally influence site-specific cancer risk, supporting early intervention on autonomic dysfunction and emotional dysregulation as plausible cancer-prevention strategies.