The bidirectional causal relationships of insomnia with eleven cancers: A Mendelian randomization study

Insomnia is closely associated with tumors and is recognized as a risk factor for cancer development. This two-sample Mendelian randomization (MR) study investigated the potential causal link between genetically determined insomnia and various cancers, including brain, colorectal, esophageal, gastric, hepatic bile duct, liver, lung, malignant lymphoma, pancreatic, skin, and thyroid cancers. Summary statistics from genome-wide association studies for insomnia and eleven cancer types were examined. instrumental variables (IVs) were selected from single nucleotide polymorphisms that passed strict quality control for minimal linkage disequilibrium and genome-wide significance. All IVs demonstrated strong predictive power for insomnia, with F-statistics exceeding the conventional threshold of 10. The primary analysis was conducted using the inverse variance weighted method. Sensitivity analyses were performed using MR-Egger regression, weighted median, and weighted mode methods to test robustness, pleiotropy, and heterogeneity. MR analysis suggested potential causal associations between insomnia and increased risk of hepatic bile duct cancer (odds ratio [OR] = 4.458, 95% confidence interval [CI]: 1.074-18.493, P = .040), reduced risk of hepatic cancer (OR = 0.312, 95% CI: 0.100-0.973, P = .045), and reduced risk of skin cancers (OR = 0.599, 95% CI: 0.439-0.818, P = .001). However, after Bonferroni correction (adjusted threshold P < .0045), these associations did not retain statistical significance. No notable causal influence of these cancers on insomnia was observed. Sensitivity analyses showed no evidence of reverse causality or significant bias. These findings, though not retaining statistical significance after stringent multiple testing correction, provide suggestive evidence that genetically predicted insomnia may influence the risk of certain cancers, potentially through mechanisms involving genetic predisposition and biological pathways that modulate inflammation, immune function, and circadian rhythms. The study highlights the translational value of understanding insomnia's role in cancer risk, suggesting that clinicians should consider this association when managing patients with insomnia. Further research with larger sample sizes is warranted to validate these findings.