Sleep Traits and Malignant Risk of Pulmonary Nodules: Evidence Triangulation From Questionnaire, Cohort, and Mendelian Randomization

To investigate the association between sleep-related phenotypes and the risk of malignancy in pulmonary nodules, and to provide complementary evidence from a general population cohort and genetic analyses.

This study comprised three parts. Part 1 was a cross-sectional study that consecutively enrolled patients with imaging-confirmed pulmonary nodules at the First Hospital of China Medical University from November 2024 to December 2025. Nine sleep domains were constructed using items from the Pittsburgh sleep quality index (PSQI), with domain severity coded on a 0-6 scale according to the frequency of occurrence. Benign or malignant status of pulmonary nodules was determined based on pathological results or clinical follow-up. Multivariable Logistic regression models with progressive adjustment were constructed. Stratified, interaction, and dose-response analyses (including categorical grouping and restricted cubic splines) were performed focusing on the insomnia symptom domain to explore the association between sleep-related phenotypes and the risk of malignant pulmonary nodules. Part 2 was a prospective cohort study using the China Health and Retirement Longitudinal Study (CHARLS) to investigate the association between sleep duration and incident lung cancer risk in the general population. Part 3 comprised genetic causality analyses, including two-sample Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC), using data from the OpenGWAS database, to assess whether directionally consistent genetic association signals exist between sleep-related phenotypes and lung cancer risk.

In the cross-sectional study, a total of 800 patients with pulmonary nodules were included, of whom 288 (36.0%) were in the malignant group. In the continuous-variable main model fully adjusted for baseline confounders, all nine sleep domains, imaging findings, and depression and anxiety status, the severity of the insomnia symptom domain showed a positive association signal with the risk of malignant pulmonary nodules (fully adjusted model: per 1-point increase, OR=1.147, 95% CI: 1.034-1.272, P=0.010). However, categorical dose-response analysis and restricted cubic spline analysis revealed no clear monotonic trend for this association. Stratified analyses showed that the direction of the association between insomnia symptom domain severity and malignant nodule risk was generally consistent across subgroups. In interaction analyses, the interaction term between insomnia symptom domain severity and smoking status reached nominal statistical significance, suggesting potential effect heterogeneity. The prospective cohort study included 35 159 participants aged ≥45 years, with a total follow-up of approximately 8.0×10⁴ person-years, during which 96 patients developed incident lung cancer. Using a sleep duration of 6-8 hours as the reference group, the short sleep duration group (< 6 hours) showed a trend toward increased lung cancer risk (HR=1.45, 95% CI: 0.55-3.83, P=0.452), but this did not reach statistical significance. The long sleep duration group (> 8 hours) did not show an increased risk of lung cancer (HR=0.82, 95% CI: 0.50-1.33, P=0.414). In the genetic causality analyses, the primary inverse-variance weighted MR analysis showed that genetically predicted tendency to insomnia/difficulty falling asleep(OR=1.76, 95% CI: 1.00-3.10, P=0.049) and longer sleep duration were both associated with an increased risk of lung cancer (OR=1.61, 95% CI: 1.02-2.56, P=0.042). However, multiple alternative methods did not provide consistent evidence to support these findings. LDSC analysis revealed a stable positive genetic correlation between insomnia/difficulty falling asleep and lung cancer risk.

In patients with pulmonary nodules, an association signal exists between insomnia-related symptoms and the risk of malignancy, but the dose-response relationship remains unclear. The CHARLS cohort and genetic analyses provide supplementary directional clues for the above associations, albeit with limited statistical strength and result consistency. Definitive conclusions regarding the association between sleep phenotypes and the risk of malignant pulmonary nodules require further validation in prospective studies.