Habitual Napping and Cancer Incidence: A Prospective Study from the UK Biobank with Metabolomic Mediation Analysis

Abstract Study Objectives This study aims to investigate the association between daytime napping frequency and cancer incidence and elucidate the underlying biological mechanisms. Methods Using data from the UK Biobank, Cox regression was employed to assess the association between self-reported daytime napping frequency and risks for overall and site-specific cancers. A polygenic risk score (PRS) was conducted to assess whether genetic predisposition to daytime napping influenced cancer incidence. Finally, mediation analysis was performed on a panel of 325 nuclear magnetic resonance (NMR) metabolites to identify potential biological pathways, which linked napping to cancer risk. Results In this cohort of 460 923 participants, both sometimes (HR = 1.04, p<.001) and usually (HR = 1.03, p=.046) napping were significantly associated with a higher risk of overall cancer compared to never napping. Site-specific analysis showed an elevated breast cancer risk for sometimes napping (HR = 1.06, p=.005) and esophageal cancer risk for usually napping (HR = 1.21, p=.038). Furthermore, a high PRS for daytime napping also predicted increased cancer incidence (HR = 1.02, p=.017), suggesting a role for genetic predisposition. Mediation analysis revealed 29 NMR biomarkers that each explained over 10% of the napping-cancer association. The most significant mediator is the percentage of cholesterol in large LDL particles (LDL_C_pct), which accounted for 13.3% of napping-cancer relationship. Conclusions Increased daytime napping frequency is potentially associated with elevated cancer risk. Further research is warranted to validate this association and elucidate the underlying biological mechanisms. Statement of Significance This study provides the comprehensive investigation of how daytime napping influence cancer risk through biological mechanisms. By analyzing data from 461 000 individuals in the UK Biobank, we demonstrated that increased daytime napping frequency is associated with elevated cancer risk, particularly for breast and esophageal cancers. Our research employed both observational and genetic approaches, using PRS to assess the contribution of genetic liability and to provide evidence which was less susceptible to traditional confounding. Through mediation analysis of 325 NMR metabolites, we identified lipid metabolic dysfunction as the key biological pathway linking napping to cancer development. Specifically, cholesterol composition in small low-density lipoproteins explained 13.3% of this association. These findings provide the biological explanation for how daytime napping influences cancer development and highlight lipid metabolism as a potential intervention target for cancer prevention. Future studies are essential to validate this association and elucidate the underlying biological mechanisms.