Multi-omics integration reveals evening circadian preference as a causal risk factor for cancer-depression comorbidity through shared neuro-endocrine-immune pathways

Background: The comorbidity of cancer and depression leads to substantially poor prognosis, yet its shared mechanisms remain elusive. Circadian disruption, particularly evening circadian preference, is a plausible link but its role and underlying pathways in comorbidity warrant further investigation. Methods : We conducted an integrative multi-omics analysis. Utilizing prospective UK Biobank data (N=299155), we assessed the association of evening chronotype with cancer-depression comorbidity risk across distinct transition pathways (baseline to comorbidity, cancer to comorbidity, depression to comorbidity). Mendelian randomization (MR) and polygenic risk scores (PRS) for morning chronotype were performed for causal inference and genetic stratification. To uncover molecular mechanisms, we integrated summary-data-based MR (SMR) and colocalization analyses using GWAS and eQTL data to identify circadian clock-related genes (CRGs) consistently associated with breast (BCa), prostate (PCa), colorectal cancer (CRC), and depression. Pathway enrichment analysis and immune cell infiltration analysis were also conducted to investigate shared mechanisms. Results: Evening chronotype significantly increased the risk of transitioning from a healthy baseline state to comorbidity for overall cancer, CRC, and BCa (fully adjusted HRs = 1.30, 1.55, and 1.43, respectively), and on the transition from cancer to comorbidity (HRs=1.29, 1.50, and 1.34, respectively). The effect was more pronounced in subgroups such as women, smokers, individuals with higher levels of education, and those with a lower socioeconomic status. Genetically, morning chronotype PRS showed protective effects, and individuals with both evening chronotype and low PRS constituted the highest-risk subgroup. Two-sample MR confirmed a causal protective effect of morning chronotype on BCa, CRC, and depression. Multi-omics integration identified five key CRGs (GAL, ALAS1, SUCNR1, PTK2, DDIT3) with consistent causal effects on both cancer and depression. Pathway enrichment analysis revealed that these genes were significantly clustered in neuroendocrine regulation and metabolic pathways. GAL and SUCNR1/PTK2 were significantly correlated with mast cells and CD8+ T cells infiltration, respectively, revealing a pathway from circadian disruption to comorbidity through neuro-endocrine-immune dysregulation. Conclusion: Our study elucidates evening chronotype as a significant and modifiable risk factor for cancer-depression comorbidity. We identify a high-risk genetic subgroup and delineate shared biological mechanisms, providing a foundational framework for targeted circadian-based interventions to mitigate comorbidity risk.