Causal Association Between Sleep Deprivation and Glioblastoma Risk: Insights from Multi-Omics Analysis

Emerging evidence suggests that sleep deprivation may contribute to cancer risk. However, the genetic association between sleep deprivation and glioblastoma (GBM) remains unexplored. This study aimed to investigate the causal relationship between sleep traits and GBM using genome-wide association study (GWAS) data of sleep duration, sleeplessness, GBM, and immune cell traits from the UK Biobank and FinnGen databases. Mendelian randomization (MR) analyses were conducted to assess potential causal links between sleep traits and GBM risk. Mediation analysis was performed to identify immune mediators affected by sleep duration that might influence GBM development. Single-nucleus RNA sequencing (snRNA-seq) was utilized to examine cellular subpopulation changes in brain tissue from sleep-deprived (SD) and ad libitum sleep mice. Additionally, a mouse model of sleep deprivation was established for transcriptomic analysis. We found a significant causal association between reduced sleep duration and increased GBM risk (IVW OR = 6.000 × 10^-5, P = 0.003, Bonferroni P = 0.025). Sleeplessness also emerged as a potential risk factor for GBM (OR-IVW = 20.221, P = 0.038). Mediation analysis identified CD80 expression on plasmacytoid dendritic cells (pDCs) as a mediator in the association between sleep duration and GBM, with a mediation effect of 0.256. SnRNA-seq confirmed significant alterations in CD80 + pDCs in sleep-deprived mice. Transcriptomic analysis of SD mice demonstrated upregulation of GBM-related markers (Egfr, Tert, and Mgmt) and associated signaling pathways. These findings suggest a potential causal link between insufficient sleep and increased GBM risk, highlighting the importance of sleep management for GBM patients.