Cell senescence-related pathogenic genes in sleep disorders: a multi-omics Mendelian randomization study

OBJECTIVES: Sleep disorders are multifactorial conditions influenced by genetic and environmental factors. However, the causal roles of specific cellular senescence-related genes in distinct sleep disorders subtypes remain unclear. This study aimed to dissect these relationships by integrating multi-omics data to identify potential causal pathways in sleep apnea and insomnia. METHODS: We conducted a multi-stage Mendelian randomization (SMR) study. We first performed an exploratory SMR analysis integrating a comprehensive list of senescence-related genes with genome-wide association study (GWAS) data for a broad sleep disorders phenotype from the FinnGen consortium. To address phenotype heterogeneity, we then performed in-depth, phenotype-specific SMR analyses for sleep apnea and insomnia, integrating data across three molecular levels: DNA methylation (mQTL), gene expression (eQTL), and protein abundance (pQTL). Significant findings were validated using colocalization, HEIDI tests, replication cohorts, and two-sample MR sensitivity analyses. RESULTS: Our discovery analysis on broad sleep disorders phenotype identified several candidate genes. Subsequent phenotype-specific analyses revealed distinct genetic architectures. Genetically predicted lower CTSB expression was associated with a reduced risk of sleep apnea (OR = 0.943, 95% CI = 0.905-0.983, P = 0.006, FDR = 0.23) a finding potentially mediated by methylation at cg19746565. Furthermore, SIRT6 emerged as a shared risk factor. Genetically predicted higher SIRT6 expression was associated with an increased risk of both sleep apnea (OR = 1.279, 95% CI = 1.124-1.456, P = 0.0002, FDR = 0.06) and insomnia (OR = 1.573, 95% CI = 1.099-2.251, P = 0.013, FDR = 0.61), with its effect on insomnia being validated in brain hypothalamus tissue. CONCLUSIONS: Our multi-omics MR analysis has identified BLK, CTSB, TP53INP1, DNMT3A, ITPR1, and SLC16A7 as pivotal factors in the pathogenesis of sleep disorders. These findings provide a foundation for innovative early interventions and therapeutic strategies for sleep disorders.