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Objectives <p>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.</p> Methods <p>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.</p> Results <p>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, <i>P</i> = 0.006, FDR = 0.23) a finding potentially mediated by methylation at cg19746565. Furthermore, <i>SIRT6</i> emerged as a shared risk factor. Genetically predicted higher <i>SIRT6</i> expression was associated with an increased risk of both sleep apnea (OR = 1.279, 95% CI = 1.124–1.456, <i>P</i> = 0.0002, FDR = 0.06) and insomnia (OR = 1.573, 95% CI = 1.099–2.251, <i>P</i> = 0.013, FDR = 0.61), with its effect on insomnia being validated in brain hypothalamus tissue.</p> Conclusions <p>Our multi-omics MR analysis has identified <i>BLK</i>, <i>CTSB</i>, <i>TP53INP1</i>,<i> DNMT3A</i>,<i> ITPR1</i>, and <i>SLC16A7</i> as pivotal factors in the pathogenesis of sleep disorders. These findings provide a foundation for innovative early interventions and therapeutic strategies for sleep disorders.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Jinying Li,
  • Suchun Ding,
  • Xingbo Zhang,
  • Li Tang,
  • Wanwei Jiang

摘要

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.