Abstract Introduction Insomnia is a prevalent sleep disorder associated with elevated systemic inflammation. Circulating levels of IL-1β, IL-6, CRP, TNFα, and TGFβ are increased in individuals with poor sleep, yet the genetic and causal relationships underlying these associations remain unclear. Understanding whether insomnia drives inflammation or vice versa is critical for elucidating mechanisms linking sleep disruption to immune dysregulation and neuroimmune processes. Here, we aimed to identify and characterize shared genetic mechanisms between insomnia and multiple inflammatory markers. Methods We analyzed GWAS summary statistics for insomnia (UK Biobank and 23andMe; ~593,000 cases, ~1.7 million controls) and inflammatory markers (UK Biobank). CRP GWAS data included ~436,345 individuals; GWAS for IL-6, IL-1β, TNFα, and TGFβ included ~50,000 individuals each. We estimated genome-wide genetic correlations using LDSC. We then identified pleiotropic genetic loci using PLACO and performed functional annotation, as well as pathway and tissue expression enrichment analyses through FUMA. To detect shared causal variants, we conducted colocalization analyses using SuSiE coloc. Finally, we applied bidirectional Mendelian randomization to assess the direction of causality between insomnia and each inflammatory marker. Results We observed significant positive genetic correlations between insomnia and all inflammatory markers (rg = 0.11–0.22, Bonferroni-corrected p 0.01). We identified 125 pleiotropic loci for CRP and 3–8 loci per other cytokine, which were enriched in key brain regions (e.g. hypothalamus, amygdala). Pathway analyses revealed cytokine-specific mechanisms shared with insomnia: CRP loci mapped to chromatin organization and cellular senescence; IL-6 and TNFα loci were enriched for interferon-γ signaling; and TGFβ loci highlighted integrin signaling, MAPK linkage, and vascular smooth muscle contraction. Colocalization analyses identified shared causal variants, including rs429358 (APOE E4) for CRP, linking insomnia with neuroinflammatory pathways. Bidirectional MR analysis found that insomnia causally increased CRP, IL-6, and TGFβ (p 0.001); however, no significant causal effects of any cytokine on insomnia were observed. Conclusion These results reveal shared genetic mechanisms and neuroimmune pathways involving APOE and cytokine-specific signaling that link insomnia directly to multiple cytokines and suggest that insomnia drives systemic inflammation. Our findings provide a comprehensive framework for understanding how disrupted sleep promotes immune dysregulation and increases risk for neuroinflammatory conditions and related comorbidities. Support (if any)
Daya et al. (Fri,) studied this question.