Expanding insights on immune cells and insomnia: A Mendelian randomization study using updated data

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Insomnia is a prevalent sleep disorder associated with cognitive impairments, mood disturbances, and increased risks of cardiovascular and psychiatric conditions. Emerging evidence suggests that immune dysregulation contributes significantly to insomnia pathogenesis; however, the causal roles of specific immune cell phenotypes remain unclear. We employed a bidirectional two-sample Mendelian randomization (MR) approach to assess causal associations between 731 immune cell traits and insomnia risk. Genetic instrumental variables for immune phenotypes were derived from genome-wide association studies (GWAS) of 3757 Sardinian participants, and insomnia data were obtained from the FinnGen consortium (Release R10), including 4801 cases and 405229 controls. Primary analyses utilized inverse-variance weighted regression, with sensitivity analyses conducted via MR-Egger, weighted median, and MR-PRESSO methods. After false discovery rate correction, 14 immune cell phenotypes showed significant associations with insomnia. Specifically, elevated levels of activated IgD⁻CD38^bright B cells (OR = 1.043, 95% CI: 1.001–1.088, p = 0.045), CD40⁺CD86⁺ dendritic cells, and CD14⁺ intermediate monocytes were positively associated with insomnia risk, whereas increased CD8 expression on regulatory CD28⁻CD8^bright T cells showed protective effects (OR = 0.918, 95% CI: 0.851–0.990, p = 0.037). Robustness checks revealed minimal pleiotropy, and reverse MR analyses did not detect significant causal effects of insomnia liability on immune traits. These findings clarify a unidirectional causal relationship, highlighting activated B cells and dendritic cells as potential inflammatory mediators involved in insomnia, and regulatory T cell subsets as protective factors. Our results provide novel immunological insights into insomnia and suggest potential targets for therapeutic interventions.

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