Genetic Analysis Links Insomnia Liability to Higher Inflammation Marker

Genetic evidence suggests insomnia may help drive systemic inflammation, according to a study published online in Sleep.¹ Researchers at Massachusetts General Hospital and the Broad Institute identified 125 genetic loci, or regions of the genome, shared between insomnia and C-reactive protein (CRP), a marker of low-grade inflammation. They found stronger support for an effect running from insomnia to CRP than the reverse.

CRP Is Higher in People With Insomnia

Using UK Biobank data, investigators compared 130,611 individuals who usually experienced insomnia symptoms with 327,375 controls. CRP was significantly higher in the insomnia group after adjustment for age, sex, and genetic ancestry (P < .001). The difference persisted in a healthy subgroup that excluded participants with psychiatric disorders, chronic disease, sleep medication use, and shift work (mean difference, 0.077 mg/L; P < .001). The authors described the gap as modest and consistent with low-grade inflammation. Within the healthy subgroup, the association was stronger in women than in men and peaked among participants aged 39 to 50 years before declining in older groups.

Genome-wide analyses showed a positive genetic correlation (r_g) of 0.186 between insomnia and CRP, a modest overlap in the genetic influences on the 2 traits (P = 2.39 × 10^-17). The correlation remained after conditioning on depression (r_g = 0.161; P = 8.97 × 10^-15). The insomnia data came from a meta-analysis of 593,724 cases and 1,771,286 controls.²

A pleiotropy analysis, which looks for variants tied to both traits, identified 125 independent loci. Only 67 variants (53.6%) had the same effect direction for both traits, a proportion that was not statistically significant.¹

Six Loci Support Shared Causal Variants

Colocalization analysis, which tests whether 2 traits share the same underlying variant, supported shared causal variants at 6 loci near APOE, HLA-B, NLGN1, AK5/DNAJB4, FAM114A2/GRIA1, and SATB1. The APOE signal showed near-complete colocalization (posterior probability, 0.9997). The APOE ε4 allele, which raises Alzheimer disease risk, was associated with lower insomnia risk and lower CRP. The investigators suggested this may reflect context-dependent roles in neuroimmune regulation, lipid metabolism, and glial biology.

Genes at the shared loci were enriched for immune and stress-response pathways, including interferon gamma response, tumor necrosis factor α signaling through NF-κB, and apoptosis. Chromatin organization and nucleosome assembly were also enriched. Enrichment appeared in several brain regions, including the hypothalamus, and in neuronal cell types in the midbrain and thalamus.

Mendelian Randomization Favors One Direction

Mendelian randomization, which uses inherited variants to test whether one trait influences another, showed that genetic liability to insomnia was associated with higher CRP (inverse variance weighted β = 0.299; P = 5.52 × 10⁻¹⁰). Weighted median, weighted mode, and simple mode estimates agreed, and there was no evidence of directional pleiotropy. One method, MR-Egger, did not reach significance, and heterogeneity across variants was present.

The reverse analysis was less consistent. CRP as the exposure produced a small positive estimate (β = 0.011; P = .0073), but other methods did not agree, and testing indicated directional pleiotropy. A sensitivity analysis using 23 variants from an independent 23andMe cohort, designed to address sample overlap, produced a significant inverse variance weighted estimate (P = .040). Other methods pointed in the same direction with less precision.

Limitations and Next Steps

Insomnia was self-reported, and residual pleiotropy and sample overlap cannot be fully excluded. Both datasets were limited to participants of European ancestry, and sex-stratified genetic analyses lacked 23andMe data and had reduced power. The study team called for longitudinal studies testing whether improved sleep lowers CRP and for functional work on the shared loci, particularly APOE.

“Targeting pathways involved in neuroimmune signaling, glial function, and synaptic regulation may offer strategies to mitigate the inflammatory consequences of sleep disruption,” the authors wrote. “Incorporating genetic information could further enable the development of individualized approaches aimed at improving sleep while reducing systemic inflammatory burden.”

References

1. Abou Daya F, Valliere J, Maher M, Saxena R. Genetic pleiotropy highlights immune mechanisms that link insomnia and C-reactive protein. Sleep. Published online 2026. doi:10.1093/sleep/zsag254
2. Watanabe K, Jansen PR, Savage JE, et al. Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways. Nat Genet. 2022;54(8):1125-1132. doi:10.1038/s41588-022-01124-w