Single-Cell eQTL Revealing Brain Cell-Type-Specific Genetic Control of Insomnia.

Insomnia is the most prevalent sleep disorder and exhibits substantial heritability. Although genome-wide association studies (GWAS) have provided broader insights, they still explain only a small proportion of the phenotypic variance, leaving critical gaps in the mechanistic understanding of insomnia. Therefore, we integrated large-scale GWAS summary statistics with single-cell expression quantitative trait loci (eQTL) data across eight major brain cell types. From 1,631 genes mapped to insomnia-associated loci, we constructed gene-cell pairs and applied rigorous filtering to derive independent, strong instrumental variables. These were analyzed using two-sample Mendelian randomization (MR) with inverse-variance weighted (IVW) estimation as the primary approach. Sensitivity analyses, including MR-Egger, Cochran’s Q test, leave-one-out, and MR-PRESSO, were employed to validate causal inferences and mitigate pleiotropy. Our analysis identified 14 genes (25 gene-cell pairs) significantly associated with insomnia risk. Notably, LINC01535 showed the strongest causal effects in astrocytes, excitatory neurons, inhibitory neurons, oligodendrocyte precursor cells, and oligodendrocytes (IVW, p < 0.001). Additionally, we identified 9 insomnia-associated genes in one specific cell type, suggesting those genes may primarily mediate insomnia in their specific cell type. Except for the outstanding genes, we identified most of the insomnia-associated genes in most of the glial cells (oligodendrocytes, OPCs, and astrocytes), suggesting its significant role in mediating insomnia risk. Our study deepens the mechanistic understanding of insomnia by revealing cell-type-specific genetic influences on insomnia, paving the way for targeted prevention and therapeutic interventions.