A multilayer genomic framework linking insomnia to glymphatic system function through pleiotropic mechanisms at 17q21.31

Abstract Sleep plays a critical role in brain waste clearance, yet whether insomnia shares a genetic basis with the glymphatic system (GS)—a glia-dependent perivascular pathway involved in metabolite removal—remains unclear. Here, we integrated large-scale genome-wide association studies (GWAS) of insomnia with diffusion tensor imaging along the perivascular space (DTI–ALPS), an imaging-derived proxy of GS function, across two independent cohorts. Polygenic enrichment analyses revealed localized genetic sharing between insomnia and multiple ALPS phenotypes despite minimal genome-wide genetic correlation. Conjunctional false discovery rate and Bayesian colocalization analyses identified shared causal signals at 17q21.31, a pleiotropic locus encompassing the MAPT inversion region. Transcriptome-wide association, gene-level fine-mapping, and summary-data Mendelian randomization converged on HEXIM1 , ACBD4 , EFTUD2 , and MAPT as shared genes influencing both insomnia and GS function. Functional characterization showed that these genes were enriched across multiple brain regions and cell types, including neurons, astrocytes, microglia, oligodendroglia, and vascular-associated cells. Notably, gene-level effects exhibited regional and phenotype-specific heterogeneity. Together, our findings demonstrate that insomnia and glymphatic function converge through a context-dependent genetic architecture centered on 17q21.31, implicating neuroglial pathways relevant to protein clearance and Alzheimer’s disease vulnerability.