Precision Medicine Targets in Glymphatic System Dysfunction: A Genomic and Molecular Perspective

The genetic basis of traits linked to glymphatic system dysfunction (GSd) remains poorly understood. Using Genomic Structural Equation Modeling (Genomic-SEM) and multiple post Genome-Wide Association Studies (GWAS) methods, we identified four potentially genome-wide significant loci and one significant gene (Transmembrane protein 106B, TMEM106B). Transcriptome-wide analyses identified susceptibility gene signaling loci and related component information, and a multigene score assessed GSd risk across chromosomes. Although TMEM106B is linked to neurological disorders, the molecular mechanisms of its missense variants remain unclear. We innovatively integrated AI-powered high-precision structural prediction, protein-model-based dynamics simulation, and thermodynamic stability analysis. This systematically revealed, for the first time, how the TMEM106B mutations (T185I, T185N, and T185S) potentially affect the glymphatic system: by disrupting protein structural integrity and influencing dynamic behavior, ultimately impairing function. Our study provides the first panoramic view of GSd’s genetic structure, offering a vital theoretical basis for understanding the glymphatic system dysfunction pathogenesis and identifying new targets for precision medicine and pharmacological interventions.