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

Area of Science:

• Neuroscience
• Genetics
• Computational Biology

Background:

• The genetic basis of glymphatic system dysfunction (GSd) is largely unknown.
• TMEM106B is a gene associated with neurological disorders, but its role in GSd is unclear.

Purpose of the Study:

• To identify genetic factors contributing to GSd.
• To elucidate the molecular mechanisms by which TMEM106B variants affect glymphatic function.

Main Methods:

• Genomic Structural Equation Modeling (Genomic-SEM) and post-Genome-Wide Association Studies (GWAS).
• Transcriptome-wide analyses and multigene risk score calculation.
• AI-powered protein structure prediction, molecular dynamics simulation, and thermodynamic stability analysis.

Main Results:

• Identified four potential genome-wide significant loci and the TMEM106B gene associated with GSd.
• Revealed that TMEM106B mutations (T185I, T185N, T185S) disrupt protein structure and dynamics, impairing glymphatic system function.
• Provided a comprehensive genetic landscape of GSd.

Conclusions:

• TMEM106B variants are implicated in glymphatic system dysfunction through structural and dynamic protein alterations.
• This research offers a foundational understanding of GSd pathogenesis and potential targets for precision medicine.