A cross-tissue transcriptome-wide association study identifies novel candidate genes associated with brain glymphatic...

Area of Science:

• Neuroscience
• Genetics
• Biomedical Imaging

Background:

• The glymphatic system is crucial for clearing waste products from the brain.
• Genetic regulation of the glymphatic system is not well understood.
• The Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) index is a key imaging biomarker for glymphatic function.

Purpose of the Study:

• To identify genes associated with glymphatic system function using genetic data.
• To investigate the genetic underpinnings of brain waste clearance.
• To validate candidate genes using multiple statistical methods.

Main Methods:

• Integrated genome-wide association study (GWAS) data with GTEx eQTL data.
• Performed transcriptome-wide association studies (TWAS) using UTMOST and FUSION.
• Validated gene associations using Multi-marker Analysis of Genomic Annotation (MAGMA), cis-Mendelian randomization (cis-MR), and summary-data-based Mendelian randomization (SMR).
• Utilized colocalization analysis to confirm causal inference stability.

Main Results:

• TWAS identified 17 candidate genes associated with DTI-ALPS.
• Six protein-coding genes were validated by MAGMA.
• Cis-MR provided evidence for causal effects of six genes, with colocalization supporting four.
• SMR identified TRIOBP, GCAT, and MAPRE3 as robustly associated with DTI-ALPS across tissues.

Conclusions:

• Statistical evidence supports the genetic regulation of glymphatic function.
• Identified specific genes (e.g., TRIOBP, MAPRE3, EMILIN1, GCAT) potentially regulating glymphatic system activity.
• Findings pave the way for understanding genetic contributions to brain waste clearance and related neurological conditions.