Association of Gene Expression and Tremor Network Structure

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Essential tremor (ET) is a neurological disorder characterized by involuntary shaking.
• The cerebello-thalamo-cortical network is implicated in ET, but its transcriptomic changes and structural associations remain unexplored.

Purpose of the Study:

• To identify molecular changes associated with imaging-derived phenotypes (IDPs) in the tremor network of essential tremor patients.
• To explore the relationship between brain structure and gene expression in ET.

Main Methods:

• An imaging-transcriptomic study was conducted using UK Biobank data from 33,224 adults.
• Genome-wide association study (GWAS) summary statistics were used to impute gene expression associations with 184 IDPs.
• Functional enrichment analysis and validation with cerebellar RNA-sequencing data from 55 ET patients and controls were performed.

Main Results:

• 2,269 genome-wide significant associations were found, primarily related to white matter pathways and genes linked to tremor.
• Cortical thickness in the tremor network correlated with a gene module for mitochondrial organization and protein quality control.
• White-gray matter MRI contrast correlated with gene modules for sphingolipid synthesis and ethanolamine metabolism. Validation data showed significant correlations for diffusion MRI phenotypes and overlap for gray matter phenotypes.

Conclusions:

• Identified genes and molecular processes represent potential therapeutic targets for essential tremor.
• These findings contribute to understanding the molecular basis of ET and may aid in future patient stratification and prognosis.