Integrating Expression Quantitative Trait Loci and Genome-Wide Association Study Identifies Druggable Genes for...

Area of Science:

• Genetics
• Pharmacology
• Otolaryngology

Background:

• Large-scale genetic studies like expression quantitative trait loci (eQTL) and genome-wide association studies (GWAS) show promise for identifying drug targets in various diseases.
• The application of these genetic approaches to tinnitus research remains largely unexplored.

Purpose of the Study:

• To investigate potential druggable target genes for tinnitus using genetic association and Mendelian randomization (MR) analyses.
• To identify causal relationships between specific genes and tinnitus.
• To explore potential therapeutic targets for tinnitus.

Main Methods:

• Utilized cis-eQTL data for 3,453 druggable genes from eQTLGen.
• Employed Mendelian randomization (MR) analysis with tinnitus phenotype data from the UK Biobank (discovery) and FinnGen (replication).
• Conducted colocalization analysis to pinpoint actionable drug targets and network MR to elucidate mediating pathways.

Main Results:

• Identified causal associations between the expression of NEU1, APOM, and TUBB genes and tinnitus.
• Replication analysis in FinnGen confirmed these associations.
• Strong colocalization was observed between the three genes and tinnitus; no association with hearing loss was found.
• Network MR suggested IL-17C and CCL20 mediate the effects of APOM on tinnitus, and IL-17C mediates the effects of NEU1 on tinnitus.

Conclusions:

• The study identifies NEU1, APOM, and TUBB as potential therapeutic targets for tinnitus.
• Findings provide insights into the pathological mechanisms of tinnitus.
• Novel strategies for future clinical trials targeting these genes are proposed.