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

Background: The investigation of druggable target genes through large-scale expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data has demonstrated promise across various diseases. This approach has yet to be explored in the context of tinnitus.

Methods: We obtained cis-eQTL data for 3,453 druggable genes from eQTLGen. Tinnitus phenotype derived from the UK Biobank was used as the discovery cohort. A large-scale Mendelian randomization (MR) analysis was conducted to investigate the inferred causal relationships between the 3,453 druggable genes and tinnitus. Replication analyses were conducted using tinnitus phenotypes from FinnGen. We further conducted colocalization analysis to identify actionable drug targets for tinnitus. Besides, MR analysis was used to explore the association of the identified genes with hearing loss and inflammation.

Results: Genetic predictions indicated that the expression of NEU1 (β = 0.137, 95% CI = 0.112 to 0.162, p = 2.21 × 10-26), APOM (β = 0.139, 95% CI = 0.112 to 0.166, p = 1.23 × 10-24), and TUBB (β = -0.043, 95% CI = -0.062 to -0.024, p = 5.46 × 10-6) was causally associated with tinnitus. Our replication analysis in FinnGen yielded consistent results. There is a strong colocalization association between the three genes and tinnitus (PPH4 > 0.8). No evidence indicated these three genes were associated with hearing loss. Network MR suggested that IL-17C and CCL20 mediates effects of APOM on tinnitus, and IL-17C accounts for effects of NEU1 on tinnitus.

Conclusions: Our findings investigated the potential pathological mechanisms and therapeutic targets of tinnitus, providing novel strategies for future clinical trials.