Identification of Risk Loci for Radiotherapy-Induced Tinnitus and Hearing Loss Through Integrated Genomic Analysis

TL;DR

This study identifies genetic variants linked to hearing loss and tinnitus caused by radiotherapy, revealing potential pathways and unexpected connections to metabolic traits.

Contribution

The study provides the first integrated genomic analysis of radiotherapy-induced tinnitus and hearing loss, uncovering distinct genetic architectures and novel metabolic associations.

Findings

97 SNPs were associated with tinnitus, and 76 with hearing loss after radiotherapy.

Tinnitus variants were linked to Wnt signaling and telomerase RNA regulation pathways.

Hearing loss variants were connected to calcium-dependent cell adhesion and neurotransmitter regulation.

Abstract

Radiotherapy-induced hearing impairment significantly affects patients’ quality of life, yet its genetic basis remains poorly understood. This study seeks to identify genetic variants associated with radiotherapy-induced tinnitus and hearing loss and explore their functional implications. A genome-wide association study (GWAS) was conducted to identify single-nucleotide polymorphisms (SNPs) associated with radiotherapy-induced tinnitus and hearing loss. Protein–protein interaction networks and functional enrichment analyses were performed to explore underlying biological pathways. A phenome-wide association study (PheWAS) analysis across five databases examined associations between identified SNPs and various phenotypes. The GWAS identified 97 SNPs significantly associated with radiotherapy-induced tinnitus and 76 SNPs with hearing loss. Tinnitus-associated variants were enriched in pathways involving Wnt signaling and telomerase RNA regulation, while hearing-loss-associated variants were linked to calcium-dependent cell adhesion and neurotransmitter receptor regulation. The PheWAS analysis revealed significant associations between these hearing-impairment-related SNPs and metabolic phenotypes, particularly BMI and metabolic disorders. A chromosomal distribution analysis showed concentrated significant SNPs on chromosomes 1, 2, 5, and 10. This study identified distinct genetic architectures underlying radiotherapy-induced tinnitus and hearing loss, revealing different molecular pathways involved in their pathogenesis. The unexpected association with metabolic phenotypes suggests potential interactions between metabolic status and susceptibility to radiotherapy-induced hearing complications. These findings provide insights for developing genetic screening tools and targeted interventions to prevent or mitigate radiotherapy-related hearing damage.

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