Inflammation and Oxidative-Stress Pathways Are Associated with Idiopathic Sudden Hearing Loss: A Genome-Wide Association Study in 15,494 Japanese Individuals

The etiology of idiopathic sudden sensorineural hearing loss (iSSNHL) remains unclear, and genome-wide genetic evidence is limited. We conducted a multicenter Japanese case-control genome-wide association study including 192 clinically defined iSSNHL cases and 15,302 controls aged ≥80 years without a history of hearing loss. After cross-platform SNP harmonization and imputation (Eagle/Minimac4), association testing was performed using dosage-based logistic regression in PLINK 2.0, adjusting for sex and principal components (PC1-PC10). Gene- and pathway-level analyses were conducted using MAGMA and the PANTHER overrepresentation test. Genomic inflation was modest (λ_GC = 1.04). Eight loci reached genome-wide significance (<i>p</i> < 5 × 10^-8), led by <i>FHIT</i>, with additional loci near <i>LHX2</i>, <i>TRMT1L</i>, <i>MEGF10</i>, <i>SPATS1</i>, <i>SAMD5</i>, <i>MYT1L</i>, and <i>ID4</i>; 21 loci met the suggestive threshold (<i>p</i> < 1 × 10^-6). MAGMA identified eight genes at FDR < 0.05 (<i>FHIT</i>, <i>TRMT1L</i>, <i>MEGF10</i>, <i>RNF2</i>, <i>SWT1</i>, <i>VAMP1</i>, <i>TAPBPL</i>, and <i>C9orf3</i>). These findings suggest that immune-inflammatory and cellular stress-homeostasis mechanisms may contribute to iSSNHL susceptibility and provide candidate loci for future replication and functional studies.