Comparison of GWAS results between de novo tinnitus and cancer treatment-related tinnitus suggests distinctive roles for genetic risk factors

Tinnitus is a common sensorineural complication that can occur de novo or after cancer treatments involving cisplatin or radiotherapy. Considering the heterogeneous etiology and pathophysiology of tinnitus, the extent to which shared genetic risk factors contribute to de novo tinnitus and cancer treatment-induced tinnitus is not clear. Here we report a GWAS for de novo tinnitus using the UK Biobank cohort with nine loci showing significantly associated variants (p < 5 × 10^–8). To our knowledge, significant associations in four of these loci are novel, represented by rs7336872, rs115125870, rs1532898 and rs2537, with UBAC2, NUDT9, TGM4 and MPP2 as their nearest protein coding genes, respectively. Through quantitative comparison of results from GWAS of de novo tinnitus with GWAS of radiation-induced tinnitus, two intronic variants (rs7023227 and rs3780395) from a locus within immunoregulatory gene PD-L1 (CD274) reached the replication threshold using comparison thresholds of 10^–5 and 10^–4, with no other shared genetic risk factors identified. We did not observe shared genetic risk factors between de novo and cisplatin-induced tinnitus. Our results suggest that genetic risk factors are mainly distinct based on etiology of tinnitus and future efforts to study, prevent or treat tinnitus are expected to benefit from strategies that allow for distinction of cases based on the primary environmental risk factor.