Genetic Contribution to Tinnitus and Tinnitus Disorder

Tinnitus is a subjective perception of sound reported in almost 15% of the global population. Tinnitus can be found associated with hearing loss, hyperacusis, noise exposure, and several comorbidities such as anxiety or headache. Several environmental factors may trigger this symptomatology, though genetic variation may modulate and facilitate the development of a chronic or severe tinnitus phenotype. Currently, a strong genetic heritability has been observed in studies with twins and adoptees. Also, sex differences and familial aggregation have been observed in tinnitus, suggesting a relevant genetic background. Genome-wide association studies and exome/genome sequencing can decipher the contribution of common and rare genetic variations in the genome to the different phenotypes observed in tinnitus patients. A burden of rare missense variants in several synaptic genes, including ANK2, AKAP9, and TSC2, was found in Spanish individuals with MD and tinnitus extreme phenotype and replicated in Swedish patients with severe tinnitus. However, several of these new candidate variants are pending confirmation, and replication in an independent cohort and functional validation is needed before their clinical translation. High-throughput sequencing may elucidate the genetic structure of severe tinnitus combining genetic and clinical data in early personalized diagnosis and genetic therapy.