Contribution of rare variants in coding regions to severe tinnitus

Abstract

Tinnitus is the subjective perception of tonal broad-band noise without an external acoustic source. The prevalence in the world population is between 10% and 30%; nevertheless, tinnitus is considered a disorder when it is associated with emotional distress, cognitive dysfunction and autonomic arousal. Meniere Disease (MD) is an inner ear disorder characterised by episodic vertigo associated with sensorineural hearing loss, tinnitus and aural fullness. Although vertigo attacks are considered the main symptom in the first years of the disease, persistent tinnitus is described as the most troublesome symptom by many MD patients. This thesis hypothesis was that tinnitus severity is related to an overload of rare variants in the coding regions of the individuals; therefore, the aim was to identify the central genes and biological processes associated with severe tinnitus. Exome sequencing was performed for the 310 MD patients included in this study. According to the Tinnitus Handicap Inventory (THI) questionnaire, they were clustered into four subgroups. Individuals with a THI above the third quartile composed the severe tinnitus subgroup (I4) and those below the first quartile were the subgroup without disturbance caused by tinnitus (I1). Gene Burden Analyses (GBA) were carried out to target genes enriched in variants with high confidence of being loss-of-function (LoF) or variants with low confidence of being LoF and with a moderate impact in the protein, being missense most of them. Moreover, copy number variants (CNV) and structural variants (SV) were studied. The results show: (1) Eleven genes have been associated with familial MD through a systematic review. (2) Twenty-eight genes were identified as candidates for severe tinnitus, clustering in four groups according to their expression and involved axogenesis, auditory brainstem response, synaptic transmission and hair cell stereocilia organisation as main biological functions. (3) Sixteen genes were identified as candidates for individuals without tinnitus, clustering also in four subgroups by the expression and being part of the protection of cochlear hair cells against damage and the structure of the tectorial membrane. (4) Tinnitus and hyperacusis were strongly associated in MD patients, which shared genetic causes. These results support that MD patients who experience bothersome tinnitus can be partially explained by differences in the rare genetic variants that they carry.