Heritability and genetic risk factors for tinnitus

Tinnitus is a condition in which patients perceive sound without a measurable stimulus. Tinnitus affects approximately 15% of the population, with an increasing prevalence with age, hearing loss, and occupational exposure to noise1,2. Within the Netherlands, tinnitus presents a large financial burden, accounting for 2 billion euros of health care costs yearly3. Tinnitus has major impact on the quality of life and is associated with a variety of somatic and psychosocial comorbidities, including hypertension, head injury, arthritis, diabetes mellitus and hearing loss4–6 as well anxiety and depression7. Tinnitus is even associated with mental health issues and early cognitive decline (e.g. Alzheimer’s disease)8–11. Tinnitus is a complex and heterogeneous disorder with complex symptom presentation12, and diagnosis of tinnitus is based on subjective parameters, with severity scores using questionnaires (e.g. the Tinnitus Handicap Inventory)13.  In Lifelines, tinnitus is assessed based on a self-reported question, namely ‘Do you hear soughing or whistling in your ear/ears?’. In which the participant can respond with three answers: 1) no never; 2) yes, sometimes; 3) yes always14. 

Unfortunately, there are currently no effective or reliable treatment options for tinnitus largely due to the limited understanding of the underlying genetic contributions and pathophysiological mechanisms15.  Human genetic studies would provide enormous insight into the underlying pathophysiology and could even provide novel pharmacological treatments for the treatment and prevention of tinnitus16. To this end, a few studies indicate that tinnitus, like other complex disorders, has a genetic component. Specifically, differences in the prevalence according to ethnic background, familial aggregation, and higher concordance in monozygotic twins than in dizygotic twins17,18. Moreover, recent GWAS studies have identified three potential candidate genes associated with tinnitus, namely ADD1, KCNE1 and SLC12A219,20. Another study, which failed to identify genome-wide significant SNPs, nevertheless identified several enriched metabolic pathways that associated with tinnitus21. Unfortunately, most of these studies are underpowered, badly controlled or fail to correct for multiple testing. Thus, there is need for a larger hypothesis-free study on the genetics of tinnitus. 

Therefore, in this application we propose to build on our previous investigation (unpublished) of tinnitus within the Lifelines population14,22 and contribution to the genotyping efforts of the UMCG Genetics Lifelines Initiative (UGLI) consortium, to investigate the heritability and genetic risk factors for tinnitus. The Lifelines cohort offers a unique population-based cohort study to overcome these previous limitations with sample size and design. Furthermore, as part of UGLI, the department of otorhinolaryngology with expertise provided by the unit of genetic epidemiology at the department of epidemiology aims to better understand the human genetics of tinnitus. The Lifelines cohort study, together with the large-scale genotyping effort by UGLI, makes it possible to perform a unique study within the field of tinnitus research, which tries to identify genetic risk factors for tinnitus.