Novel Risk Loci in Tinnitus and Causal Inference With Neuropsychiatric Disorders Among Adults of European Ancestry.

Importance: Tinnitus affects at least 16 million US adults, but its pathophysiology is complicated, and treatment options remain limited. A heritable component has been identified in family and twin studies; however, no large-scale genome-wide association studies (GWAS) have been accomplished. Objective: To identify genetic risk loci associated with tinnitus, determine genetic correlations, and infer possible relationships of tinnitus with hearing loss and neuropsychiatric disorders and traits. Design, Setting, and Participants: A GWAS of self-reported tinnitus was performed in the UK Biobank (UKB) cohort using a linear mixed-model method implemented in BOLT-LMM (linear mixed model). Replication of significant findings was sought in the nonoverlapping US Million Veteran Program (MVP) cohort. A total of 172 995 UKB (discovery) and 260 832 MVP (replication) participants of European ancestry with self-report regarding tinnitus and hearing loss underwent genomic analysis. Linkage-disequilibrium score regression and mendelian randomization were performed between tinnitus and hearing loss and neuropsychiatric disorders. Data from the UKB were acquired and analyzed from September 24, 2018, to December 13, 2019. Data acquisition for the MVP cohort was completed July 22, 2019. Data analysis for both cohorts was completed on February 11, 2020. Main Outcomes and Measures: Estimates of single nucleotide variation (SNV)-based heritability for tinnitus, identification of genetic risk loci and genes, functional mapping, and replication were performed. Genetic association and inferred causality of tinnitus compared with hearing loss and neuropsychiatric disorders and traits were analyzed. Results: Of 172 995 UKB participants (53.7% female; mean [SD], 58.0 [8.2] years), 155 395 unrelated participants underwent SNV-based heritability analyses across a range of tinnitus phenotype definitions that explained approximately 6% of the heritability. The GWAS based on the most heritable model in the full UKB cohort identified 6 genome-wide significant loci and 27 genes in gene-based analyses, with replication of 3 of 6 loci and 8 of 27 genes in 260 832 MVP cohort participants (92.8% men; mean [SD] age, 63.8 [13.2] years). Mendelian randomization indicated that major depressive disorder had a permissive effect (ß = 0.133; P = .003) and years of education had a protective effect (ß = -0.322, P = <.001) on tinnitus, whereas tinnitus and hearing loss inferred a bidirectional association (ß = 0.072, P = .001 and ß = 1.546, P = <.001, respectively). Conclusions and Relevance: This large GWAS characterizes the genetic architecture of tinnitus, demonstrating modest but significant heritability and a polygenic profile with multiple significant risk loci and genes. Genetic correlation and inferred causation between tinnitus and major depressive disorder, educational level, and hearing impairment were identified, consistent with clinical and neuroimaging evidence. These findings may guide gene-based diagnostic and therapeutic approaches to this pervasive disorder.

Prevalence of and Risk Factors for Tinnitus and Tinnitus-Related Handicap in a College-Aged Population.

OBJECTIVE: Tinnitus is a common otological condition that affects almost 10% of US adults. Research suggests that college students are vulnerable to tinnitus and hearing loss as they are exposed to traumatic levels of noise on a regular basis. Tinnitus and its influence in daily living continue to be underappreciated in the college-aged population. Therefore, the objective for the present study was to analyze prevalence and associated risk factors of tinnitus and tinnitus-related handicap in a sample of college-aged students. DESIGN: A survey was administered to 678 students aged 18-30 years in a cross-section of randomly selected university classes. The survey was adopted from the National Health and Nutrition Examination Survey (2010). It inquired about demographic details, medical and audiological history, routine noise exposure, smoking, sound level tolerance, tinnitus, and tinnitus-related handicap in daily living. Tinnitus-related handicap was assessed by the Tinnitus Handicap Inventory (THI). Participants were divided into four groups: chronic tinnitus (bothersome tinnitus for >1 year), acute tinnitus (bothersome tinnitus for ≤1 year), subacute tinnitus (at least one experience of tinnitus in a lifetime), and no tinnitus (no experience of tinnitus in a lifetime). RESULTS: The prevalence of chronic, acute, subacute, and no tinnitus was 8.4%, 13.0%, 37.9%, and 40.7% respectively. Almost 9% of subjects with any form of tinnitus reported more than a slight tinnitus-related handicap (i.e., THI score ≥18). A multinomial regression analysis revealed that individuals with high noise exposure, high sound level tolerance score, recurring ear infections, and self-reported hearing loss had high odds of chronic tinnitus. Females showed higher prevalence of acute tinnitus than males. Individuals with European American ethnicity and smoking history showed high odds of reporting subacute tinnitus. Almost 10% of the subjects reported that they were music students. The prevalence of chronic, acute, and subacute tinnitus was 11.3%, 22.5%, and 32.4%, respectively, for musicians, which was significantly higher than that for nonmusicians. Music exposure, firearm noise exposure, and occupational noise exposure were significantly correlated with tinnitus. Temporal characteristics of tinnitus, self-reported tinnitus loudness, and sound level tolerance were identified as major predictors for the overall THI score. CONCLUSIONS: Despite the reluctance to complain about tinnitus, a substantial portion of college-aged individuals reported tinnitus experience and its adverse influence in daily living. It was concluded that environmental and health-related factors can trigger tinnitus perception, while self-reported psychoacoustic descriptors of tinnitus may explain perceived tinnitus-related handicap in daily living by college-aged individuals. Future research is required to explore effects of tinnitus on educational achievements, social interaction, and vocational aspects of college students.