Table 2.
Summary of the main findings in the genetic association studies obtained
| Reference | Country | Design | Genes | Main objective | Sample size | Sex (male/female) | Average age (years) | Tinnitus prevalence | SNHL prevalence | Results | Replication |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Amanat et al. [8] | Spain | WES | ANK2, TSC2, AKAP9 | To identify rare variants in synaptic genes by exome sequencing in patients with severe tinnitus | n = 91; cases: 59; controls: 32 | Cases: 42 M–17F; controls: unknown; replication cohort (cases: 42 M–55F; controls: unknown) | N/A | Cases: 100% (persistent tinnitus); controls: 0% (fluctuating tinnitus) |
Reference cohort: N/A Replication cohort: 64% |
Enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort (more significant in PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E − 04)), compared with reference datasets. It was replicated for ANK2 in a Swedish cohort, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 (p < 2E − 02). This association was not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus |
Yes Independent WGS Swedish cohort (TIGER) n = 97 Cases: 34; controls: 63 Independent epilepsy WES cohort (CoGIE) n = 701 Cases: 152 Control: 549 |
| Bhatt et al. [48] | USA | Panel | KCNQ1, KCNE1 | To examine the relationship between selected genetic variants and measures of tinnitus in a sample of young musicians | n = 186; cases: 106; controls: 80 | Cohort: 99 M–87F | 20.3 | Cases: 100%; controls: 0% | N/A | Individuals with at least one minor allele of rs163171 (C > T) in KCNQ1 exhibit significantly higher odds of reporting tinnitus compared to individuals carrying the major allele of rs163171. KCNE1 rs2070358 revealed a suggestive association (p = 0.049) with tinnitus, but the FDR corrected p-value did not achieve statistical significance (p < 0.05) | No |
| Bhatt et al. [9] | UK | GWAS | GPM6A | To conduct a GWAS analysis in the UK Biobank, adjusting for known environmental risk factors, and interrogating the genetic underpinnings of tinnitus-related distress | n = 132,438; cases: 38,525; controls: 93,013 | Cohort: 61,646 M–70,792F | 40– > 70 | Cases: 100%; controls: 0% | N/A | A genomic region containing SNP (rs71595470) near GPM6A revealed a significant association with tinnitus, and 19 SNPs showed suggestive associations with tinnitus. Fifteen SNPs showed association with tinnitus-related distress. The enrichment analysis with FUMA identified 23 gene sets associated with tinnitus | No |
| Gallego-Martinez et al. [49] | Sweden | WGS | CACNA1E, NAV2, TMEM132D | To explore the association of rare single-nucleotide variants (SNVs), large structural variations (LSVs), and copy number variants (CNVs) in the genome of Swedish patients with severe tinnitus | n = 97 (TIGER cohort) |
TIGER cohort: 43 M–54F; Replication cohort: 146 M–152F |
46 ± 12.86 (TIGER cohort) 47 ± 11.52 (replication cohort) |
100% (TIGER cohort) 72.2% (replication cohort) |
64% (TIGER cohort; 79% in severe tinnitus cohort) 56% (replication cohort) |
Enrichment of rare missense variants in 6 and 8 high-constraint genes in SEVTIN and TIGER cohorts, respectively. There is also an enrichment of missense variants in the CACNA1E in both SEVTIN and TIGER. The burden of missense variants was replicated in 9 high-constrained genes in the JAGUAR cohort, including the NAV2, compared with NFE. Moreover, LSVs in constrained regions overlapping CACNA1E, NAV2, and TMEM132D were observed in TIGER and SEVTIN |
Yes Independent Swedish WES cohort (JAGUAR) n = 298; cases: 143; control: 155 |
| Haider et al. [35] | Portugal | Genotyping Cohort vs reference population | GRM7 | To study the relationships between presbycusis, tinnitus, co-morbidities, and the genotypes of GRM7 and NAT2, in a sample of older Portuguese adults | n = 78 | 33 M–45F | 64.6 (± 5.58) | 64.1%, 24% (severe tinnitus) | 24% | For GRM7 gen, individuals with a T/T genotype have a higher risk for age-related HL and 33% lower risk for tinnitus, compared to individuals with A/A and A/T genotype, respectively. Allele AT of GRM7 can have a statistically significant influence toward the severity of tinnitus | No |
| Jeong et al. [36] | South Korea | Genotyping Case–control study | BDNF, HTTLPR | To investigate the association of BDNF Val66Met or 5-HTTLPR polymorphisms with tinnitus and the mediating effects of psychological distress |
n = 338 Cases: 86; controls: 252 |
Cases: 41 M–45F; controls: 132 M–120F | Cases: 53.5 ± 13.7; controls: 53.1 ± 10.4 | Cases: 100%; controls: 0% | SNHL patients were excluded | No association were found between groups regarding BDNF Val66Met (p = 0.142) and 5-HTTLPR (p = 0.054). The mean THI score was significantly higher in patients with the s/s genotype (47.9 (18.9)) than in those with l/s or l/l genotype (38.2 (25.5)) of 5-HTTLPR (p = 0.024) | No |
| Lechowicz et al. [37] | Poland | MiDNA sequencing Case–control study | Mitochondrial genes | To investigate the prevalence of tinnitus among Polish HL patients with identified pathogenic mtDNA variants | n = 114; cases: 17; controls: 97 | Cases: 7 M–10F; controls: N/A | N/A | Cases: 17.6%; control: 100% | Cases: 100%; controls: 69% | There were no statistically significant differences in the prevalence of tinnitus between HL patients with mtDNA variants and the general Polish population. There were no statistically significant differences in tinnitus annoyance (VAS-A) between al the subgroups of tinnitus patients. In Polish HL patients with tinnitus, m.7511 T > C was significantly more frequent than in patients without tinnitus (p = 0.0441) | No |
| Orenay-Boyacioglu et al. [38] | Turkey | Genotyping case–control study | GDNF | To investigate the role of GDNF polymorphisms in tinnitus pathophysiology | n = 94; cases: 52; controls: 42 | Cases: 33 M–19F; controls: 29 M–13F | Cases: 43.6 ± 10.7; controls: 39.3 ± 9.8 | Cases: 100%; controls: 0% | N/A | No association was found for rs884344 and rs3812047 and subjects with tinnitus. Heterozygosity was significantly lower for GDNF rs1110149 polymorphism in tinnitus subjects compared to the controls (p = 0.02) | No |
| Orenay-Boyacioglu et al. [44] | WGBS specific regions | BDNF, GDNF |
To study the relationship between the promotor methylation of BDNF and GDNF genes and chronic tinnitus in peripheral blood samples |
n = 110; cases: 60; controls: 50 | Cases: 39 M–21F; controls: 31 M–19F | Cases: 36.5 (21–52); controls: 38.5 (23–54) | Cases: 100%; controls: 0% | N/A | Statistically significant differences were detected between BDNF CpG6 and GDNF CpG3-5–6 methylation ratios in the comparison of control group and the chronic tinnitus patients (p = 0.002, 0.0005, 0.00003, and 0.0029, respectively) | No | |
| Rottenberg et al. [45] | Slovenia | Genotyping case–control study | GABA(A) beta-3 subunit gene | To explore associations between manifestation of tinnitus, auditory evoked potentials and genetic background of gamma-aminobutyric acid type A (GABA(A) receptors) to support the disinhibited feedback hypothesis of tinnitus generation | n = 131 | Cohort: 61 M–71F | Cohort: 52 ± 13.8 | Cohort: 100% | Cohort: 100% | Statistically significant difference in the tinnitus score in relation to the genotype of (CA)n tandem repeat of the GABRß3 receptor subunit gene (p = 0.002) | No |
| Urbanek et al. [47] | UK | GWAS | WDPCP | To define underlying genes that may preclude tinnitus, through a GWAS in the UK Biobank | n = 23,742; cases: 526; control: 19,047 | Cases: 226M300F; controls: 7315 M–11,732F | 40–70 | Cases: 100%; controls: 0% | Self-reported SNHL patients were excluded | Seventeen suggestive SNP (p < 1e − 5) spanning 13 genes were identified in two sex-separated cohorts reporting chronic, bothersome tinnitus. A significant missense mutation in WDPCP (p = 3.959e − 10) was identified in the female cohort | No |
| Vanneste et al. [39] | USA | Genotyping case–control study | COMT | To study the role of COMT polymorphisms in the activity in the ventromedial PFC/anterior cingulate cortex and its effect on tinnitus perception | n = 60; cases: 40; controls: 20 | Cases: 28 M–12F; controls: 13 M–7F | Cases: 45.97 ± 14.19; controls: 45.6 ± 16.27 | Cases: 100%; controls: 0% | No significant differences in audiograms between healthy controls and tinnitus patients | An interaction between the SNHL degree and the COMT Val158Met polymorphism can increase susceptibility to the clinical manifestation of tinnitus (loudness). No significant was observed in THI scores between the Val/Val genotype and Met carriers | No |
| Vanneste et al. [40] | USA | Genotyping case–control study | BDNF | To study the effect of BDNF Val/Met carriers and Val-homozygotes and perception of distress due to tinnitus | n = 110; cases: 55; controls: 55 | Cases: 38 M–17F; controls: 36 M–19F | Cases: 54.49 ± 15.3; controls: 54.63 ± 12.7 | Cases: 100%; controls: 0% | No significant differences in audiograms between healthy controls and tinnitus patients | Val/Met carriers have a higher stress level in comparison to Val homozygotes (controls: F(1,106) = 66.97, p < 0.001; cases: F(1,106) = 54.68, p < 0.001). For the tinnitus group, we further show that there is a significant effect between Val homozygotes and Val/Met carriers for tinnitus-related distress (F(1,53) = 8.45, p = 0.005) | No |
| Watabe et al. [43] | Japan | Genotyping case–control study | BCR | To study the association between the grade of tinnitus distress and the genetic background, to identify prognostic markers | n = 138 | Cohort: 59 M–79F | Cohort: 61.3 ± 13.1 | Cohort: 100% | N/A | rs131702 of BCR is independent of depression in this study and is, therefore, a prognostic factor unique to tinnitus | No |
| Wells et al. [46] | UK | GWAS | RCOR1 | To conduct a GWAS analysis using self-reported tinnitus in the UK Biobank | n = 134,429; cases: 14,829; controls: 119,600 | Not defined | N/A | Cases: 100%; controls: 0% | N/A | Three variants in close proximity to the RCOR1 gene reached genome wide significance: rs4906228 (p = 1.7E − 08), rs4900545 (p = 1.8E − 08) and 14:103042287_CT_C (p = 3.50E − 08) | No |
| Xie et al. [41] | China | GWAS | TNFRSF1A | To identify novel loci related to the risk of noise-induced tinnitus in the Chinese population | n = 298; cases: 65; controls: 233 | 100% males | Cases: 23.8 (1.6 SD); controls: 23.4 (1.6 SD) cases: 26.4 (3.9 SD)* controls: 24.5 (2.9 SD)* | Cases: 100%; controls: 0% | Cases: 100%; controls: 0% (noise exposure 100% subjects) | Two SNVs: rs2846071 (OR = 2.14 (1.96–3.4), combined p = 4.9 × 10−6); rs4149577 in the intron of TNFRSF1A gene at 12p13.31 (OR = 2.05 (1.9–2.51), combined p = 6.9 × 10−6), are associated to noise-induced tinnitus |
Yes Independent case and control cohort n = 413 Cases: 34; control: 379 |
| Yüce et al. [42] | Turkey | Genotyping case–control study | ACE; ADD1 | To investigate the relationship between severe chronic tinnitus and angiotensin-converting enzyme (ACE) I/D and α-adducin (ADD1) G460W gene polymorphisms | n = 193; cases: 89; control: 104 | Cases: 41 M–48F; controls: 54 M–50F | Cases: 48.1 ± 13.5; controls: 45 ± 16 | Cases: 100% (severe tinnitus); controls: 0% | SNHL patients were excluded | Combined genotype frequencies for both ACE and ADD1 allelic variants were higher in the patient group than in the control group (p = 0.007) | No |
NFE non-Finnish European, (SN)HL (sensorineural) hearing loss