A groundbreaking study in 'Nature Communications' deciphers genetic roots of tinnitus, uncovering 29 new gene locations. Insights into synaptic areas and GABA receptors suggest potential treatments, while distinctions from hearing loss and links to broader health issues redefine our understanding of tinnitus and offer new avenues for precise therapies.
A new groundbreaking study by an international group of scientists involving more than a half-million individuals has provided important insights into the genetic foundations of tinnitus.1 Its findings not only validate existing theories about why tinnitus occurs but also open new avenues for understanding the distinct genetic architecture of tinnitus and potential connections to broader health issues.
A general axiom in clinical audiology regarding tinnitus is the 80/80 rule: about 80% of people with hearing loss have tinnitus (ringing in the ears), and about 80% of people with tinnitus have hearing loss. While it seems clear that hearing loss and tinnitus are related, the multiple factors surrounding their relationship have remained murky.
Published in the January 19 edition of Nature Communications, the new study involves a genome-wide association study (GWAS) on 596,905 participants from the Million Veteran Program. Newly identified were 29 tinnitus gene locations (loci), adding to the 8 loci previously reported in the UK Biobank. Including Latinx and African ancestries in the cross-ancestry GWAS uncovered 9 additional new loci.
Loss of inhibition in nerve cell activity and potential therapeutic targets
From the new research, multiple genes were found to relate to synaptic areas—the connections where electrical signals move from one nerve cell to another. This aligns with previous theories about “hidden hearing loss,” tinnitus, and injury to the main hearing organ of the inner ear, the cochlea. Broadly, hidden hearing loss relates to the integrity of the synapses in addition to the health of the cochlea’s hair cells when assessing and treating hearing disorders.
The proper functioning of nerve cells is vital for carrying auditory information about intensity and timing to the brain's processing centers, where it is interpreted as sound.
A gene called GRK6 that controls “GABA receptors” emerged as a potential key player. GABA (gamma-aminobutyric acid) is a kind of brake pedal for cell signaling; when GABA is present, it's like applying the brakes on a car, inhibiting the speed and preventing neurons from firing too rapidly or excessively. When GABA levels are reduced, the "release of inhibition" contributes to increased spontaneous activity, bursting, and enhanced sound-evoked response. The GRK6 gene is associated with reduced GABA levels and reduced inhibitory neurotransmission in the auditory cortex and thus may play a role in tinnitus.
This new data could help inform future directions in pharmaceutical research for treating tinnitus. Drug-class analysis indicates it could be possible to target the enrichment of GABA receptors. The study also suggests dopamine receptors, which are also controlled by the GRK6 gene, may provide new therapeutic avenues. A greater understanding of the role of these receptors could pave the way for interventions that target the restoration of the excitatory-inhibitory balance—and help reduce or even eliminate tinnitus symptoms.
However, the study’s lead author, Royce Clifford, MD, of the Veterans Affairs San Diego Healthcare System and University of California San Diego, is quick to caution that more research is needed since the findings are based primarily on computer modeling.
“It must be emphasized that although the data points to genes like GRK6 and others, it hasn't been proven,” Dr. Clifford told Hearing Tracker. “These are suggestions based on the evidence, but it's important to know [the conclusions are] pretty much all ‘in silico,’ suggested by evidence and computations.” She also noted some GABA receptor drugs have been tested in the cochlea, and some are even in clinical trials.
Distinguishing tinnitus from hearing loss
In the study, about half of those with tinnitus had hearing difficulty as judged through diagnosis or self-report. Despite the high correlation between tinnitus and hearing loss, advanced statistical techniques used in the study revealed distinct differences in their genetic architecture.
Tinnitus differentiated itself from hearing loss by involving more genes and having genetic variants with lower discoverability, challenging previous assumptions that genes involving hearing loss and tinnitus are the same. The study found that of the 4,100 single nucleotide polymorphisms (SNPs) predicted to be implicated in hearing loss, 3,900 (95%) are shared with tinnitus, and only 200 are unique to hearing loss. In contrast, of the 9,500 SNPs suggested to cause tinnitus, 5,600 (59%) are unique to tinnitus.
Tissue expression analyses of the brain also highlight the separation between tinnitus and hearing loss, with tinnitus genes showing broader expression across multiple brain areas. This supports the idea that tinnitus has its source and perception within a wider brain network, contrasting with the more localized focus of hearing loss within the cochlea or auditory cortex. Changes in gray and white matter, magnetoencephalography findings, and alterations in the default mode network further emphasized the intricate neural networks involved in tinnitus.
Correlations with psychiatric and health traits
The study also explored correlations between tinnitus and psychiatric and health-related traits, revealing significant associations with self-reported hearing loss, speech understanding, pain syndromes, wellness measures, and internalizing disorders.
These findings suggest a meaningful relationship between tinnitus and psychological distress shared with subjective wellbeing and neuroticism, as well as moderate associations with other health factors, particularly physical distress, and headache.”— Clifford, Maihofer, Chatzinakos, et al.
In total, the findings may provide a better framework for understanding tinnitus as a multifaceted condition with potential connections to broader health issues, while expanding the genetic exploration of the disorder. The identified loci, genetic correlations, and associated traits could lay the groundwork for future precision therapies tailored to the unique aspects of tinnitus.
Additionally, the discovery of genes involved in excitatory-inhibitory balance and the new tissue analysis shed new light on tinnitus—validating existing theories about hidden hearing loss while also presenting opportunities for innovative interventions that could bridge the gap between genetic insights and clinical applications. Although much more work needs to be done, tinnitus, once enigmatic, is now under real genetic scrutiny, bringing hope for more effective and targeted treatments.
- Clifford RE, Maihofer AX, Chatzinakos C, Coleman JRI, Daskalakis NP, Gasperi M, Hogan K, Mikita EA, Stein MB, Tcheandjieu C, Telese F, Zuo Y, Ryan AF, Nievergelt CM. Genetic architecture distinguishes tinnitus from hearing loss. Nat Commun. 2024;15:614. https://doi.org/10.1038/s41467-024-44842-x