Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus

Area of Science:

• Genetics
• Neuroscience
• Audiology

Background:

• Tinnitus, a phantom auditory perception affecting 15% of the population, is often linked to hearing and brain disorders.
• The contribution of structural variants (SVs) to tinnitus, particularly in severe cases, remains under-explored.
• Severe tinnitus patients often exhibit higher rates of hyperacusis, hearing loss, and anxiety.

Purpose of the Study:

• To investigate the role of rare single nucleotide variants (SNVs), large structural variants (LSVs), and copy number variations (CNVs) in Swedish individuals with chronic tinnitus.
• To perform gene enrichment analysis in patients with severe tinnitus (SEVTIN) and a broader chronic tinnitus cohort (TIGER).
• To replicate findings using an independent exome sequencing dataset (JAGUAR cohort) and population controls (SweGen, gnomAD).

Main Methods:

• Whole-genome sequencing was performed on 97 unrelated Swedish individuals with chronic tinnitus (TIGER cohort).
• Gene enrichment analysis was conducted for SNVs, LSVs, and CNVs in TIGER and SEVTIN cohorts.
• Exome sequencing data from 147 Swedish tinnitus patients (JAGUAR cohort) were used for replication, with comparisons to population-specific control datasets.

Main Results:

• An enrichment of rare missense variants was observed in high-constraint genes in both SEVTIN (6 genes) and TIGER (8 genes) cohorts.
• The CACNA1E gene showed an enrichment of missense variants in both SEVTIN and TIGER cohorts.
• Replication analysis in the JAGUAR cohort revealed a burden of missense variants in 9 high-constrained genes, including NAV2, compared to non-Finnish European controls (NFE).
• LSVs overlapping CACNA1E, NAV2, and TMEM132D genes were identified in the TIGER and SEVTIN cohorts.

Conclusions:

• Rare missense variants in high-constraint genes, including CACNA1E and NAV2, are associated with chronic and severe tinnitus.
• Structural variants in constrained genomic regions, particularly those involving CACNA1E, NAV2, and TMEM132D, may contribute to tinnitus pathophysiology.
• These findings highlight the potential of genetic investigations in understanding the underlying mechanisms of tinnitus.