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

Abstract

Tinnitus is the phantom percept of an internal non-verbal set of noises and tones. It is reported by 15% of the population and it is usually associated with hearing and/or brain disorders. The role of structural variants (SVs) in coding and non-coding regions has not been investigated in patients with severe tinnitus. In this study, we performed whole-genome sequencing in 97 unrelated Swedish individuals with chronic tinnitus (TIGER cohort). Rare single nucleotide variants (SNV), large structural variants (LSV), and copy number variations (CNV) were retrieved to perform a gene enrichment analysis in TIGER and in a subgroup of patients with severe tinnitus (SEVTIN, n = 34), according to the tinnitus handicap inventory (THI) scores. An independent exome sequencing dataset of 147 Swedish tinnitus patients was used as a replication cohort (JAGUAR cohort) and population-specific datasets from Sweden (SweGen) and Non-Finish Europeans (NFE) from gnomAD were used as control groups. SEVTIN patients showed a higher prevalence of hyperacusis, hearing loss, and anxiety when they were compared to individuals in the TIGER cohort. We found an enrichment of rare missense variants in 6 and 8 high-constraint genes in SEVTIN and TIGER cohorts, respectively. Of note, an enrichment of missense variants was found in the CACNA1E gene in both SEVTIN and TIGER. We replicated the burden of missense variants in 9 high-constrained genes in the JAGUAR cohort, including the gene NAV2, when data were compared with NFE. Moreover, LSVs in constrained regions overlapping CACNA1E, NAV2, and TMEM132D genes were observed in TIGER and SEVTIN.

A Systematic Review on the Genetic Contribution to Tinnitus

“…Seventeen genetic studies were included [ 8 , 9 , 35 – 49 ], with a global sample size of 294,143 subjects (45.4% males), and 55,267 patients with tinnitus (18.8% males).…”

“…All the studies included reported no significant differences in terms of age between subgroups. Three studies excluded patients with SNHL [ 36 , 42 , 47 ], two studies reported no significant differences in audiograms between tinnitus and control subjects [ 39 , 40 ], six studies included subjects with some degree of hearing impairment, including SNHL [ 8 , 37 , 45 , 49 ], presbycusis [ 35 ], or noise-induced hearing loss [ 41 ], and the rest of them failed to report information on hearing stage [ 9 , 38 , 43 , 44 , 46 , 48 ].…”

Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery

“…The pipeline has been used within the field of cancer research ( 22–27 ) and beyond, such as the identification of rare variants in tinnitus patients ( 28 ), finding SNPs in driver genes related to stress-response in cowpeas ( 29 ), the genomic profiling of wild and commercial bumble bee populations ( 30 ), or the Personal Genome Project-UK ( 31 ).…”

Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery

“…The pipeline has been used within the field of cancer research [22][23][24][25][26][27] and beyond, such as the identification of rare variants in tinnitus patients [28], finding SNPs in driver genes related to stress-response in cowpeas [29], the genomic profiling of wild and commercial bumble bee populations [30], or the Personal Genome Project-UK [31].…”

“…The pipeline has been used within the field of cancer research [22–27] and beyond, such as the identification of rare variants in tinnitus patients [28], finding SNPs in driver genes related to stress-response in cowpeas [29], the genomic profiling of wild and commercial bumble bee populations [30], or the Personal Genome Project-UK [31]. Here, we present a re-implementation of the nf-core/sarek pipeline using the Nextflow DSL2 framework, an extension of the Nextflow syntax allowing to develop pipelines in a modular fashion, which increases user-based customization to maintain a modern pipeline.…”