RT Journal Article
T1 Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus
A1 Gallego-Martinez, Alvaro
A1 Escalera-Balsera, Alba
A1 Trpchevska, Natalia
A1 Robles-Bolivar, Paula
A1 Roman-Naranjo, Pablo
A1 Frejo, Lidia
A1 Perez-Carpena, Patricia
A1 Bulla, Jan
A1 Gallus, Silvano
A1 Canlon, Barbara
A1 Cederroth, Christopher R. R.
A1 Lopez-Escamez, Jose A. A.
K1 Joint consensus recommendation
K1 Structural variants
K1 Mammalian homolog
K1 Medical genetics
K1 American-college
K1 Association
K1 Mechanisms
K1 Guidelines
K1 Standards
K1 Framework
AB 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.
PB Nature portfolio
PB Nature Publishing Group
YR 2022
FD 2022-11-18
LK http://hdl.handle.net/10668/19555
UL http://hdl.handle.net/10668/19555
LA en
NO Gallego-Martinez A, Escalera-Balsera A, Trpchevska N, Robles-Bolivar P, Roman-Naranjo P, Frejo L, et al.  Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus. NPJ Genom Med. 2022 Nov 30;7(1):70.
NO This study was partially funded by GNP-182 GENDER-Net Co-Plus Fund including supportfrom “La Caixa” Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002and H2020-SC1-2019-848261 (JALE and CRC). JALE and CRC also received additionalsupport from the European Union’s Horizon 2020 Research and Innovation Programme, Grant Agreement No 848261 and the European Union’s Horizon 2020 research andinnovation program under the Marie Skłodowska-Curie grant agreement No 722046. CRCreceived additional funding from Svenska Läkaresällskapet (SLS-779681), Hörselforskningsfonden (503), Tysta Skolan and Forschung Für Leben. JALE has received fundsfrom Andalusian Goverment (CECEU 2020, grant code: DOC_01677). LF has receivedfunds from Sara Borrell postdoctoral Fellowship (ISCIII; grant code: CD20/00153). PPC hasreceived funds from the Andalusian Health Government (CSyF 2020 POSTDOC, Grantcode: RH-0150-2020). The computations and data handling were enabled by resourcesprovided by the Swedish National Infrastructure for Computing (SNIC) at SNIC/UPPMAXpartially funded by the Swedish Research Council through grant agreement no. 2018-05973. We are indebted to Nancy Pedersen for sharing DNA material from LifeGene.
DS RISalud
RD Apr 11, 2025