Tinnitus is a common phantom sensation resulting most often from sensory deprivation, and for which little knowledge on the molecular mechanisms exists. While the existing evidence for a genetic influence on the condition has been until now sparse and underpowered, recent data suggest that specific forms of tinnitus have a strong genetic component revealing that not all tinnitus percepts are alike, at least in how they are genetically driven. These new findings pave the way for a better understanding on how phantom sensations are molecularly driven and call for international biobanking efforts

Cederroth, Christopher R.

Kähler, Anna K.

Lopez-Escamez, Jose A.

Sullivan, Patrick F.

Frontiers in Genetics

English

Christopher R. Cederroth

Anna K. Kähler

Patrick F. Sullivan

Jose A. Lopez-Escamez

Crossref

Genetics of Tinnitus: Time to Biobank Phantom Sounds

Cederroth, Christopher R

Kähler, Anna K

Sullivan, Patrick F

Lopez-Escamez, Jose A

Fondo Bibliográfico Digital Institucional

Genetics of Tinnitus: Time to Biobank Phantom Sounds.

Carolina Digital Repository

fgene-08-00110 August 31, 2017 Time: 17:8 # 1PERSPECTIVEpublished: 04 September 2017doi: 10.3389/fgene.2017.00110Edited by:M. Geoffrey Hayes,Northwestern University,United StatesReviewed by:Srikantan S. Nagarajan,University of California,San Francisco, United StatesFernando Cendes,Universidade Estadual de Campinas,Brazil*Correspondence:Christopher R. Cederrothchristopher.cederroth@ki.seJose A. Lopez-Escamezantonio.lopezescamez@genyo.esSpecialty section:This article was submitted toApplied Genetic Epidemiology,a section of the journalFrontiers in GeneticsReceived: 10 July 2017Accepted: 09 August 2017Published: 04 September 2017Citation:Cederroth CR, Kähler AK,Sullivan PF and Lopez-Escamez JA(2017) Genetics of Tinnitus: Timeto Biobank Phantom Sounds.Front. Genet. 8:110.doi: 10.3389/fgene.2017.00110Genetics of Tinnitus: Time toBiobank Phantom SoundsChristopher R. Cederroth1*, Anna K. Kähler2, Patrick F. Sullivan2,3,4 andJose A. Lopez-Escamez5,6*1 Experimental Audiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden,2 Department of Molecular Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, 3 Department ofGenetics, University of North Carolina, Chapel Hill, NC, United States, 4 Department of Psychiatry, University of NorthCarolina, Chapel Hill, NC, United States, 5 Otology & Neurotology Group, Department of Genomic Medicine,Pfizer-Universidad de Granada-Junta de Andalucía Centre for Genomics and Oncology Research (GENyO), Granada, Spain,6 Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Virgen de las Nieves,Universidad de Granada, Granada, SpainTinnitus is a common phantom sensation resulting most often from sensory deprivation,and for which little knowledge on the molecular mechanisms exists. While the existingevidence for a genetic influence on the condition has been until now sparse andunderpowered, recent data suggest that specific forms of tinnitus have a strong geneticcomponent revealing that not all tinnitus percepts are alike, at least in how they aregenetically driven. These new findings pave the way for a better understanding on howphantom sensations are molecularly driven and call for international biobanking efforts.Keywords: tinnitus, genetics, heritability, subtype, neuropsychiatry, GWAS (genome-wide association study),whole exome sequencingPERSPECTIVEFor decades, tinnitus was considered a consequence of environmental factors, with low geneticcontribution. The numerous etiologies, such as aging (presbycusis), noise exposure, stress,hypertension, diabetes, ototoxic medications, temporomandibular joint disorders, traumatic orischemic damage, vascular problems, middle-ear problems, and the complex pathophysiologyinvolving peripheral and central auditory and non-auditory structures, have led to the belief thattinnitus is a consequence of some other disease.The knowledge on the genetic basis of tinnitus was recently reviewed (Vona et al., 2017)and phenotyping strategies have been proposed based on the assumption that tinnitus should beconsidered as an ensemble of sub-entities called subtypes (Lopez-Escamez et al., 2016). A smallfamilial aggregation study (n= 198 families) found no obvious heritability (Hendrickx et al., 2007),and the first large population-based family study (n = 52,045) made an estimate of heritability of0.11 (Kvestad et al., 2010). But a recent twin study revealed a higher heritability of 0.4, indicatingthat a larger fraction of the variance can be due to genetic variants than previously reported (Bogoet al., 2016). Such discrepancies may originate from differences in the design and formulationof the questionnaires, which have been found to vary greatly in prevalence studies on tinnitus(McCormack et al., 2016).The tinnitus phenotype could also be grounds for diverging heritability values, butwhat defines a tinnitus phenotype is highly debated. We indeed consider that a moreprecise definition of a homogeneous phenotype will be essential in the design of geneticstudies. A larger twin study performed by members of the TINNET1 consortium recently1http://tinnet.tinnitusresearch.net/Frontiers in Genetics | www.frontiersin.org 1 September 2017 | Volume 8 | Article 110fgene-08-00110 August 31, 2017 Time: 17:8 # 2Cederroth et al. Biobanking Tinnitusconsidered the laterality of tinnitus as a potential genetic subtype(Maas et al., 2017). A key finding was that bilateral tinnitushad higher heritability than unilateral tinnitus. The study wasbased on self-reported data from the Swedish Twin Registry, oneof the largest twin registries in the world (Lichtenstein et al.,2002, 2006; Pedersen et al., 2002; van Dongen et al., 2012).Of a total of 70,186 twins that answered questions related totinnitus, 15% of them experienced tinnitus. 10,464 concordantor discordant pairs for tinnitus were identified, in which 6,990subjects had tinnitus. When considering tinnitus as a whole,a moderate genetic contribution (near 40%) was found (Bogoet al., 2016). However, when twins were stratified – based ontinnitus experienced in one ear (unilateral) or in both ears(bilateral) as well as on gender – bilateral tinnitus reached aheritability of 0.68 in men (Maas et al., 2017). Such valuesare close to the levels of heritability for schizophrenia andattention deficit hyperactive disorder (ADHD), two well knownheritable conditions (Table 1). Although more work is requiredfor establishing the contribution of hearing loss in such highheritability values (e.g., by including exhaustive auditory data),these findings open the possibility of specific forms of tinnitusbeing more genetically driven than others and pave the wayfor future genetic studies considering subtypes. These findings,however, need to be replicated in other twin cohorts as well asfamilial studies.In line with genetic association studies of other complextraits, published studies to find genetic markers for chronictinnitus patients in candidate genes have been underpowered(n = 95–288) and failed to identify robustly associated geneticvariants (Sand et al., 2010, 2011, 2012a,b; Gallant et al.,2013). In spite of a lowly powered tinnitus group (N = 167)and no significant associations found, a recent genome-wideassociation study (GWAS) identified some pathways (e.g.,TABLE 1 | Classification of tinnitus heritability against other disorders.Trait Heritability Number of Twin pairsDiabetes, type 1 0.88 22 650Schizophrenia 0.81 Meta-analysisADHD 0.76 ReviewAutism 0.71 11 535Bilateral tinnitus (men) 0.68 10 464Diabetes, type 2 0.64 13 888Coronary heart disease 0.57 10 483Alzheimer’s disease 0.48 662Any tinnitus 0.43 10 464Prostate cancer 0.42 21 000Systolic blood pressure 0.42 1 617Bilateral tinnitus (women) 0.41 10 464Colorectal cancer 0.35 44 788Parkinson’s disease 0.34 46 436Breast cancer 0.27 23 788Unilateral tinnitus 0.27 10 464MS 0.25 ReviewModified from van Dongen et al. (2012) with permission from the Nature PublishingGroup. Tinnitus values are marked in red.oxidative stress, endoplasmatic reticulum stress, and serotoninreception mediated signaling) potentially involved in tinnitus(Gilles et al., 2017). Supporting the need of better characterizingthe tinnitus cases, Pawelczyk and colleagues investigated 99single nucleotide polymorphisms targeting 10 genes involved inthe potassium recycling pathway in the inner ear (128 tinnituscases and 498 controls both exposed to occupational noise)(Pawelczyk et al., 2012). However, two of the identified SNPswere not subjected to multiple testing and were thus considerednominally significant. An important lesson from GWAS onother complex traits, such as schizophrenia and major depressivedisorder (Sullivan et al., in press), is that far larger sample sizesare needed in order to identify genome-wide significant geneticvariants. Therefore, an important next step in the search forgenetic variants associated with tinnitus will be to perform jointGWAS analysis of thousands of tinnitus patients and healthycontrols.Since familial tinnitus is a rare condition, the selection ofmultiplex tinnitus families, in addition to unrelated cases andcontrols, for exome sequencing, is another potential strategyto be used for the discovery of genes involved in tinnitus.This strategy has been successful in the identification of DTNA,PRKCB, SEMA3D and DPT in autosomal dominant Menieredisease (Requena et al., 2015; Martin-Sierra et al., 2016, 2017).With tinnitus being a condition with highly unmet clinicalneeds (Cederroth et al., 2013), the recent identification of a highheritability opens door to exciting research. Since it is more thanlikely that tinnitus is a polygenic trait and it will require thestudy of several thousand samples, audiologists and ENT doctorsshould optimize their phenotyping strategies for instance byusing high frequency audiometry and multivariate questionnairedata (Muller et al., 2016; Schlee et al., 2017), initiate incentivesto allocate a specific ICD-code for bilateral tinnitus, and startbiobanking samples (Lopez-Escamez et al., 2016). Regarding thelatter, since it is not custom for an ENT clinic to collect samplesfor DNA biobanking, guidelines should emerge to promote goodpractice (Fuller et al., 2017) and enable the creation of a largeconsortium to join efforts to decipher the genetic basis of tinnitus.AUTHOR CONTRIBUTIONSCC conceived the paper and prepared the table. CC co-wrotethe paper with JL-E. AK and PS helped to develop the scientificarguments. All authors played a role in writing the manuscriptand approved the final version.FUNDINGCC has received funding from Tysta Skolan, KarolinskaInstitutet, Lars Hiertas Minne, Magnus Bergvalls Stiftelserna,Hörselforskningsfonden, and Loo och Hans Ostermans. Thework was supported by an independent research programfunded under the Biomedicine and Molecular BiosciencesEuropean Cooperation in Science and Technology (COST)Action framework (TINNET BM1306).Frontiers in Genetics | www.frontiersin.org 2 September 2017 | Volume 8 | Article 110fgene-08-00110 August 31, 2017 Time: 17:8 # 3Cederroth et al. Biobanking TinnitusREFERENCESBogo, R., Farah, A., Karlsson, K. K., Pedersen, N. L., Svartengren, M., andSkjonsberg, A. (2016). Prevalence, incidence proportion, and heritability fortinnitus: a longitudinal twin study. Ear Hear. 38, 292–300. doi: 10.1097/AUD.0000000000000397Cederroth, C. R., Canlon, B., and Langguth, B. (2013). Hearing loss and tinnitus–are funders and industry listening? Nat. 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K., Langguth, B., Canlon, B., and Cederroth, C. R.(2017). Visualization of global disease burden for the optimization of patientmanagement and treatment. Front. Med. 4:86. doi: 10.3389/fmed.2017.00086Sullivan, P. F., Agrawal, A., Bulik, C. M., Andreassen, O. A., Børglum, A. D., Breen,G., et al. (in press). Psychiatric genomics: an update and an agenda. Am. J.Psychiatry.van Dongen, J., Slagboom, P. E., Draisma, H. H., Martin, N. G., and Boomsma, D. I.(2012). The continuing value of twin studies in the omics era. Nat. Rev. Genet.13, 640–653. doi: 10.1038/nrg3243Vona, B., Nanda, I., Shehata-Dieler, W., and Haaf, T. (2017). Genetics of tinnitus:still in its infancy. Front. Neurosci. 11:236. doi: 10.3389/fnins.2017.00236Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2017 Cederroth, Kähler, Sullivan and Lopez-Escamez. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense (CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) or licensor are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Genetics | www.frontiersin.org 3 September 2017 | Volume 8 | Article 110

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