Environmental and genetic risk factors for tinnitus

Tinnitus is a phantom auditory sensation, most often referred to as “ringing in the ears” with detrimental effect on quality of life. Between 4% and 37% of the global population has experienced tinnitus at some point in their life. For every 1 out of 10 individuals experiencing tinnitus, it becomes a severely impactful condition, affecting concentration, sleep, mood, and general quality of life. Despite its high prevalence and severe socio-economic burden, there is no successful treatment.

The work presented in this thesis uses multiple scientific approaches to better understand the etiology of tinnitus, with the emphasis on the genetic landscape in order to gain insight into its molecular origins.

First, we identify important gaps in knowledge on environmental risk factors associated with tinnitus. Second, we show using genetic epidemiology methods that severe tinnitus runs in families, which changes the current narrative that tinnitus would be generated purely due to environmental factors. Third, as tinnitus is commonly linked to hearing loss, we used a genome-wide biostatistical approach to reveal the genetic architecture of hearing loss, that will be further essential in distinguishing the two conditions. Fourth, we investigated the whole genome in relation to tinnitus to map correlated genomic regions and consequently, specific genes associated with tinnitus. Finally, we used a high-throughput sequencing of protein coding regions of the genome to identify disease-causing mutations impacting severe tinnitus.

The work presented in this thesis provides insights from multiple aspects into the origins of tinnitus and will serve as a backbone to understanding the pathophysiology of the disorder.

List of scientific papers

I. Biswas R*, Genitsaridi E*, TRPCHEVSKA N*, Lugo A, Akeroyd MA, Cederroth CR, Schlee W, Gallus S, Hall DA. Low evidence for tinnitus risk factors: A systematic review and meta-analysis. *These authors contributed equally. [Manuscript]

II. TRPCHEVSKA N, Bulla J, Hellberg PM, Edvall KN, Lazar A, Mehraei G, Uhlen I, Schlee W, Canlon B, Gallus S, Lopez-Escamez JA, Cederroth RC. Sex-Dependant Aggregation of Tinnitus in Swedish Families. J Clin Med. 2020 Nov 25;9(12):3812.
https://doi.org/10.3390/jcm9123812

III. Cederroth CR, PirouziFard MN, TRPCHEVSKA N, Idrizbegovic E, Canlon C, Sundquist J, Sundquist K, Zöller B. Association of Genetic vs Environmental Factors in Swedish Adoptees with Clinically Significant Tinnitus. JAMA Otolaryngol Head Neck Surg. 2019 Mar 1;145(3):222-229.
https://doi.org/10.1001/jamaoto.2018.3852

IV. TRPCHEVSKA N, Scarcella D, Edvall NK, Lazar A, Uhlén I, Canlon B, Cederroth CR. Lack of involvement of COMT Val158Met polymorphism in tinnitus severity. [Manuscript]

V. TRPCHEVSKA N*, Freidin MB*, Broer L*, Oosterloo BC, Yao S, Zhou Y, Vona B, Bishop C, Bizaki-Vallaskangas A, Canlon B, Castellana F, Chasman DI, Cherny S, Christensen K, Concas MP, Correa A, Elkon R, Estonian Biobank Research Team, Mengel-From J, Gao Y, Giersch ABS, Girotto G, Gudjonsson A, Gudnason V, Heard-Costa NL, Hertzano R, Hjelmborg JvB, Hjerling-Leffler J, Hoffman HJ, Kaprio J, Kettunen K, Krebs K, Kähler AK, Lallemend F, Launer JL, Lee IM, Leonard H, Li CM, Lowenheim H, Magnusson PKE, Meurs Jvan, Milani L, Morton CC, Mäkitie A, Nalls MA, Giovanni Nardone G, Nygaard M, Palviainen T, Pratt S, Quaranta N, Rämö J, Saarentaus E, Sardone R, Satizabal Barrera CL, Schweinfurth JM, Seshadri S, Shiroma E, Shulman E, Simonsick E, Spankovich E, Tropitzsch A, Lauschke VM, Sullivan PF, Goedegebure A, Cederroth CR, Williams FMK, Nagtegaal AP. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss. Am J Hum Genet. 2022 Jun 2;109(6):1077-1091. *These authors contributed equally.
https://doi.org/10.1016/j.ajhg.2022.04.010

VI. TRPCHEVSKA N*, Freidin MB*, Broer L*, Oosterloo BC, Yao S, Zhou Y, Vona B, Bishop C, Bizaki-Vallaskangas A, Canlon B, Castellana F, Chasman DI, Cherny S, Christensen K, Concas MP, Correa A, Elkon R, Estonian Biobank Research Team, Mengel-From J, Gao Y, Giersch ABS, Girotto G, Gudjonsson A, Gudnason V, Heard-Costa NL, Hertzano R, Hjelmborg JvB, Hjerling-Leffler J, Hoffman HJ, Kaprio J, Kettunen K, Krebs K, Kähler AK, Lallemend F, Launer JL, Lee IM, Leonard H, Li CM, Lowenheim H, Magnusson PKE, Meurs Jvan, Milani L, Morton CC, Mäkitie A, Nalls MA, Giovanni Nardone G, Nygaard M, Palviainen T, Pratt S, Quaranta N, Rämö J, Saarentaus E, Sardone R, Satizabal Barrera CL, Schweinfurth JM, Seshadri S, Shiroma E, Shulman E, Simonsick E, Spankovich E, Tropitzsch A, Lauschke VM, Sullivan PF, Goedegebure A, Cederroth CR, Williams FMK, Nagtegaal AP. Genome-wide association meta-analysis on tinnitus indicates low independence from hearing loss. *These authors contributed equally. [Manuscript]

VII. Gallego-Martinez A, Escalera-Balsera A, TRPCHEVSKA N, Robles- Bolivar P, Roman-Naranjo P, Frejo L, Perez-Carpena P, Canlon B, Cederroth CR, Lopez-Escamez JA. Comprehensive analysis of coding and non-coding rare variants in the genomes of Swedish patients with severe tinnitus. [Submitted]