The combined role of genetic and environmental risk factors in the gender-specific development of severe tinnitus

Tinnitus is the most frequent phantom sensation, affecting 70 million individuals in Europe. It dramatically increases with age, with near 40% of the elderlies experiencing tinnitus. It can be severely debilitating, increasing the risk for sick leave, disability pension and even suicide. While prevalence is higher in men, women show greater psychological burden and loss of life quality, suggesting that different coping mechanisms operate in the two genders. From a genetic perspective, we recently found that specific forms of tinnitus displayed significant heritability in men. However, when segregated according to age, young women showed such high genetic influences.

The results described are grouped according to the three principal goals of TIGER. Note that we describe only those results where a member of the Norwegian team was involved. 1.) The very first analyses carried out within TIGER focus on a set of key co-morbidities frequently reported by tinnitus patients in order to improve the understanding of their (joint) occurrence and possible causal relationships. These co-morbidities are temporo-mandibular joint (TMJ) disorders, headaches, and hyperacusis. In three sequential studies (Edvall et al. 2019, Lugo et al. 2020, Cederroth et al. 2020), we showed the lack of sex-influences in their association with tinnitus. Moreover, TIGER proposes that the mechanisms underlying tinnitus with hyperacusis are distinct from those associating tinnitus with TMJ or headache. These findings base on a deep phenotyping strategy. 2.) In Trpchevska et al. (2020) we estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population. Our ?ndings strongly support the notion that genetic factors impact on the development of (severe) tinnitus. This provided additional insight into the relationship of tinnitus severity and sex, which was useful for the design of our subsequently carried out genetic study. The results of this study are presented in Gallego-Martinez et al. (2022): using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus, we found an enrichment of rare missense variants in 6 and 8, respectively, high-constraint genes in two cohorts. Concerning the identification of tinnitus-relevant biomarkers, our analyses show that a link between circulating inflammatory and neurology proteins in plasma and constant / chronic tinnitus cannot be established (Cederroth et al., 2023, submitted). Moreover, on a supplementary clinical sample we could establish that the link between common blood parameters and tinnitus is at best very limited (Bulla et al., 2023, submitted). 3.) In preparation of the risk analysis to be carried out within the last project goal, we developed two statistical modelling approaches suitable for the analysis of longitudinal data. Both fall into the class of hidden (semi-)Markov models: first, we developed Bayesian estimation techniques for mixed hidden semi-Markov models (Haji-Maghsoudi et al., 2021). Secondly, we developed a highly efficient estimation framework for hidden Markov models (Bacri et al. 2022, Bacri et al. 2023, submitted). It was originally planned use this modelling class for estimating risk models before the end of the project. Unfortunately, this part has only been delayed. However, in Edvall et al. (2022) we were already able to improve our understanding of the dynamics of transitioning between occasional and constant tinnitus in a longitudinal setting.

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