Mendelian randomization analyses support causal relationships between tinnitus of different stages and severity and structural characteristics of specific brain regions

Abstract

This study aims to delineate the causal relationships between idiopathic tinnitus in different stages and severity and the morphological properties in specific brain regions. We utilized a two-sample bidirectional Mendelian randomization (MR) analysis to ascertain the causal effects of brain structural attributes on varying severities and stages of tinnitus. Our approach involved harnessing genetic variables derived from extensive genome-wide association studies as instrumental variables, centered mainly on pertinent single-nucleotide polymorphisms associated with tinnitus. Subsequently, we integrated this data with brain structural imaging inputs to facilitate the MR analysis. We also applied reverse MR analysis to pinpoint the critical brain regions implicated in the onset of tinnitus. Our analysis revealed a demonstrable causal relationship between tinnitus and brain structural alterations, including changes primarily within the auditory cortex and hub regions of the limbic system, as well as portions of the frontal-temporal-occipital circuit. We found that individuals exhibiting cortical thickness alterations in the bilateral peri-calcarine and right superior occipital gyrus might have previously experienced tinnitus. Changes in the cortical areas of the right rectus, left inferior frontal gyrus, and right pars-orbitalis appeared unrelated to tinnitus. Furthermore, moderate tinnitus patients showed more pronounced structural alterations. This study substantiates that tinnitus could instigate substantial structural alterations mainly within the auditory-limbic-frontal-visual system, while the reciprocal causality was not supported. Moreover, the data underscores that moderate, rather than severe, tinnitus precipitates the most significant structural changes. Morphological alterations in several specific brain areas either indicate a history of tinnitus or bear no relation to it.

Keywords: Auditory-limbic system; Mendelian randomization; Morphological characteristics; Severity; Tinnitus.