Integrating GWAS meta-analysis with human brain cell mapping implicates the amygdala and the midbrain in the pathogenesis of tinnitus

Abstract

Tinnitus is a distressing condition affecting millions of people worldwide, yet treatment options remain very limited. Molecular evidence on the cellular origins of tinnitus in humans is lacking. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported tinnitus on 888,214 individuals (75,250 tinnitus cases and 812,964 controls) from 19 independent cohorts. We identified five independent loci, two of which have not been reported previously. Mapping onto a single-cell transcriptomic atlas of the adult human brain, we found enrichment in amygdala excitatory neurons, midbrain-derived inhibitory neurons, and medial ganglionic eminence-derived interneurons, implicating the involvement of these cell types within tinnitus. Moreover, we observed that these cell-types overlapped with those associated with major depressive disorder, insomnia, and neuroticism, pathologies and personality traits which were also genetically correlated with tinnitus. Our findings confirm previously reported genetic associations with tinnitus and identify novel ones, highlighting the amygdalas excitatory and the midbrains inhibitory neurons as crucial cell types involved in tinnitus pathophysiology. Our work, which leverages multiple cohorts, provides a framework for identifying genetic and cellular contributors to tinnitus and defining common mechanisms and treatments.