Genome-Wide Association Study Reveals Novel Associations of Annexin A13 to Secretory and GAS2L2 with Mucous Otitis Media

Abstract Purpose: To evaluate the genetics of chronic non-suppurative otitis media (OM). Methods: We performed a genome-wide association study of 429,599 individuals included in the FinnGen study using three different case definitions: any type of chronic non-suppurative OM (7,034 cases), mucous chronic OM (5,953 cases), and secretory chronic OM (1,689 cases). Individuals without otitis media were used as controls (417,745 controls). We used immunohistochemistry of the murine middle ear to evaluate the expression of annexin A13. Results: Four loci were significantly associated (p<1.7x10-8) with non-suppurative OM. Three out of the four association signals included missense variants in genes having a plausible role in otitis media pathobiology. In subtype-specific analyses, one novel locus, near ANXA13, was associated with secretory OM. Three loci (near TNFRSF13B, GAS2L2, and TBX1) were associated with mucous OM. Immunohistochemistry of the murine middle ear samples revealed expression of annexin A13 at the apical pole of the Eustachian tube’s epithelium as well as variable intensity in the secretory cells of the glandular structure in the proximity of the Eustachian tube. Conclusions: We demonstrate that secretory and mucous OM have distinct and shared genetic associations. The association of GAS2L2 implies a connection with ciliary epithelium function and the pathogenesis of dysfunctional mucosa in mucous OM. The abundant expression of annexin A13 in the Eustachian tube epithelium, along with its implicated role in apical transport for the binding and transfer of phospholipids, indicates the role of annexin A13 and phospholipids in Eustachian tube dysfunction.