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Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure.

Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure. Nature communications Ramo, J. T., Kiiskinen, T., Seist, R., Krebs, K., Kanai, M., Karjalainen, J., Kurki, M., Hamalainen, E., Happola, P., Havulinna, A. S., Hautakangas, H., FinnGen, Magi, R., Palta, P., Esko, T., Metspalu, A., Pirinen, M., Karczewski, K. J., Ripatti, S., Milani, L., Stankovic, K. M., Makitie, A., Daly, M. J., Palotie, A. 2023; 14 (1): 157

Abstract

Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p<5*10-8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.

View details for DOI 10.1038/s41467-022-32936-3

View details for PubMedID 36653343