Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure [article]

Joel T Rämö, Tuomo Kiiskinen, Juha Karjalainen, Kristi Krebs, Mitja Kurki, Aki S Havulinna, Eija Hämäläinen, Paavo Häppölä, Heidi Hautakangas, Konrad J Karczewski, Masahiro Kanai, Reedik Mägi (+10 others)
2020 medRxiv   pre-print
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 and treatment options are limited. 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
more » ... e population-based biobanks comprising 2,413 cases and 762,382 controls. We identify 15 novel risk loci (p < 5*10-8) and replicate the regions of RELN and two previously reported candidate genes (TGFB1 and MEPE). Implicated genes in many loci are essential for bone remodelling or mineralization. Otosclerosis is genetically correlated with height and fracture risk, and the association loci overlap with severe skeletal disorders. Our results highlight TGFβ1 signalling for follow-up mechanistic studies.
doi:10.1101/2020.11.15.20227868 fatcat:ja2ete45cja7nlwp637haoxz74