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

Joel T Rämö; Tuomo Kiiskinen; Juha M Karjalainen; Kristi Krebs; Mitja Kurki; Aki Samuli Havulinna; Eija Hämäläinen; Paavo Häppölä; Heidi M Hautakangas; FinnGen; Konrad J. Karczewski; Masahiro Kanai; Reedik Mägi; Priit Palta; Tõnu Esko; Andres Metspalu; Matti Pirinen; Samuli Ripatti; Lili A. Milani; Antti A. Mäkitie; Mark J. Daly; Aarno V. Palotie

doi:10.1101/2020.11.15.20227868

Genetic & Genomic MedicinemedRxivNov 15, 2020

Preprint

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

Joel T Rämö iD, Tuomo Kiiskinen iD, Juha M Karjalainen iD, Kristi Krebs iD, Mitja Kurki iD, Aki Samuli Havulinna iD, Eija Hämäläinen, Paavo Häppölä iD, Heidi M Hautakangas iD, FinnGen iD, Konrad J. Karczewski iD, Masahiro Kanai iD, Reedik Mägi iD, Priit Palta iD, Tõnu Esko iD, Andres Metspalu iD, Matti Pirinen iD, Samuli Ripatti iD, Lili A. Milani iD, Antti A. Mäkitie iD, Mark J. Daly iD, Aarno V. Palotie iD

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 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 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 TGF{beta}1 signalling for follow-up mechanistic studies.

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