| Title: | Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure |
| Journal: | Nature Communications |
| Published: | 18 Jan 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36653343/ |
| DOI: | https://doi.org/10.1038/s41467-022-32936-3 |
| URL: | https://www.nature.com/articles/s41467-022-32936-3.pdf |
Publication 10968
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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.</p>
23 Authors
- Joel T. Rämö
- Tuomo Kiiskinen
- Richard Seist
- Kristi Krebs
- Masahiro Kanai
- Juha Karjalainen
- Mitja Kurki
- Eija Hämäläinen
- Paavo Häppölä
- Aki S. Havulinna
- Heidi Hautakangas
- Reedik Mägi
- Priit Palta
- Tõnu Esko
- Andres Metspalu
- Matti Pirinen
- Konrad J. Karczewski
- Samuli Ripatti
- Lili Milani
- Konstantina M. Stankovic
- Antti Mäkitie
- Mark J. Daly
- Aarno Palotie
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