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

Joel T Rämö; Tuomo Kiiskinen; Richard Seist; Kristi Krebs; Masahiro Kanai; Juha Karjalainen; Mitja Kurki; Eija Hämäläinen; Paavo Häppölä; Aki S Havulinna; Heidi Hautakangas; FinnGen; 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

doi:10.1038/s41467-022-32936-3

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

Nat Commun. 2023 Jan 18;14(1):157. doi: 10.1038/s41467-022-32936-3.

Authors

Joel T Rämö¹, Tuomo Kiiskinen¹, Richard Seist², Kristi Krebs³, Masahiro Kanai^{1

4

5

6}, Juha Karjalainen^{1

4

5

6}, Mitja Kurki^{1

4

5

6}, Eija Hämäläinen¹, Paavo Häppölä¹, Aki S Havulinna^{1

7}, Heidi Hautakangas¹; FinnGen; Reedik Mägi³, Priit Palta^{1

3}, Tõnu Esko³, Andres Metspalu³, Matti Pirinen^{1

8

9}, Konrad J Karczewski^{1

4

5

6}, Samuli Ripatti^{1

4

6

8}, Lili Milani³, Konstantina M Stankovic², Antti Mäkitie¹⁰, Mark J Daly^{1

4

5

6

11}, Aarno Palotie^{12

13

14

15}

Affiliations

¹ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
² Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
³ Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁷ Finnish Institute for Health and Welfare, Helsinki, Finland.
⁸ Department of Public Health, Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁹ Department of Mathematics and Statistics, Faculty of Science, University of Helsinki, Helsinki, Finland.
¹⁰ Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland. aarno.palotie@helsinki.fi.
¹³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aarno.palotie@helsinki.fi.
¹⁴ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. aarno.palotie@helsinki.fi.
¹⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. aarno.palotie@helsinki.fi.

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.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Specimen Banks
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study*
Mice
Otosclerosis* / genetics
Polymorphism, Single Nucleotide

Grants and funding

MC_PC_17228/MRC_/Medical Research Council/United Kingdom