TY - JOUR
T1 - A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis
AU - Højland, Allan Thomas
AU - Tavernier, Lisse J.M.
AU - Schrauwen, Isabelle
AU - Sommen, Manou
AU - Topsakal, Vedat
AU - Schatteman, Isabelle
AU - Dhooge, Ingeborg
AU - Huber, Alex
AU - Zanetti, Diego
AU - Kunst, Henricus P.M.
AU - Hoischen, Alexander
AU - Petersen, Michael B.
AU - Van Camp, Guy
AU - Fransen, Erik
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/4
Y1 - 2022/4
N2 - In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5′-UTR and 3′-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3′-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.
AB - In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5′-UTR and 3′-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3′-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.
UR - http://www.scopus.com/inward/record.url?scp=85112862223&partnerID=8YFLogxK
U2 - 10.1007/s00439-021-02334-8
DO - 10.1007/s00439-021-02334-8
M3 - Journal article
AN - SCOPUS:85112862223
SN - 0340-6717
VL - 141
SP - 951
EP - 963
JO - Human Genetics
JF - Human Genetics
IS - 3-4
ER -