{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:11:43Z","timestamp":1791961903417,"version":"4.3.4"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3\u20130.4% in the European population. Clinical symptoms usually occur between the second and fifth decade of life. Different studies have been performed to unravel the genetic architecture of the disease. Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes. In this study, seven candidate genes from the GWAS were resequenced using single molecule molecular inversion probes (smMIPs). smMIPs were used to capture the exonic regions and the 3\u2032 and 5\u2032 untranslated regions (UTR). Discovered variants were tested for association with the disease using single variant and gene-based association analysis. The single variant results showed that 13 significant variants were associated with otosclerosis. Associated variants were found in five of the seven genes studied here, including AHSG, LINC01482, MARK3, SUPT3H and RELN. Conversely, burden testing did not show a major role of rare variants in the disease. In conclusion, this study was able to replicate five out of seven candidate genes reported in the previous GWAS. This association is likely mainly driven by common variants.<\/jats:p>","DOI":"10.3390\/jcm11236978","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T06:04:36Z","timestamp":1669615476000},"page":"6978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3267-7844","authenticated-orcid":false,"given":"Lisse J. M.","family":"Tavernier","sequence":"first","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4942-6315","authenticated-orcid":false,"given":"Thomas","family":"Vanpoucke","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7310-6082","authenticated-orcid":false,"given":"Isabelle","family":"Schrauwen","sequence":"additional","affiliation":[{"name":"Center for Statistical Genetics, Department of Neurology, Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5105-9000","authenticated-orcid":false,"given":"Guy","family":"Van Camp","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Fransen","sequence":"additional","affiliation":[{"name":"Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, 2650 Antwerp, Belgium"},{"name":"StatUA Center for Statistics, University of Antwerp, 2610 Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1017\/S0022215100111946","article-title":"Pathology of the otic capsule","volume":"104","author":"Milroy","year":"1990","journal-title":"J. Laryngol. Otol."},{"key":"ref_2","first-page":"246","article-title":"Histologic otosclerosis","volume":"53","author":"Guild","year":"1944","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1177\/000348948409300201","article-title":"Histologically Proven Cochlear Otosclerosis with Pure Sensorineural Hearing Loss","volume":"93","author":"Balle","year":"1984","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1177\/000348948409300104","article-title":"Sensorineural Hearing Loss in Stapedial Otosclerosis","volume":"93","author":"Browning","year":"1984","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1097\/00129492-200109000-00006","article-title":"Prevalence of Otosclerosis in an Unselected Series of Temporal Bones","volume":"22","author":"Declau","year":"2001","journal-title":"Otol. Neurotol."},{"key":"ref_6","first-page":"1","article-title":"Otosclerosis. A genetic and clinical study","volume":"154","author":"Larsson","year":"1960","journal-title":"Acta Otolaryngol. Suppl."},{"key":"ref_7","first-page":"202","article-title":"Genetic factors in otosclerosis","volume":"41","author":"Morrison","year":"1967","journal-title":"Ann. R. Coll. Surg. Engl."},{"key":"ref_8","first-page":"267","article-title":"A new locus for otosclerosis, OTSC8, maps to the pericentromeric region of chromosome 9","volume":"123","author":"Ali","year":"2008","journal-title":"Qual. Life Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1001\/archotol.132.4.416","article-title":"Chromosomal Mapping and Phenotypic Characterization of Hereditary Otosclerosis Linked to the OTSC4 Locus","volume":"132","author":"Brownstein","year":"2006","journal-title":"Arch. Otolaryngol.-Head Neck Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1136\/jmg.39.7.473","article-title":"Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3","volume":"39","author":"Chen","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1399-0004.2010.01576.x","article-title":"A new locus for otosclerosis, OTSC10, maps to chromosome 1q41-44","volume":"79","author":"Schrauwen","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/sj.ejhg.5201761","article-title":"A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13\u201316.1","volume":"15","author":"Thys","year":"2007","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/hmg\/7.2.285","article-title":"Localization of a gene for otosclerosis to chromosome 15q25-q26","volume":"7","author":"Tomek","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1136\/jmg.2004.018671","article-title":"A fifth locus for otosclerosis, OTSC5, maps to chromosome 3q22-24","volume":"41","author":"Bogaert","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1086\/318185","article-title":"A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36","volume":"68","author":"Govaerts","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","first-page":"951","article-title":"A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis","volume":"141","author":"Tavernier","year":"2021","journal-title":"Qual. Life Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/s41436-018-0300-5","article-title":"Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis","volume":"21","author":"Schrauwen","year":"2019","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"R\u00e4m\u00f6, J.T., Kiiskinen, T., Karjalainen, J., Krebs, K., Kurki, M., Havulinna, A.S., and Palotie, A. (2020). Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure. medRxiv.","DOI":"10.1101\/2020.11.15.20227868"},{"key":"ref_19","first-page":"155","article-title":"Genetic variants in the RELN gene are associated with otosclerosis in multiple European populations","volume":"127","author":"Schrauwen","year":"2010","journal-title":"Qual. Life Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1002\/ajmg.a.35276","article-title":"COL1A1 association and otosclerosis: A meta-analysis","volume":"158A","author":"Schrauwen","year":"2012","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1359\/jbmr.071112","article-title":"Association of bone morphogenetic proteins with otosclerosis","volume":"23","author":"Schrauwen","year":"2008","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1469-1809.2009.00505.x","article-title":"Detection of Rare Nonsynonymous Variants in TGFB1 in Otosclerosis Patients","volume":"73","author":"Thys","year":"2009","journal-title":"Ann. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s00438-019-01558-8","article-title":"Insufficient evidence for a role of SERPINF1 in otosclerosis","volume":"294","author":"Valgaeren","year":"2019","journal-title":"Mol. Genet. Genomics."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1093\/bioinformatics\/btu353","article-title":"MIPgen: Optimized modeling and design of molecular inversion probes for targeted resequencing","volume":"30","author":"Boyle","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1101\/gr.147686.112","article-title":"Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation","volume":"23","author":"Hiatt","year":"2013","journal-title":"Genome Res."},{"key":"ref_26","unstructured":"Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1093\/bioinformatics\/btr667","article-title":"Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools","volume":"28","author":"Lucas","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"Storey","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"The 1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1093\/hmg\/ddm150","article-title":"The coding polymorphism T263I in TGF-beta1 is associated with otosclerosis in two independent populations","volume":"16","author":"Thys","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Helmholz, H., Adejube, B., Luthringer-Feyerabend, B., and Willumeit-R\u00f6mer, R. (2021). In Vitro Investigation on Degradable Mg-Based Biomaterial under the Impact of the Serum Glycoprotein Fetuin. Materials, 14.","DOI":"10.3390\/ma14175005"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.tcm.2012.07.020","article-title":"Fetuin-A Function in Systemic Mineral Metabolism","volume":"22","author":"Herrmann","year":"2012","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1111\/j.1469-1809.2011.00665.x","article-title":"Association of COL1A1 and TGFB1 Polymorphisms with Otosclerosis in a Tunisian Population","volume":"75","author":"Khalfallah","year":"2011","journal-title":"Ann. Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"19991","DOI":"10.1074\/jbc.M112234200","article-title":"alpha 2-HS glycoprotein\/fetuin, a transforming growth factor-beta\/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling","volume":"277","author":"Szweras","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrm.2017.104","article-title":"The functions and unique features of long intergenic non-coding RNA","volume":"19","author":"Ransohoff","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kim, S.K. (2018). Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0200785"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.cels.2016.10.014","article-title":"Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module","volume":"4","author":"Calabrese","year":"2016","journal-title":"Cell Syst."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.2249","article-title":"Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture","volume":"44","author":"Estrada","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E1827","DOI":"10.1210\/jc.2013-1055","article-title":"Genetic Analysis of Recently Identified Osteoporosis Susceptibility Genes in Southern Chinese","volume":"98","author":"Xiao","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ajhg.2009.01.023","article-title":"A Genome-wide Analysis Identifies Genetic Variants in the RELN Gene Associated with Otosclerosis","volume":"84","author":"Schrauwen","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1469-1809.2010.00595.x","article-title":"Genetic variants in RELN are associated with otosclerosis in a non-European population from Tunisia","volume":"74","author":"Khalfallah","year":"2010","journal-title":"Ann. Hum. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Priyadarshi, S., Hansdah, K., Singh, N., Bouzid, A., Ray, C.S., Panda, K.C., Biswal, N.C., Desai, A., Choudhury, J.C., and Tekari, A. (2022). The risks of RELN polymorphisms and its expression in the development of otosclerosis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0269558"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1074\/jbc.M106996200","article-title":"Reelin is a serine protease of the extracellular matrix","volume":"277","author":"Quattrocchi","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3464","DOI":"10.1093\/hmg\/ddy257","article-title":"Identification of a novel, methylation-dependent, RUNX2 regulatory region associated with osteoarthritis risk","volume":"27","author":"Rice","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1210\/er.2004-0001","article-title":"Transforming growth factor-beta1 to the bone","volume":"26","author":"Janssens","year":"2005","journal-title":"Endocr. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Casta\u00f1o-Betancourt, M.C., Evans, D.S., Ramos, Y.F.M., Boer, C.G., Metrustry, S., Liu, Y., Hollander, W.D., van Rooij, J., Kraus, V.B., and Yau, M.S. (2016). Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1006260"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.bbadis.2008.01.006","article-title":"Role of transforming growth factor-\u03b2 superfamily signaling pathways in human disease","volume":"1782","author":"Gordon","year":"2008","journal-title":"Biochim. et Biophys. Acta (BBA)-Mol. Basis Dis."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/23\/6978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:26Z","timestamp":1760146046000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/23\/6978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,26]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["jcm11236978"],"URL":"https:\/\/doi.org\/10.3390\/jcm11236978","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,26]]}}}