{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:34:53Z","timestamp":1781706893497,"version":"3.54.5"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian National Health and Medical Research Council","award":["APP634301"],"award-info":[{"award-number":["APP634301"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["087436\/Z\/08\/Z"],"award-info":[{"award-number":["087436\/Z\/08\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["102858\/Z\/13\/Z"],"award-info":[{"award-number":["102858\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Our goal was to identify genetic risk factors for severe otitis media (OM) in Aboriginal Australians.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Illumina\u00ae Omni2.5 BeadChip and imputed data were compared between 21 children with severe OM (multiple episodes chronic suppurative OM and\/or perforations or tympanic sclerosis) and 370 individuals without this phenotype, followed by FUnctional Mapping and Annotation (FUMA). Exome data filtered for common (EXaC_all\u2005\u2265\u20050.1) putative deleterious variants influencing protein coding (CADD-scaled scores \u226515] were used to compare 15 severe OM cases with 9 mild cases (single episode of acute OM recorded over \u22653 consecutive years). Rare (ExAC_all\u2005\u2264\u20050.01) such variants were filtered for those present only in severe OM. Enrichr was used to determine enrichment of genes contributing to pathways\/processes relevant to OM.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>FUMA analysis identified 2 plausible genetic risk loci for severe OM: NR3C1 (Pimputed_1000G = 3.62\u2005\u00d7\u200510\u22126) encoding the glucocorticoid receptor, and NREP (Pimputed_1000G = 3.67\u2005\u00d7\u200510\u22126) encoding neuronal regeneration-related protein. Exome analysis showed: (i) association of severe OM with variants influencing protein coding (CADD-scaled\u2005\u2265\u200515) in a gene-set (GRXCR1, CDH23, LRP2, FAT4, ARSA, EYA4) enriched for Mammalian Phenotype Level 4 abnormal hair cell stereociliary bundle morphology and related phenotypes; (ii) rare variants influencing protein coding only seen in severe OM provided gene-sets enriched for \u201cabnormal ear\u201d (LMNA, CDH23, LRP2, MYO7A, FGFR1), integrin interactions, transforming growth factor signaling, and cell projection phenotypes including hair cell stereociliary bundles and cilium assembly.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study highlights interacting genes and pathways related to cilium structure and function that may contribute to extreme susceptibility to OM in Aboriginal Australian children.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciab216","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T12:48:10Z","timestamp":1615294090000},"page":"1860-1870","source":"Crossref","is-referenced-by-count":9,"title":["Common and Rare Genetic Variants That Could Contribute to Severe Otitis Media in an Australian Aboriginal Population"],"prefix":"10.1093","volume":"73","author":[{"given":"Sarra E","family":"Jamieson","sequence":"first","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Fakiola","sequence":"additional","affiliation":[{"name":"FIRC Institute of Molecular Oncology (IFOM), Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Tang","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Scaman","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Syn","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W","family":"Francis","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey L","family":"Coates","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Anderson","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Lassmann","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J","family":"Cordell","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0784-7277","authenticated-orcid":false,"given":"Jenefer M","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Telethon Kids Institute, The University of Western Australia, Perth, Western Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021111804335556200_CIT0001","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1016\/j.vaccine.2006.09.006","article-title":"An overview of acute otitis media in Australian Aboriginal children living in remote communities","volume":"25","author":"Morris","year":"2007","journal-title":"Vaccine"},{"key":"2021111804335556200_CIT0002","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1093\/clinids\/22.6.1079","article-title":"A meta-analytic review of the risk factors for acute otitis media","volume":"22","author":"Uhari","year":"1996","journal-title":"Clin Infect Dis"},{"key":"2021111804335556200_CIT0003","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.3389\/fgene.2019.01395","article-title":"Current understanding of host genetics of otitis media","volume":"10","author":"Geng","year":"2019","journal-title":"Front Genet"},{"key":"2021111804335556200_CIT0004","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1093\/aje\/155.10.958","article-title":"Heritability of symptom domains in otitis media: a longitudinal study of 1373 twin pairs","volume":"155","author":"Rovers","year":"2002","journal-title":"Am J Epidemiol"},{"key":"2021111804335556200_CIT0005","doi-asserted-by":"crossref","first-page":"e0140758","DOI":"10.1371\/journal.pone.0140758","article-title":"Expression quantitative trait loci information improves predictive modeling of disease relevance of non-coding genetic variation","volume":"10","author":"Croteau-Chonka","year":"2015","journal-title":"PLoS One"},{"key":"2021111804335556200_CIT0006","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/ng.3347","article-title":"Rare A2ML1 variants confer susceptibility to otitis media","volume":"47","author":"Santos-Cortez","year":"2015","journal-title":"Nat Genet"},{"key":"2021111804335556200_CIT0007","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60 706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2021111804335556200_CIT0008","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg3241","article-title":"De novo mutations in human genetic disease","volume":"13","author":"Veltman","year":"2012","journal-title":"Nat Rev Genet"},{"key":"2021111804335556200_CIT0009","volume-title":"The Mardu Aborigines, living the dream in Australia\u2019s desert","author":"Tonkinson","year":"1991"},{"key":"2021111804335556200_CIT0010","doi-asserted-by":"crossref","first-page":"e0119333","DOI":"10.1371\/journal.pone.0119333","article-title":"First genome-wide association study in an Australian aboriginal population provides insights into genetic risk factors for body mass index and type 2 diabetes","volume":"10","author":"Anderson","year":"2015","journal-title":"PLoS One"},{"key":"2021111804335556200_CIT0011","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1111\/j.0006-341X.1999.00997.x","article-title":"Genomic control for association studies","volume":"55","author":"Devlin","year":"1999","journal-title":"Biometrics"},{"key":"2021111804335556200_CIT0012","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","article-title":"LocusZoom: regional visualization of genome-wide association scan results","volume":"26","author":"Pruim","year":"2010","journal-title":"Bioinformatics"},{"key":"2021111804335556200_CIT0013","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1038\/s41467-017-01261-5","article-title":"Functional mapping and annotation of genetic associations with FUMA","volume":"8","author":"Watanabe","year":"2017","journal-title":"Nat Commun"},{"key":"2021111804335556200_CIT0014","doi-asserted-by":"crossref","first-page":"160023","DOI":"10.1038\/sdata.2016.23","article-title":"Reference genotype and exome data from an Australian Aboriginal population for health-based research","volume":"3","author":"Tang","year":"2016","journal-title":"Sci Data"},{"key":"2021111804335556200_CIT0015","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2021111804335556200_CIT0016","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/s40168-018-0611-4","article-title":"Signatures within the esophageal microbiome are associated with host genetics, age, and disease","volume":"6","author":"Deshpande","year":"2018","journal-title":"Microbiome"},{"key":"2021111804335556200_CIT0017","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s12866-018-1154-3","article-title":"A microbiome case-control study of recurrent acute otitis media identified potentially protective bacterial genera","volume":"18","author":"Lappan","year":"2018","journal-title":"BMC Microbiol"},{"key":"2021111804335556200_CIT0018","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat Genet"},{"key":"2021111804335556200_CIT0019","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1183\/09031936.06.00125404","article-title":"Corticosteroid effects on cell signalling","volume":"27","author":"Barnes","year":"2006","journal-title":"Eur Respir J"},{"key":"2021111804335556200_CIT0020","article-title":"Hypothalamic-pituitary-adrenal axis suppression in asthma: A glucocorticoid receptor polymorphism may protect","author":"Akurugu","year":"2020","journal-title":"Pediatr Allergy Immunol"},{"key":"2021111804335556200_CIT0021","doi-asserted-by":"crossref","first-page":"853","DOI":"10.4161\/epi.21180","article-title":"Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight","volume":"7","author":"Mulligan","year":"2012","journal-title":"Epigenetics"},{"key":"2021111804335556200_CIT0022","article-title":"Harsh parenting predicts novel HPA receptor gene methylation and NR3C1 methylation predicts cortisol daily slope in middle childhood","author":"Lewis","year":"2020","journal-title":"Cell Mol Neurobiol"},{"key":"2021111804335556200_CIT0023","doi-asserted-by":"crossref","first-page":"33971","DOI":"10.1074\/jbc.M114.609495","article-title":"Novel RNA-binding protein P311 binds eukaryotic translation initiation factor 3 subunit b (eIF3b) to promote translation of transforming growth factor \u03b21-3 (TGF-\u03b21-3)","volume":"289","author":"Yue","year":"2014","journal-title":"J Biol Chem"},{"key":"2021111804335556200_CIT0024","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1165\/rcmb.2018-0028OC","article-title":"P311 promotes lung fibrosis via stimulation of transforming growth factor-\u03b21, -\u03b22, and -\u03b23 translation","volume":"60","author":"Duan","year":"2019","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2021111804335556200_CIT0025","doi-asserted-by":"crossref","first-page":"17032","DOI":"10.1038\/srep17032","article-title":"P311 promotes renal fibrosis via TGF\u03b21\/Smad signaling","volume":"5","author":"Yao","year":"2015","journal-title":"Sci Rep"},{"key":"2021111804335556200_CIT0026","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1093\/hmg\/ddt103","article-title":"Otitis media in the Tgif knockout mouse implicates TGF\u03b2 signalling in chronic middle ear inflammatory disease","volume":"22","author":"Tateossian","year":"2013","journal-title":"Hum Mol Genet"},{"key":"2021111804335556200_CIT0027","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/gene.2011.2","article-title":"FBXO11, a regulator of the TGF\u03b2 pathway, is associated with severe otitis media in Western Australian children","volume":"12","author":"Rye","year":"2011","journal-title":"Genes Immun"},{"key":"2021111804335556200_CIT0028","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1097\/00006454-199411000-00009","article-title":"Bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in Australian aboriginal infants","volume":"13","author":"Leach","year":"1994","journal-title":"Pediatr Infect Dis J"},{"key":"2021111804335556200_CIT0029","doi-asserted-by":"crossref","first-page":"e0212473","DOI":"10.1371\/journal.pone.0212473","article-title":"Nasal microbial composition and chronic otitis media with effusion: A case-control study","volume":"14","author":"Walker","year":"2019","journal-title":"PLoS One"},{"key":"2021111804335556200_CIT0030","article-title":"Otitis media susceptibility and shifts in the head and neck microbiome due to SPINK5 variants","author":"Frank","year":"2020","journal-title":"J Med Genet"},{"key":"2021111804335556200_CIT0031","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s40249-016-0189-7","article-title":"Middle ear microbiome differences in indigenous Filipinos with chronic otitis media due to a duplication in the A2ML1 gene","volume":"5","author":"Santos-Cortez","year":"2016","journal-title":"Infect Dis Poverty"},{"key":"2021111804335556200_CIT0032","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1471-2121-10-17","article-title":"Cep70 and Cep131 contribute to ciliogenesis in zebrafish embryos","volume":"10","author":"Wilkinson","year":"2009","journal-title":"BMC Cell Biol"},{"key":"2021111804335556200_CIT0033","first-page":"33","article-title":"The impact of primary ciliary dyskinesia on the upper respiratory tract","volume":"18","author":"Morgan","year":"2016","journal-title":"Paediatr Respir Rev"},{"key":"2021111804335556200_CIT0034","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/bs.ctdb.2015.07.007","article-title":"Development and integration of the ear","volume":"115","author":"Fuchs","year":"2015","journal-title":"Curr Top Dev Biol"},{"key":"2021111804335556200_CIT0035","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1083\/jcb.201001138","article-title":"Review series: The cell biology of hearing","volume":"190","author":"Schwander","year":"2010","journal-title":"J Cell Biol"},{"key":"2021111804335556200_CIT0036","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.matbio.2011.10.001","article-title":"Molecular functions of syndecan-1 in disease","volume":"31","author":"Teng","year":"2012","journal-title":"Matrix Biol"},{"key":"2021111804335556200_CIT0037","doi-asserted-by":"crossref","first-page":"11542","DOI":"10.1038\/srep11542","article-title":"Latent progenitor cells as potential regulators for tympanic membrane regeneration","volume":"5","author":"Kim","year":"2015","journal-title":"Sci Rep"},{"key":"2021111804335556200_CIT0038","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.2353\/ajpath.2009.090393","article-title":"Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders","volume":"175","author":"Nishimura","year":"2009","journal-title":"Am J Pathol"},{"key":"2021111804335556200_CIT0039","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.celrep.2013.05.020","article-title":"TGF-\u03b2 signaling is associated with endocytosis at the pocket region of the primary cilium","volume":"3","author":"Clement","year":"2013","journal-title":"Cell Rep"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciab216\/40785855\/ciab216.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/73\/10\/1860\/41157405\/ciab216.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/73\/10\/1860\/41157405\/ciab216.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T07:20:48Z","timestamp":1637220048000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/73\/10\/1860\/6164939"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,3,9]]},"published-print":{"date-parts":[[2021,11,16]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciab216","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,15]]},"published":{"date-parts":[[2021,3,9]]}}}