{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T02:26:30Z","timestamp":1789179990672,"version":"build-2803163510"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["P50 DC 000422"],"award-info":[{"award-number":["P50 DC 000422"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Age-related hearing loss is a common, heterogeneous disease with a strong genetic component. More than 100 loci have been reported to be involved in human hearing impairment to date, but most of the genes underlying human adult-onset hearing loss remain unknown. Most genetic studies have focussed on very rare variants (such as family studies and patient cohort screens) or very common variants (genome-wide association studies). However, the contribution of variants present in the human population at intermediate frequencies is hard to quantify using these methods, and as a result, the landscape of variation associated with adult-onset hearing loss remains largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here we present a study based on exome sequencing and self-reported hearing difficulty in the UK Biobank, a large-scale biomedical database. We have carried out variant load analyses using different minor allele frequency and impact filters, and compared the resulting gene lists to a manually curated list of nearly 700 genes known to be involved in hearing in humans and\/or mice. An allele frequency cutoff of 0.1, combined with a high predicted variant impact, was found to be the most effective filter setting for our analysis. We also found that separating the participants by sex produced markedly different gene lists. The gene lists obtained were investigated using gene ontology annotation, functional prioritisation and expression analysis, and this identified good candidates for further study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results suggest that relatively common as well as rare variants with a high predicted impact contribute to age-related hearing impairment and that the genetic contributions to adult hearing difficulty may differ between the sexes. Our manually curated list of deafness genes is a useful resource for candidate gene prioritisation in hearing loss.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12915-022-01349-5","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T11:02:45Z","timestamp":1656327765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Investigating the characteristics of genes and variants associated with self-reported hearing difficulty in older adults in the UK Biobank"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1846-8600","authenticated-orcid":false,"given":"Morag A.","family":"Lewis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley A.","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy R.","family":"Dubno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen P.","family":"Steel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"1349_CR1","unstructured":"Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage. https:\/\/hereditaryhearingloss.org\/. Accessed Dec 2021."},{"issue":"4","key":"1349_CR2","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.ajhg.2018.08.006","volume":"103","author":"H Azaiez","year":"2018","unstructured":"Azaiez H, Booth KT, Ephraim SS, Crone B, Black-Ziegelbein EA, Marini RJ, et al. Genomic landscape and mutational signatures of deafness-associated genes. Am J Hum Genet. 2018;103(4):484\u201397.","journal-title":"Am J Hum Genet"},{"issue":"4","key":"1349_CR3","first-page":"758","volume":"60","author":"G Van Camp","year":"1997","unstructured":"Van Camp G, Willems PJ, Smith RJ. Nonsyndromic hearing impairment: unparalleled heterogeneity. Am J Hum Genet. 1997;60(4):758\u201364.","journal-title":"Am J Hum Genet"},{"issue":"5","key":"1349_CR4","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/ng.355","volume":"41","author":"A Mencia","year":"2009","unstructured":"Mencia A, Modamio-Hoybjor S, Redshaw N, Morin M, Mayo-Merino F, Olavarrieta L, et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet. 2009;41(5):609\u201313.","journal-title":"Nat Genet"},{"issue":"49","key":"1349_CR5","doi-asserted-by":"publisher","first-page":"31278","DOI":"10.1073\/pnas.2010782117","volume":"117","author":"S Boucher","year":"2020","unstructured":"Boucher S, Tai FWJ, Delmaghani S, Lelli A, Singh-Estivalet A, Dupont T, et al. Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis. Proc Natl Acad Sci U S A. 2020;117(49):31278\u201389.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"1349_CR6","doi-asserted-by":"publisher","first-page":"7518","DOI":"10.1073\/pnas.102091699","volume":"99","author":"T Walsh","year":"2002","unstructured":"Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies\u2019 eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A. 2002;99(11):7518\u201323.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1349_CR7","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1750-1172-7-60","volume":"7","author":"JI Baek","year":"2012","unstructured":"Baek JI, Oh SK, Kim DB, Choi SY, Kim UK, Lee KY, et al. Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J Rare Dis. 2012;7:60.","journal-title":"Orphanet J Rare Dis"},{"issue":"9","key":"1349_CR8","doi-asserted-by":"publisher","first-page":"e1009025","DOI":"10.1371\/journal.pgen.1009025","volume":"16","author":"G Kalra","year":"2020","unstructured":"Kalra G, Milon B, Casella AM, Herb BR, Humphries E, Song Y, et al. Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty. Plos Genet. 2020;16(9):e1009025.","journal-title":"Plos Genet"},{"issue":"4","key":"1349_CR9","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1016\/j.ajhg.2019.09.008","volume":"105","author":"HRR Wells","year":"2019","unstructured":"Wells HRR, Freidin MB, Zainul Abidin FN, Payton A, Dawes P, Munro KJ, et al. GWAS identifies 44 independent associated genomic loci for self-reported adult hearing difficulty in UK Biobank. Am J Hum Genet. 2019;105(4):788\u2013802.","journal-title":"Am J Hum Genet"},{"issue":"2021","key":"1349_CR10","first-page":"2027","volume":"2021","author":"K Praveen","year":"2009","unstructured":"Praveen K, Dobbyn L, Gurski L, Ayer AH, Staples J, Mishra S, et al. Population-scale analysis of common and rare genetic variation associated with hearing loss in adults. medRxiv. 2009;2021(2021):2027\u201321264091.","journal-title":"medRxiv"},{"issue":"9","key":"1349_CR11","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1093\/oxfordjournals.aje.a009713","volume":"148","author":"KJ Cruickshanks","year":"1998","unstructured":"Cruickshanks KJ, Wiley TL, Tweed TS, Klein BE, Klein R, Mares-Perlman JA, et al. Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin. The Epidemiology of Hearing Loss Study. Am J Epidemiol. 1998;148(9):879\u201386.","journal-title":"Am J Epidemiol"},{"issue":"1-2","key":"1349_CR12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.heares.2009.09.009","volume":"259","author":"C Hederstierna","year":"2010","unstructured":"Hederstierna C, Hultcrantz M, Collins A, Rosenhall U. The menopause triggers hearing decline in healthy women. Hear Res. 2010;259(1-2):31\u20135.","journal-title":"Hear Res"},{"issue":"12","key":"1349_CR13","doi-asserted-by":"publisher","first-page":"2119","DOI":"10.1111\/j.1532-5415.2005.00525.x","volume":"53","author":"EP Helzner","year":"2005","unstructured":"Helzner EP, Cauley JA, Pratt SR, Wisniewski SR, Zmuda JM, Talbott EO, et al. Race and sex differences in age-related hearing loss: the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2005;53(12):2119\u201327.","journal-title":"J Am Geriatr Soc"},{"issue":"2","key":"1349_CR14","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nmeth.3739","volume":"13","author":"Y Itan","year":"2016","unstructured":"Itan Y, Shang L, Boisson B, Ciancanelli MJ, Markle JG, Martinez-Barricarte R, et al. The mutation significance cutoff: gene-level thresholds for variant predictions. Nat Methods. 2016;13(2):109\u201310.","journal-title":"Nat Methods"},{"issue":"1","key":"1349_CR15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000512576","volume":"85","author":"D Curtis","year":"2020","unstructured":"Curtis D. Multiple linear regression allows weighted burden analysis of rare coding variants in an ethnically heterogeneous population. Hum Hered. 2020;85(1):1\u201310.","journal-title":"Hum Hered"},{"issue":"1","key":"1349_CR16","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/ahg.12135","volume":"80","author":"Curtis D, Consortium UK","year":"2016","unstructured":"Curtis D, Consortium UK. Practical experience of the application of a weighted burden test to whole exome sequence data for obesity and schizophrenia. Ann Hum Genet. 2016;80(1):38\u201349.","journal-title":"Ann Hum Genet"},{"issue":"W1","key":"1349_CR17","doi-asserted-by":"publisher","first-page":"W191","DOI":"10.1093\/nar\/gkz369","volume":"47","author":"U Raudvere","year":"2019","unstructured":"Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, et al. g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 2019;47(W1):W191\u20138.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"1349_CR18","doi-asserted-by":"publisher","first-page":"3801","DOI":"10.1038\/s41467-019-11712-w","volume":"10","author":"X Wu","year":"2019","unstructured":"Wu X, Ivanchenko MV, Al Jandal H, Cicconet M, Indzhykulian AA, Corey DP. PKHD1L1 is a coat protein of hair-cell stereocilia and is required for normal hearing. Nat Commun. 2019;10(1):3801.","journal-title":"Nat Commun"},{"issue":"12","key":"1349_CR19","doi-asserted-by":"publisher","first-page":"4796","DOI":"10.1172\/JCI60405","volume":"121","author":"Y Kawashima","year":"2011","unstructured":"Kawashima Y, Geleoc GS, Kurima K, Labay V, Lelli A, Asai Y, et al. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest. 2011;121(12):4796\u2013809.","journal-title":"J Clin Invest"},{"issue":"Web Server issu","key":"1349_CR20","doi-asserted-by":"publisher","first-page":"W305","DOI":"10.1093\/nar\/gkp427","volume":"37","author":"J Chen","year":"2009","unstructured":"Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37(Web Server issue):W305\u201311.","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"1349_CR21","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1038\/s41592-021-01200-9","volume":"18","author":"J Orvis","year":"2021","unstructured":"Orvis J, Gottfried B, Kancherla J, Adkins RS, Song Y, Dror AA, et al. gEAR: Gene Expression Analysis Resource portal for community-driven, multi-omic data exploration. Nat Methods. 2021;18(8):843\u20134.","journal-title":"Nat Methods"},{"issue":"1","key":"1349_CR22","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/ng0994-77","volume":"8","author":"T Mochizuki","year":"1994","unstructured":"Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, et al. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet. 1994;8(1):77\u201381.","journal-title":"Nat Genet"},{"issue":"10","key":"1349_CR23","doi-asserted-by":"publisher","first-page":"4280","DOI":"10.1523\/JNEUROSCI.5063-14.2015","volume":"35","author":"AP Nagtegaal","year":"2015","unstructured":"Nagtegaal AP, Rainey RN, van der Pluijm I, Brandt RM, van der Horst GT, Borst JG, et al. Cockayne syndrome group B (Csb) and group a (Csa) deficiencies predispose to hearing loss and cochlear hair cell degeneration in mice. J Neurosci. 2015;35(10):4280\u20136.","journal-title":"J Neurosci"},{"issue":"1","key":"1349_CR24","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1121\/1.2817362","volume":"123","author":"JR Dubno","year":"2008","unstructured":"Dubno JR, Lee FS, Matthews LJ, Ahlstrom JB, Horwitz AR, Mills JH. Longitudinal changes in speech recognition in older persons. J Acoust Soc Am. 2008;123(1):462\u201375.","journal-title":"J Acoust Soc Am"},{"issue":"2","key":"1349_CR25","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1044\/jslhr.4002.444","volume":"40","author":"JR Dubno","year":"1997","unstructured":"Dubno JR, Lee FS, Matthews LJ, Mills JH. Age-related and gender-related changes in monaural speech recognition. J Speech Lang Hear Res. 1997;40(2):444\u201352.","journal-title":"J Speech Lang Hear Res"},{"issue":"1","key":"1349_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00003446-200502000-00001","volume":"26","author":"FS Lee","year":"2005","unstructured":"Lee FS, Matthews LJ, Dubno JR, Mills JH. Longitudinal study of pure-tone thresholds in older persons. Ear Hear. 2005;26(1):1\u201311.","journal-title":"Ear Hear"},{"issue":"2","key":"1349_CR27","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1121\/1.412231","volume":"97","author":"JD Pearson","year":"1995","unstructured":"Pearson JD, Morrell CH, Gordon-Salant S, Brant LJ, Metter EJ, Klein LL, et al. Gender differences in a longitudinal study of age-associated hearing loss. J Acoust Soc Am. 1995;97(2):1196\u2013205.","journal-title":"J Acoust Soc Am"},{"issue":"9","key":"1349_CR28","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1002\/jnr.24647","volume":"98","author":"LS Nolan","year":"2020","unstructured":"Nolan LS. Age-related hearing loss: why we need to think about sex as a biological variable. J Neurosci Res. 2020;98(9):1705\u201320.","journal-title":"J Neurosci Res"},{"key":"1349_CR29","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1111\/j.1749-6632.1999.tb08656.x","volume":"884","author":"JH Mills","year":"1999","unstructured":"Mills JH, Matthews LJ, Lee FS, Dubno JR, Schulte BA, Weber PC. Gender-specific effects of drugs on hearing levels of older persons. Ann N Y Acad Sci. 1999;884:381\u20138.","journal-title":"Ann N Y Acad Sci"},{"issue":"2","key":"1349_CR30","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1001\/archotol.1993.01880140038006","volume":"119","author":"GA Gates","year":"1993","unstructured":"Gates GA, Cobb JL, D'Agostino RB, Wolf PA. The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors. Arch Otolaryngol Head Neck Surg. 1993;119(2):156\u201361.","journal-title":"Arch Otolaryngol Head Neck Surg"},{"issue":"1","key":"1349_CR31","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/coa.12936","volume":"43","author":"HE Tan","year":"2018","unstructured":"Tan HE, Lan NSR, Knuiman MW, Divitini ML, Swanepoel DW, Hunter M, et al. Associations between cardiovascular disease and its risk factors with hearing loss-a cross-sectional analysis. Clin Otolaryngol. 2018;43(1):172\u201381.","journal-title":"Clin Otolaryngol"},{"issue":"1","key":"1349_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physrev.00021.2015","volume":"97","author":"V Regitz-Zagrosek","year":"2017","unstructured":"Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. 2017;97(1):1\u201337.","journal-title":"Physiol Rev"},{"issue":"1-2","key":"1349_CR33","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.heares.2010.05.007","volume":"268","author":"D Al-Mana","year":"2010","unstructured":"Al-Mana D, Ceranic B, Djahanbakhch O, Luxon LM. Alteration in auditory function during the ovarian cycle. Hear Res. 2010;268(1-2):114\u201322.","journal-title":"Hear Res"},{"issue":"2","key":"1349_CR34","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0378-5955(94)90112-0","volume":"80","author":"JR Coleman","year":"1994","unstructured":"Coleman JR, Campbell D, Cooper WA, Welsh MG, Moyer J. Auditory brainstem responses after ovariectomy and estrogen replacement in rat. Hear Res. 1994;80(2):209\u201315.","journal-title":"Hear Res"},{"issue":"4","key":"1349_CR35","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1055\/s-0037-1598601","volume":"21","author":"DDS Souza","year":"2017","unstructured":"Souza DDS, Luckwu B, Andrade WTL, Pessoa LSF, Nascimento JAD, Rosa M. Variation in the hearing threshold in women during the menstrual cycle. Int Arch Otorhinolaryngol. 2017;21(4):323\u20138.","journal-title":"Int Arch Otorhinolaryngol"},{"issue":"3","key":"1349_CR36","doi-asserted-by":"publisher","first-page":"191","DOI":"10.15252\/emmm.201505523","volume":"8","author":"A Buniello","year":"2016","unstructured":"Buniello A, Ingham NJ, Lewis MA, Huma AC, Martinez-Vega R, Varela-Nieto I, et al. Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing. EMBO Mol Med. 2016;8(3):191\u2013207.","journal-title":"EMBO Mol Med"},{"issue":"2","key":"1349_CR37","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1096\/fj.07-9171com","volume":"22","author":"O Konig","year":"2008","unstructured":"Konig O, Ruttiger L, Muller M, Zimmermann U, Erdmann B, Kalbacher H, et al. Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss. FASEB J. 2008;22(2):410\u20137.","journal-title":"FASEB J"},{"issue":"8","key":"1349_CR38","doi-asserted-by":"publisher","first-page":"2077 e2071","DOI":"10.1016\/j.neurobiolaging.2013.02.009","volume":"34","author":"LS Nolan","year":"2013","unstructured":"Nolan LS, Maier H, Hermans-Borgmeyer I, Girotto G, Ecob R, Pirastu N, et al. Estrogen-related receptor gamma and hearing function: evidence of a role in humans and mice. Neurobiol Aging. 2013;34(8):2077 e2071\u20139.","journal-title":"Neurobiol Aging"},{"key":"1349_CR39","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1093\/oxfordjournals.bmb.a069918","volume":"17","author":"CO Carter","year":"1961","unstructured":"Carter CO. The inheritance of congenital pyloric stenosis. Br Med Bull. 1961;17:251\u20134.","journal-title":"Br Med Bull"},{"issue":"3","key":"1349_CR40","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1136\/jmg.6.3.233","volume":"6","author":"CO Carter","year":"1969","unstructured":"Carter CO, Evans KA. Inheritance of congenital pyloric stenosis. J Med Genet. 1969;6(3):233\u201354.","journal-title":"J Med Genet"},{"issue":"11","key":"1349_CR41","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1002\/humu.23630","volume":"39","author":"AM Oza","year":"2018","unstructured":"Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, et al. Expert specification of the ACMG\/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39(11):1593\u2013613.","journal-title":"Hum Mutat"},{"key":"1349_CR42","doi-asserted-by":"crossref","unstructured":"Trpchevska N, Freidin MB, Broer L, Oosterloo BC, Yao S, Zhou Y, et al. Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss. Am J Hum Genet. 2022;109(6):1077\u201391.","DOI":"10.1016\/j.ajhg.2022.04.010"},{"issue":"1","key":"1349_CR43","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s42003-021-02224-9","volume":"4","author":"EV Ivarsdottir","year":"2021","unstructured":"Ivarsdottir EV, Holm H, Benonisdottir S, Olafsdottir T, Sveinbjornsson G, Thorleifsson G, et al. The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis. Commun Biol. 2021;4(1):706.","journal-title":"Commun Biol"},{"key":"1349_CR44","doi-asserted-by":"publisher","unstructured":"Kelly JJ, Abitbol JM, Hulme S, Press ER, Laird DW, Allman BL. The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss. J Cell Sci. 2019;132(2);jcs224097. https:\/\/doi.org\/10.1242\/jcs.224097.","DOI":"10.1242\/jcs.224097"},{"key":"1349_CR45","unstructured":"Akbari P, Gilani A, Sosina O, Kosmicki JA, Khrimian L, Fang YY, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021;373(6550)."},{"issue":"6572","key":"1349_CR46","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1126\/science.abe0348","volume":"374","author":"ME Montasser","year":"2021","unstructured":"Montasser ME, Van Hout CV, Miloscio L, Howard AD, Rosenberg A, Callaway M, et al. Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen. Science. 2021;374(6572):1221\u20137.","journal-title":"Science"},{"issue":"8","key":"1349_CR47","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1038\/s41431-020-0603-2","volume":"28","author":"SS Cherny","year":"2020","unstructured":"Cherny SS, Livshits G, Wells HRR, Freidin MB, Malkin I, Dawson SJ, et al. Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank. Eur J Hum Genet. 2020;28(8):1056\u201365.","journal-title":"Eur J Hum Genet"},{"issue":"5","key":"1349_CR48","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1007\/s10162-013-0396-x","volume":"14","author":"JR Dubno","year":"2013","unstructured":"Dubno JR, Eckert MA, Lee FS, Matthews LJ, Schmiedt RA. Classifying human audiometric phenotypes of age-related hearing loss from animal models. J Assoc Res Otolaryngol. 2013;14(5):687\u2013701.","journal-title":"J Assoc Res Otolaryngol"},{"issue":"2","key":"1349_CR49","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/s10162-016-0596-2","volume":"18","author":"KI Vaden Jr","year":"2017","unstructured":"Vaden KI Jr, Matthews LJ, Eckert MA, Dubno JR. Longitudinal changes in audiometric phenotypes of age-related hearing loss. J Assoc Res Otolaryngol. 2017;18(2):371\u201385.","journal-title":"J Assoc Res Otolaryngol"},{"key":"1349_CR50","doi-asserted-by":"crossref","unstructured":"Vaden KI, Eckert MA, Matthews LJ, Schmiedt RA, Dubno JR. Metabolic and sensory components of age-related hearing loss. J Assoc Res Otolaryngol. 2022.","DOI":"10.1007\/s10162-021-00826-y"},{"issue":"9","key":"1349_CR51","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1093\/aje\/kwx246","volume":"186","author":"A Fry","year":"2017","unstructured":"Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, et al. Comparison of sociodemographic and health-related characteristics of uk biobank participants with those of the general population. Am J Epidemiol. 2017;186(9):1026\u201334.","journal-title":"Am J Epidemiol"},{"issue":"7","key":"1349_CR52","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/s41588-021-00885-0","volume":"53","author":"JD Szustakowski","year":"2021","unstructured":"Szustakowski JD, Balasubramanian S, Kvikstad E, Khalid S, Bronson PG, Sasson A, et al. Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank. Nat Genet. 2021;53(7):942\u20138.","journal-title":"Nat Genet"},{"issue":"7831","key":"1349_CR53","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/s41586-020-2853-0","volume":"586","author":"CV Van Hout","year":"2020","unstructured":"Van Hout CV, Tachmazidou I, Backman JD, Hoffman JD, Liu D, Pandey AK, et al. Exome sequencing and characterization of 49,960 individuals in the UK Biobank. Nature. 2020;586(7831):749\u201356.","journal-title":"Nature"},{"issue":"1","key":"1349_CR54","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The Ensembl variant effect predictor. Genome Biol. 2016;17(1):122.","journal-title":"Genome Biol"},{"issue":"3","key":"1349_CR55","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.ajhg.2016.07.005","volume":"99","author":"D Smedley","year":"2016","unstructured":"Smedley D, Schubach M, Jacobsen JOB, Kohler S, Zemojtel T, Spielmann M, et al. A whole-genome analysis framework for effective identification of pathogenic regulatory variants in mendelian disease. Am J Hum Genet. 2016;99(3):595\u2013606.","journal-title":"Am J Hum Genet"},{"issue":"3","key":"1349_CR56","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","volume":"176","author":"K Jaganathan","year":"2019","unstructured":"Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. Predicting splicing from primary sequence with deep learning. Cell. 2019;176(3):535\u2013548 e524.","journal-title":"Cell"},{"key":"1349_CR57","unstructured":"Pajusalu S. 5utr. https:\/\/github.com\/leklab\/5utr. 2021."},{"issue":"D1","key":"1349_CR58","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886\u201394.","journal-title":"Nucleic Acids Res"},{"issue":"7809","key":"1349_CR59","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434\u201343.","journal-title":"Nature"},{"issue":"7571","key":"1349_CR60","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"A Auton","year":"2015","unstructured":"Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68\u201374.","journal-title":"Nature"},{"issue":"7845","key":"1349_CR61","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s41586-021-03205-y","volume":"590","author":"D Taliun","year":"2021","unstructured":"Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290\u20139.","journal-title":"Nature"},{"issue":"7431","key":"1349_CR62","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nature11690","volume":"493","author":"W Fu","year":"2013","unstructured":"Fu W, O'Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493(7431):216\u201320.","journal-title":"Nature"},{"issue":"3","key":"1349_CR63","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1073\/pnas.1808403116","volume":"116","author":"P Maffucci","year":"2019","unstructured":"Maffucci P, Bigio B, Rapaport F, Cobat A, Borghesi A, Lopez M, et al. Blacklisting variants common in private cohorts but not in public databases optimizes human exome analysis. Proc Natl Acad Sci U S A. 2019;116(3):950\u20139.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"8","key":"1349_CR64","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1038\/s41431-018-0126-2","volume":"26","author":"D Vuckovic","year":"2018","unstructured":"Vuckovic D, Mezzavilla M, Cocca M, Morgan A, Brumat M, Catamo E, et al. Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection. Eur J Hum Genet. 2018;26(8):1167\u201379.","journal-title":"Eur J Hum Genet"},{"issue":"1","key":"1349_CR65","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/s41431-018-0272-6","volume":"27","author":"D Curtis","year":"2019","unstructured":"Curtis D. A weighted burden test using logistic regression for integrated analysis of sequence variants, copy number variants and polygenic risk score. Eur J Hum Genet. 2019;27(1):114\u201324.","journal-title":"Eur J Hum Genet"},{"key":"1349_CR66","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.","journal-title":"Gigascience"},{"issue":"4","key":"1349_CR67","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/s41588-021-00825-y","volume":"53","author":"MC Birling","year":"2021","unstructured":"Birling MC, Yoshiki A, Adams DJ, Ayabe S, Beaudet AL, Bottomley J, et al. A resource of targeted mutant mouse lines for 5,061 genes. Nat Genet. 2021;53(4):416\u20139.","journal-title":"Nat Genet"},{"issue":"7621","key":"1349_CR68","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/nature19356","volume":"537","author":"ME Dickinson","year":"2016","unstructured":"Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537(7621):508\u201314.","journal-title":"Nature"},{"issue":"4","key":"1349_CR69","doi-asserted-by":"publisher","first-page":"e3000194","DOI":"10.1371\/journal.pbio.3000194","volume":"17","author":"NJ Ingham","year":"2019","unstructured":"Ingham NJ, Pearson SA, Vancollie VE, Rook V, Lewis MA, Chen J, et al. Mouse screen reveals multiple new genes underlying mouse and human hearing loss. Plos Biol. 2019;17(4):e3000194.","journal-title":"Plos Biol"},{"issue":"6","key":"1349_CR70","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s10162-016-0589-1","volume":"17","author":"KK Ohlemiller","year":"2016","unstructured":"Ohlemiller KK, Jones SM, Johnson KR. Application of mouse models to research in hearing and balance. J Assoc Res Otolaryngol. 2016;17(6):493\u2013523.","journal-title":"J Assoc Res Otolaryngol"},{"issue":"2","key":"1349_CR71","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1111\/j.1399-0004.2007.00739.x","volume":"71","author":"S Kitajiri","year":"2007","unstructured":"Kitajiri S, Makishima T, Friedman TB, Griffith AJ. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin Genet. 2007;71(2):148\u201352.","journal-title":"Clin Genet"},{"issue":"3","key":"1349_CR72","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/ng842","volume":"30","author":"K Kurima","year":"2002","unstructured":"Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002;30(3):277\u201384.","journal-title":"Nat Genet"},{"issue":"4","key":"1349_CR73","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1002\/humu.22035","volume":"33","author":"DR Adams","year":"2012","unstructured":"Adams DR, Sincan M, Fuentes Fajardo K, Mullikin JC, Pierson TM, Toro C, et al. Analysis of DNA sequence variants detected by high-throughput sequencing. Hum Mutat. 2012;33(4):599\u2013608.","journal-title":"Hum Mutat"},{"issue":"4","key":"1349_CR74","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1002\/humu.22033","volume":"33","author":"KV Fuentes Fajardo","year":"2012","unstructured":"Fuentes Fajardo KV, Adams D, Program NCS, Mason CE, Sincan M, Tifft C, et al. Detecting false-positive signals in exome sequencing. Hum Mutat. 2012;33(4):609\u201313.","journal-title":"Hum Mutat"},{"issue":"Suppl 8","key":"1349_CR75","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1186\/s12864-019-5863-2","volume":"20","author":"MA Field","year":"2019","unstructured":"Field MA, Burgio G, Chuah A, Al Shekaili J, Hassan B, Al Sukaiti N, et al. Recurrent miscalling of missense variation from short-read genome sequence data. BMC Genomics. 2019;20(Suppl 8):546.","journal-title":"BMC Genomics"},{"key":"1349_CR76","volume-title":"Characterization of cochlear development at the single cell level","author":"MC Kelly","year":"2020","unstructured":"Kelly MC, Kolla L, Kelley LA, Morell RJ. Characterization of cochlear development at the single cell level: GEO; 2020. https:\/\/identifiers.org\/geo. GSE137299. Accessed Dec 2021"},{"issue":"1","key":"1349_CR77","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.1038\/s41467-020-16113-y","volume":"11","author":"L Kolla","year":"2020","unstructured":"Kolla L, Kelly MC, Mann ZF, Anaya-Rocha A, Ellis K, Lemons A, et al. Characterization of the development of the mouse cochlear epithelium at the single cell level. Nat Commun. 2020;11(1):2389.","journal-title":"Nat Commun"},{"issue":"11","key":"1349_CR78","doi-asserted-by":"publisher","first-page":"3160","DOI":"10.1016\/j.celrep.2019.02.053","volume":"26","author":"PT Ranum","year":"2019","unstructured":"Ranum PT, Goodwin AT, Yoshimura H, Kolbe DL, Walls WD, Koh JY, et al. Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing. Cell Rep. 2019;26(11):3160\u20133171 e3163.","journal-title":"Cell Rep"},{"key":"1349_CR79","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.053","volume-title":"Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing","author":"PT Ranum","year":"2019","unstructured":"Ranum PT, Smith RJ. Insights into the biology of hearing and deafness revealed by single-cell RNA sequencing: GEO; 2019. https:\/\/identifiers.org\/geo. GSE114157. Accessed Dec 2021"},{"key":"1349_CR80","doi-asserted-by":"publisher","first-page":"108347","DOI":"10.1016\/j.heares.2021.108347","volume":"410","author":"N Xue","year":"2021","unstructured":"Xue N, Song L, Song Q, Santos-Sacchi J, Wu H, Navaratnam D. Genes related to SNPs identified by genome-wide association studies of age-related hearing loss show restriction to specific cell types in the adult mouse cochlea. Hear Res. 2021;410:108347.","journal-title":"Hear Res"},{"key":"1349_CR81","volume-title":"scRNA-seq of P20 mouse cochlea","author":"N Xue","year":"2021","unstructured":"Xue N, Song L, Wu H, Navaratnam D. scRNA-seq of P20 mouse cochlea: GEO; 2021. https:\/\/identifiers.org\/geo. GSE181454. Accessed Dec 2021."},{"key":"1349_CR82","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3389\/fnmol.2018.00356","volume":"11","author":"H Liu","year":"2018","unstructured":"Liu H, Chen L, Giffen KP, Stringham ST, Li Y, Judge PD, et al. Cell-specific transcriptome analysis shows that adult pillar and Deiters\u2019 cells express genes encoding machinery for specializations of cochlear hair cells. Front Mol Neurosci. 2018;11:356.","journal-title":"Front Mol Neurosci"},{"key":"1349_CR83","volume-title":"RNA-sequencing of adult mouse inner hair cells and outer hair cells of the organ of Corti","author":"H Liu","year":"2018","unstructured":"Liu H, Chen L, Giffen KP, Stringham ST, Li Y, Judge PD, et al. RNA-sequencing of adult mouse inner hair cells and outer hair cells of the organ of Corti: GEO; 2018. https:\/\/identifiers.org\/geo. GSE111348. Accessed Dec 2021"},{"key":"1349_CR84","volume-title":"RNA-sequencing of adult mouse pillar and Deiters\u2019 supporting cells of the organ of Cort","author":"H Liu","year":"2018","unstructured":"Liu H, Chen L, Giffen KP, Stringham ST, Li Y, Judge PD, et al. RNA-sequencing of adult mouse pillar and Deiters\u2019 supporting cells of the organ of Cort: GEO; 2018. https:\/\/identifiers.org\/geo. GSE111347. Accessed Dec 2021"},{"key":"1349_CR85","volume-title":"Characterizing cellular heterogeneity and homeostatic gene regulatory networks in the adult mammalian stria vascularis using single cell and single nucleus transcriptional profiling","author":"M Hoa","year":"2019","unstructured":"Hoa M. Characterizing cellular heterogeneity and homeostatic gene regulatory networks in the adult mammalian stria vascularis using single cell and single nucleus transcrivariable genes showed significant enrichment, in a subset of the listsptional profiling: GEO; 2019. https:\/\/identifiers.org\/geo. GSE136196. Accessed Dec 2021"},{"key":"1349_CR86","doi-asserted-by":"publisher","first-page":"316","DOI":"10.3389\/fnmol.2019.00316","volume":"12","author":"S Korrapati","year":"2019","unstructured":"Korrapati S, Taukulis I, Olszewski R, Pyle M, Gu S, Singh R, et al. Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis. Front Mol Neurosci. 2019;12:316.","journal-title":"Front Mol Neurosci"},{"issue":"1","key":"1349_CR87","doi-asserted-by":"publisher","first-page":"3691","DOI":"10.1038\/s41467-018-06033-3","volume":"9","author":"C Petitpre","year":"2018","unstructured":"Petitpre C, Wu H, Sharma A, Tokarska A, Fontanet P, Wang Y, et al. Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system. Nat Commun. 2018;9(1):3691.","journal-title":"Nat Commun"},{"key":"1349_CR88","doi-asserted-by":"crossref","unstructured":"Petitpre C, Wu H, Sharma A, Tokarska A, Fontanet P, Wang Y, et al. Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system. GEO. 2018; https:\/\/identifiers.org\/geo. GSE117055. Accessed Dec 2021.","DOI":"10.1038\/s41467-018-06033-3"}],"container-title":["BMC Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12915-022-01349-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12915-022-01349-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12915-022-01349-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T22:05:57Z","timestamp":1666562757000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcbiol.biomedcentral.com\/articles\/10.1186\/s12915-022-01349-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,27]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["1349"],"URL":"https:\/\/doi.org\/10.1186\/s12915-022-01349-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.01.28.22269991","asserted-by":"object"}]},"ISSN":["1741-7007"],"issn-type":[{"value":"1741-7007","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,27]]},"assertion":[{"value":"31 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"UK Biobank has ethics approval from the North West Multi-centre Research Ethics Committee (MREC), as a Research Tissue Bank (RTB) approval (number 21\/NW\/0157). Informed consent was obtained from all participants. Use of the relevant data for this study has been approved by the UK Biobank (ID 49593).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"150"}}