{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:51:41Z","timestamp":1791474701002,"version":"4.3.4"},"reference-count":53,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Otolaryngol Head Neck Surg"],"abstract":"\n Importance<\/jats:title>\n The genetic architecture underlying hearing sensitivity as a quantitative trait is critical for advancing precision medicine in hearing health. Despite extensive genome-wide association study (GWAS) efforts, few strong genetic drivers have been identified.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To compare the sensitivity for detecting genetic variants associated with sensorineural hearing loss (SNHL) using precision phenotyping with pure-tone averages (PTAs) with common phenotyping using diagnostic coding approaches.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n In this genetic association study, 2 separate GWASs were conducted using different phenotyping approaches for SNHL: (1) diagnostic code control and (2) precision phenotyping with PTA data. Whole-genome sequencing data from a population with European genetic ancestry collected at a single tertiary center biobank was used. For the control GWAS based on diagnostic codes, case and control participants were defined using primarily\n International Classification of Diseases, Ninth Revision<\/jats:italic>\n (\n ICD-9<\/jats:italic>\n ) and\n International Statistical Classification of Diseases and Related Health Problems, Tenth Revision<\/jats:italic>\n (\n ICD-10<\/jats:italic>\n ) diagnosis and procedure codes related to SNHL hearing loss. For the precision phenotyping GWAS, hearing status was defined as a continuous variable, using the standard 3-frequency PTA of the better hearing ear from the audiogram. Data analysis was conducted from August 2025 to April 2026.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n GWAS summary statistics were used to calculate estimates of single-nucleotide variant (SNV)\u2013based heritability for PTA and\n ICD<\/jats:italic>\n phenotypes; to map the genetic risk loci to candidate genes using functional annotation; to evaluate genetic correlations with existing GWASs; and to calculate polygenic risk scores for testing in an independent cohort from the National Institutes of Health\u2019s All of Us Research Program.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Overall, 10\u202f164 case participants (mean [SD] age, 63.9 [21.3] years; 5118 [50.4%] female) and 51\u202f305 control participants (mean [SD] age, 51.1 [21.0] years; 28\u202f784 [56.1%] female) were included in the first GWAS; 16\u202f057 participants with PTA (mean [SD] age, 55.5 [21.8] years; 9147 [57.0%] female) were included in the second GWAS. PTA-based GWAS identified 3 genome-wide significant loci mapped to 4 genes:\n EML6<\/jats:italic>\n ,\n SPTBN1<\/jats:italic>\n ,\n ARHGEF28<\/jats:italic>\n , and\n EYA4<\/jats:italic>\n (SNV-based heritability estimate [\n h<\/jats:italic>\n 2<\/jats:sup>\n ]\u2009=\u200911.78%; SE\u2009=\u20092.84%).\n ICD<\/jats:italic>\n -based GWAS identified no significant loci (\n h<\/jats:italic>\n 2<\/jats:sup>\n \u2009=\u20092.90%; SE\u2009=\u20090.77%). Genome-wide correlations between the PTA-based GWAS and 3 hearing-related ability traits were found (eg, PTA-based GWAS and hearing aid use:\n r<\/jats:italic>\n \u2009=\u20090.985; SE\u2009=\u20090.163;\n P<\/jats:italic>\n \u2009=\u20091.56\u2009\u00d7\u200910\n \u22129<\/jats:sup>\n ). In the All of Us cohort, PTA-derived polygenic risk scores were significantly associated with self-reported deafness (odds ratio [OR], 1.09; 95% CI, 1.07-1.12), whereas\n ICD<\/jats:italic>\n -derived scores were not (OR, 1.00; 95% CI, 0.97-1.02).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this genetic association study, precision phenotyping using audiometric PTAs improved genetic discovery for SNHL compared with diagnostic code\u2013based approaches. Higher heritability estimates, identification of genome-wide significant loci, and stronger polygenic risk estimation indicate that quantitative hearing measures better capture genetic architecture, supporting precision medicine in hearing health.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoto.2026.3089","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:00:18Z","timestamp":1791471618000},"source":"Crossref","is-referenced-by-count":0,"title":["Precision Phenotyping With Audiometric Data and Gene Discovery for Sensorineural Hearing Loss"],"prefix":"10.1001","author":[{"given":"Andrea J.","family":"DeFreese","sequence":"first","affiliation":[{"name":"Department of Hearing and Speech Sciences, Vanderbilt University, Nashville, Tennessee"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanguy","family":"Rubat du M\u00e9rac","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Human Genetics Program, Vanderbilt School of Medicine, Vanderbilt University, Nashville, Tennessee"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanhu","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srishti","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taha A.","family":"Jan","sequence":"additional","affiliation":[{"name":"Department of Hearing and Speech Sciences, Vanderbilt University, Nashville, Tennessee"},{"name":"Department of Otolaryngology\u2013Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee"},{"name":"Department of Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt Center for Stem Cell Biology, Center for Computational Systems Biology, Vanderbilt University Medical Center, Nashville, 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