{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T09:19:36Z","timestamp":1771060776033,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,11]]},"group-title":"Genetic and Genomic Medicine","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  M\u00e9ni\u00e8re\u2019s disease (MD) is a chronic inner ear disorder characterized by recurrent vertigo, fluctuating sensorineural hearing loss, and tinnitus. Despite these distinctive symptoms, its etiology remains poorly understood. We performed a genome-wide meta-analysis of 8,969 cases and 1,962,542 controls across five large biobanks, identifying five independent genome-wide significant loci and estimating an observed-scale SNP heritability of 7% (SE 0.8%), consistent with a modest but significant genetic contribution to MD risk. Fine-mapping and integrative functional analyses implicate two convergent biological processes \u2013 developmental regulation of the inner ear, involving\n                  <jats:italic>EYA4, EYA1<\/jats:italic>\n                  , and\n                  <jats:italic>LMO4<\/jats:italic>\n                  \u2013 and retinoic acid metabolism, with loci near\n                  <jats:italic>CYP26A1\/C1<\/jats:italic>\n                  and\n                  <jats:italic>ALDH1A2<\/jats:italic>\n                  suggesting disrupted RA signaling in sensory and fluid-pressure homeostasis. These developmental regulator genes are robustly expressed in fetal and adult human inner ear cell types, supporting a model in which altered developmental programs predispose to adult vestibular and auditory dysfunction. Phenome-wide and genetic correlation analyses further reveal shared genetic architecture between MD and related traits, including vertigo, tinnitus, hearing loss, migraine, and sleep apnea, situating MD within a broader spectrum of sensory and neurological disorders. Collectively, these findings establish a genetic framework for M\u00e9ni\u00e8re\u2019s disease risk and implicate developmental regulators and retinoic acid signaling as key contributing pathways.\n                <\/jats:p>","DOI":"10.64898\/2026.02.09.26345758","type":"posted-content","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:15:31Z","timestamp":1770855331000},"source":"Crossref","is-referenced-by-count":0,"title":["Genome-wide analysis implicates inner ear development in M\u00e9ni\u00e8re\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9769-9027","authenticated-orcid":false,"given":"Zhuozheng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 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Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan (Eleanor)","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sixing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5906-9446","authenticated-orcid":false,"given":"Sandra","family":"Lapinska","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander O.","family":"Flynn-Carroll","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0227-2056","authenticated-orcid":false,"given":"Bogdan","family":"Pasaniuc","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"name":"Department of Computer and Information Science, School of 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