{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:58:39Z","timestamp":1768571919645,"version":"3.49.0"},"posted":{"date-parts":[[2025,11,6]]},"group-title":"Genetic and Genomic Medicine","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Neurodevelopmental disorders have been associated with hearing problems (HP) later in life, but there is limited information regarding their shared biology.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We leveraged large-scale genome-wide datasets to estimate genetic correlation (global and local), polygenic overlap, and locus-specific pleiotropy among HP, autism spectrum disorder (ASD), attention-deficit\/hyperactivity disorder (ADHD), and Tourette syndrome (TS). Then, we investigated shared molecular functions, biological processes, and cellular components, and performed a drug-repurposing analysis to identify compounds that may target the pathogenic processes linking neurodevelopmental disorders to HP.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We observed high genetic correlation of HP with ASD (rg=0.72) and TS (rg=0.69). While HP-ADHD genetic correlation was low (rg=0.07), 40% of the causal variants were shared between these conditions, with only 53% of them showing concordant effect directions. We also identified nine chromosomal regions with evidence of ADHD-HP local genetic correlations with pleiotropic effects on other outcomes such as smoking initiation, brain-imaging phenotypes, and bilirubin levels. With respect to HP-ASD, we observed an inverse local genetic correlation within\n                    <jats:italic>CD33<\/jats:italic>\n                    chromosomal region. Pleiotropy among HP, ASD, and ADHD was also identified in two variants (rs325485 and rs2207286) included within 95% credible sets related to neuropsychiatric conditions, altered hearing function, and other traits such as risk taking and insomnia. Drug-repurposing analyses identified anisomycin for HP-ASD shared biological mechanisms and five compounds related to HP-ADHD pleiotropy.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings provide evidence that the comorbidity between neurodevelopmental disorders and HP is at least partially due to shared pathogenic processes acting through intrinsic and extrinsic factors.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.03.25339410","type":"posted-content","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T17:25:16Z","timestamp":1762449916000},"source":"Crossref","is-referenced-by-count":0,"title":["Genome-wide investigation highlights global and local pleiotropy linking neurodevelopmental disorders to acquired hearing 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