{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:20:38Z","timestamp":1785464438519,"version":"3.56.0"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R21 DC018098"],"award-info":[{"award-number":["R21 DC018098"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R33 DA047527"],"award-info":[{"award-number":["R33 DA047527"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["RF1 MH132337"],"award-info":[{"award-number":["RF1 MH132337"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K99 AG078503"],"award-info":[{"award-number":["K99 AG078503"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer\u2019s Association Research Fellowship","award":["AARF-22-967171"],"award-info":[{"award-number":["AARF-22-967171"]}]},{"name":"Yale Franke Program in Science and Humanities"},{"DOI":"10.13039\/100010665","name":"Horizon 2020 Marie Sklodowska-Curie Individual Fellowship","doi-asserted-by":"publisher","award":["101028810"],"award-info":[{"award-number":["101028810"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hearing difficulty (HD) is a major health burden in older adults. While ageing-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition.<\/jats:p>\n               <jats:p>We analysed a large-scale HD genome-wide association study (GWAS; ntotal = 501 825, 56% females) and GWAS data related to 3935 brain imaging-derived phenotypes (IDPs) assessed in up to 33 224 individuals (52% females) using multiple MRI modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait co-localization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs.<\/jats:p>\n               <jats:p>We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 in males and 171 in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven of them, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume\u2192HD in the sex-combined analysis; hippocampus volume\u2192HD, cerebellum grey matter volume\u2192HD, primary visual cortex volume\u2192HD and HD\u2192fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness\u2192HD and HD\u2192mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a co-localization signal for the rs13026575 variant between HD, primary visual cortex volume and SPTBN1 transcriptomic regulation in females.<\/jats:p>\n               <jats:p>Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.<\/jats:p>","DOI":"10.1093\/brain\/awae077","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T05:46:25Z","timestamp":1709876785000},"page":"3395-3408","source":"Crossref","is-referenced-by-count":17,"title":["Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation"],"prefix":"10.1093","volume":"147","author":[{"given":"Jun","family":"He","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Cabrera-Mendoza","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), Veteran Affairs Connecticut Healthcare System , West Haven, CT 06516 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"De Angelis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gita A","family":"Pathak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), Veteran Affairs Connecticut Healthcare System , West Haven, CT 06516 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora","family":"Koller","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona , Barcelona 08028 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon G","family":"Curhan","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary C","family":"Curhan","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P","family":"Mecca","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Alzheimer\u2019s Disease Research Unit, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher H","family":"van Dyck","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Alzheimer\u2019s Disease Research Unit, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Departments of Neuroscience and Neurology, Yale University School of Medicine , New Haven, CT 06511 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-6046","authenticated-orcid":false,"given":"Renato","family":"Polimanti","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yale University School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Cooperative Studies Program Clinical Epidemiology Research Center (CSP-CERC), Veteran Affairs Connecticut Healthcare System , West Haven, CT 06516 ,","place":["USA"]},{"name":"Wu Tsai Institute, Yale University , New Haven, CT 06511 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