{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:28:46Z","timestamp":1768516126645,"version":"3.49.0"},"posted":{"date-parts":[[2024,11,2]]},"group-title":"Genetics","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T00:00:00Z","timestamp":1730505600000},"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":[[2024,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Our ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus,\n                  <jats:italic>GDF5<\/jats:italic>\n                  associates with many diseases and has a complex cis-regulatory architecture. We interrogate\n                  <jats:italic>GDF5<\/jats:italic>\n                  regulatory interactions and model disease variants\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . For all regulatory regions we see that local epigenetic activation\/repression impacts patterns of joint-specific expression and disease risk. By modeling the most cited risk variant in mice we found that it had no impact on expression, joint morphology, or disease. Yet, we identified significant epistatic expression interactions between this risk variant and others lying within regulatory regions subject to repression or activation. These findings are important lessons on how regulatory interactions and local epistasis work in the etiology of disease risk, and that assessment of individual variants of high GWAS significance need not alone be considered causal.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Teaser<\/jats:title>\n                  <jats:p>Genetic interactions at the most studied skeletal disease locus reveal hidden complexities in pinpointing causal mutations.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.11.01.621374","type":"posted-content","created":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T04:55:16Z","timestamp":1730523316000},"source":"Crossref","is-referenced-by-count":0,"title":["Complex regulatory interactions at\n                  <i>GDF5<\/i>\n                  shape joint morphology and osteoarthritis disease risk"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8177-7353","authenticated-orcid":false,"given":"Clarissa R.","family":"Coveney","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Maridas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pushpanathan","family":"Muthuirulan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn","family":"Jagoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siddharth","family":"Yarlagadda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammadreza","family":"Movahhedi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Proffen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vicki","family":"Rosen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7742-5769","authenticated-orcid":false,"given":"Ata M.","family":"Kiapour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terence D.","family":"Capellini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024110504150778000_2024.11.01.621374v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(23)00163-7"},{"key":"2024110504150778000_2024.11.01.621374v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2011.11.013"},{"key":"2024110504150778000_2024.11.01.621374v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2019.09.018"},{"key":"2024110504150778000_2024.11.01.621374v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2012.09.012"},{"key":"2024110504150778000_2024.11.01.621374v1.5","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000673"},{"key":"2024110504150778000_2024.11.01.621374v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2020.12.003"},{"key":"2024110504150778000_2024.11.01.621374v1.7","doi-asserted-by":"publisher","DOI":"10.1097\/BPO.0b013e3182770a8d"},{"key":"2024110504150778000_2024.11.01.621374v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3605"},{"key":"2024110504150778000_2024.11.01.621374v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24345-9"},{"key":"2024110504150778000_2024.11.01.621374v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abq4884"},{"key":"2024110504150778000_2024.11.01.621374v1.11","doi-asserted-by":"publisher","DOI":"10.1242\/dev.122.12.3969"},{"key":"2024110504150778000_2024.11.01.621374v1.12","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5368.1455"},{"key":"2024110504150778000_2024.11.01.621374v1.13","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.9129"},{"key":"2024110504150778000_2024.11.01.621374v1.14","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212475"},{"key":"2024110504150778000_2024.11.01.621374v1.15","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.134619"},{"key":"2024110504150778000_2024.11.01.621374v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm174"},{"key":"2024110504150778000_2024.11.01.621374v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/art.24616"},{"key":"2024110504150778000_2024.11.01.621374v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3911"},{"key":"2024110504150778000_2024.11.01.621374v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006454"},{"key":"2024110504150778000_2024.11.01.621374v1.20","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003557"},{"key":"2024110504150778000_2024.11.01.621374v1.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-014-1447-z"},{"key":"2024110504150778000_2024.11.01.621374v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/2005"},{"key":"2024110504150778000_2024.11.01.621374v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac251"},{"key":"2024110504150778000_2024.11.01.621374v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-57011-8"},{"key":"2024110504150778000_2024.11.01.621374v1.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0202785"},{"key":"2024110504150778000_2024.11.01.621374v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.057"},{"key":"2024110504150778000_2024.11.01.621374v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.4.1612"},{"key":"2024110504150778000_2024.11.01.621374v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/148.1.401"},{"key":"2024110504150778000_2024.11.01.621374v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/368639a0"},{"key":"2024110504150778000_2024.11.01.621374v1.30","doi-asserted-by":"publisher","DOI":"10.1101\/gr.225502. Article published online before print in April 2002"},{"key":"2024110504150778000_2024.11.01.621374v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh095"},{"key":"2024110504150778000_2024.11.01.621374v1.32","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01811"},{"key":"2024110504150778000_2024.11.01.621374v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(98)00216-0"},{"key":"2024110504150778000_2024.11.01.621374v1.34","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104935"},{"key":"2024110504150778000_2024.11.01.621374v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.143"},{"key":"2024110504150778000_2024.11.01.621374v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199904)214:4<291::AID-AJA2>3.0.CO;2-E"},{"key":"2024110504150778000_2024.11.01.621374v1.37","doi-asserted-by":"crossref","unstructured":"Roberts JB , Rice SJ . Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease. Current rheumatology reports. 2024.","DOI":"10.1007\/s11926-024-01142-z"},{"key":"2024110504150778000_2024.11.01.621374v1.38","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-017-0787-1"},{"key":"2024110504150778000_2024.11.01.621374v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10439-y"},{"key":"2024110504150778000_2024.11.01.621374v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.07.038"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.11.01.621374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:22:26Z","timestamp":1768461746000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.11.01.621374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,2]]},"references-count":40,"URL":"https:\/\/doi.org\/10.1101\/2024.11.01.621374","relation":{},"subject":[],"published":{"date-parts":[[2024,11,2]]},"subtype":"preprint"}}