{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:10:31Z","timestamp":1793139031578,"version":"4.5.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Mitral valve prolapse (MVP) is a common heart valve disease, the most frequent indication for valve repair or replacement. MVP is characterized by excess extracellular matrix secretion and cellular disorganization, which leads to bulky valves that are unable to coapt correctly during ventricular systole resulting in mitral regurgitation, and it is associated with sudden cardiac death. Here we aim to characterize globally the biological mechanisms underlying genetic susceptibility to MVP to better characterize its triggering mechanisms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>\n              We applied\n              <jats:italic>i<\/jats:italic>\n              -GSEA4GWAS and DEPICT, two pathway enrichment tools to MVP genome-wide association studies. We followed-up the association with MVP in an independent dataset of cases and controls. This research was conducted using the UK Biobank Resource. Immunohistochemistry staining for Glis1 (GLIS family zinc finger 1) was conducted in developing heart of mice. Knockdown of\n              <jats:italic>Glis1<\/jats:italic>\n              using morpholinos was performed in zebrafish animals 72 hours postfertilization.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              We show that genes at risk loci are involved in biological functions relevant to actin filament organization, cytoskeleton biology, and cardiac development. The enrichment for positive regulation of transcription, cell proliferation, and migration motivated the follow-up of\n              <jats:italic>GLIS1<\/jats:italic>\n              , a transcription factor from the Kr\u00fcppel-like zinc finger family. In combination with previously available data, we now report a genome-wide significant association with MVP (odds ratio, 1.20;\n              <jats:italic>P<\/jats:italic>\n              =4.36\u00d710\n              <jats:sup>-10<\/jats:sup>\n              ), indicating that\n              <jats:italic>Glis1<\/jats:italic>\n              is expressed during embryonic development predominantly in nuclei of endothelial and interstitial cells of mitral valves in mouse. We also show that\n              <jats:italic>Glis1<\/jats:italic>\n              knockdown causes atrioventricular regurgitation in developing hearts in zebrafish.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>\n              Our findings define globally molecular and cellular mechanisms underlying common genetic susceptibility to MVP and implicate established and unprecedented mechanisms. Through the\n              <jats:italic>GLIS1<\/jats:italic>\n              association and function, we point at regulatory functions during cardiac development as common mechanisms to mitral valve degeneration.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002497","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T18:08:43Z","timestamp":1558462123000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Genome-Wide Association Study\u2013Driven Gene-Set Analyses, Genetic, and Functional Follow-Up Suggest\n            <i>GLIS1<\/i>\n            as a Susceptibility Gene for Mitral Valve Prolapse"],"prefix":"10.1161","volume":"12","author":[{"given":"Mengyao","family":"Yu","sequence":"first","affiliation":[{"name":"INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cit\u00e9, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Georges","sequence":"additional","affiliation":[{"name":"INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cit\u00e9, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan R.","family":"Tucker","sequence":"additional","affiliation":[{"name":"Cardiology Division, Cardiovascular Research Center (N.R.T., P.T.E., D.J.M.), Massachusetts General Hospital, Harvard Medical School, Boston."},{"name":"Precision Cardiology Laboratory, The Broad Institute, Cambridge, MA (N.R.T., P.T.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiy","family":"Kyryachenko","sequence":"additional","affiliation":[{"name":"INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cit\u00e9, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn","family":"Toomer","sequence":"additional","affiliation":[{"name":"Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children\u2019s Research Institute, Medical University of South Carolina, Charleston (K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Schott","sequence":"additional","affiliation":[{"name":"Inserm U1087, institut du thorax, University Hospital Nantes, France (J.-J.S., C.D.)."},{"name":"CNRS, UMR 6291, Universit\u00e9 de Nantes, France (J.-J.S., C.D.)."},{"name":"Universit\u00e9 de Nantes, France (J.-J.S., C.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca N.","family":"Delling","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of California, San Francisco (F.N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Fernandez-Friera","sequence":"additional","affiliation":[{"name":"HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain (L.F.-F., J.S.)."},{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (L.F.-F., J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Solis","sequence":"additional","affiliation":[{"name":"HM Hospitales-Centro Integral de Enfermedades Cardiovasculares HM-CIEC, Madrid, Spain (L.F.-F., J.S.)."},{"name":"Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (L.F.-F., J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"Cardiology Division, Cardiovascular Research Center (N.R.T., P.T.E., D.J.M.), Massachusetts General Hospital, Harvard Medical School, Boston."},{"name":"Precision Cardiology Laboratory, The Broad Institute, Cambridge, MA (N.R.T., P.T.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Levine","sequence":"additional","affiliation":[{"name":"Cardiac Ultrasound Laboratory, Cardiology Division (R.A.L.), Massachusetts General Hospital, Harvard Medical School, Boston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Slaugenhaupt","sequence":"additional","affiliation":[{"name":"Center for Human Genetic Research, Massachusetts General Hospital and Department of Neurology, Harvard Medical School, Boston (S.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert A.","family":"Hag\u00e8ge","sequence":"additional","affiliation":[{"name":"INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cit\u00e9, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Department of Cardiology (A.A.H.), Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Europ\u00e9en Georges Pompidou, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dina","sequence":"additional","affiliation":[{"name":"Inserm U1087, institut du thorax, University Hospital Nantes, France (J.-J.S., C.D.)."},{"name":"CNRS, UMR 6291, Universit\u00e9 de Nantes, France (J.-J.S., C.D.)."},{"name":"Universit\u00e9 de Nantes, France (J.-J.S., C.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Jeunemaitre","sequence":"additional","affiliation":[{"name":"INSERM, UMR970, Paris Cardiovascular Research Center, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cit\u00e9, France (M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.M.Y., A.G., S.K., A.A.H., X.J., N.B.-N.)."},{"name":"Department of Genetics (X.J.), Assistance Publique\u2013H\u00f4pitaux de Paris, H\u00f4pital Europ\u00e9en Georges Pompidou, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Milan","sequence":"additional","affiliation":[{"name":"Cardiology Division, Cardiovascular Research Center (N.R.T., P.T.E., D.J.M.), Massachusetts General Hospital, Harvard Medical School, Boston."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell 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