{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:06Z","timestamp":1791316926508,"version":"4.3.1"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>A genome-wide association study meta-analysis including 9631 cases among 65\u2009677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355\u2009618 individuals).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes,\n                      <jats:italic toggle=\"yes\">KANK2<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">ERBB4<\/jats:italic>\n                      were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas\n                      <jats:italic toggle=\"yes\">PRDM6<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">STRN<\/jats:italic>\n                      were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (\n                      <jats:italic toggle=\"yes\">WNT4<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">LEF1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">STRN<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">KANK2<\/jats:italic>\n                      ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90\u20132.25;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =5.43\u00d710\n                      <jats:sup>-62<\/jats:sup>\n                      ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.074752","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T10:00:11Z","timestamp":1770372011000},"page":"1060-1076","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-8307","authenticated-orcid":true,"given":"S\u00e9bastien","family":"Th\u00e9riault","sequence":"first","affiliation":[{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A.","family":"Holdcraft","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Boston University, MA (J.A.H., G.M.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2267-831X","authenticated-orcid":true,"given":"Dinara","family":"Sharipova","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology, Institute of Biochemistry and Biology, University of Potsdam, Germany (D.S., S.A.-S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6099-3898","authenticated-orcid":true,"given":"Ad\u00e8le","family":"Faucherre","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9nomique Fonctionnelle, University of Montpellier, Centre national de la recherche scientifique, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale, France (A. Faucherre, C.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2292-467X","authenticated-orcid":true,"given":"Radoslaw M.","family":"Debiec","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-8636","authenticated-orcid":true,"given":"Gina M.","family":"Peloso","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, School of Public Health, Boston University, MA (J.A.H., G.M.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2967-6613","authenticated-orcid":true,"given":"Baravan","family":"Al-Kassou","sequence":"additional","affiliation":[{"name":"Department of Medicine II, Heart Center Bonn (B.A.-K., G.N.), University of Bonn and University Hospital Bonn, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3129-3403","authenticated-orcid":true,"given":"Sary","family":"Aranki","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA (S.A., M.D.F., S.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1618-3046","authenticated-orcid":true,"given":"Elena","family":"Ashikhmina Swan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN (E.A.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballotta","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino Istituto di Ricovero e Cura a Carattere Scientifico Via Parea, Milan University, Italy (A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Bellino","sequence":"additional","affiliation":[{"name":"University Study of Salerno, Italy (M. Bellino)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-3609","authenticated-orcid":true,"given":"Hanna M.","family":"Bj\u00f6rck","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Center for Molecular Medicine, Department of Medicine (H.M.B., P.E.), Karolinska Institutet, Stockholm, Sweden."},{"name":"Karolinska University Hospital, Solna, Sweden (H.M.B., P.E., A.F.-C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-2014","authenticated-orcid":true,"given":"Anne Sophie","family":"Boureau","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, Centre national de la recherche scientifique, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale, L\u2019Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8540-5709","authenticated-orcid":true,"given":"Peter S.","family":"Braund","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Corriveau","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Laval, Quebec City, Canada (F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Dagenais","sequence":"additional","affiliation":[{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0708-9530","authenticated-orcid":true,"given":"Lasse","family":"Folkersen","sequence":"additional","affiliation":[{"name":"Nucleus Genomics, New York, NY (L.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amalia","family":"Forte","sequence":"additional","affiliation":[{"name":"University of Campania L. Vanvitelli, Naples, Italy (A. Forte, A.D.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Francke","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Boston, MA (S.A., M.D.F., S.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Frigiola","sequence":"additional","affiliation":[{"name":"Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, Italy (A. 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Faucherre, C.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2509-3293","authenticated-orcid":true,"given":"Fabien","family":"Laporte","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, Centre national de la recherche scientifique, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale, L\u2019Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-2125","authenticated-orcid":true,"given":"Solena","family":"Le Scouarnec","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, Centre national de la recherche scientifique, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale, L\u2019Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., 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B.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"University of Colorado, Aurora (T.B.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-5726","authenticated-orcid":true,"given":"Russell A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston (R.A.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin Siang","family":"Ong","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, CT (C.S.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3607-279X","authenticated-orcid":true,"given":"Philippe","family":"Pibarot","sequence":"additional","affiliation":[{"name":"Institut universitaire de cardiologie et de pneumologie de Qu\u00e9bec - Universit\u00e9 Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanmoy","family":"Roychowdhury","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Cardiology (T.R., I.S., C.J.W., B.Y.)"},{"name":"Department of Biology and Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonepat, India (T.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9941-8500","authenticated-orcid":true,"given":"Berardo","family":"Sarubbi","sequence":"additional","affiliation":[{"name":"Department of Biology and Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonepat, India (T.R.)."},{"name":"Adult Congenital Heart Disease and Congenital and Familial Arrhythmias Unit, Monaldi Hospital, Naples, Italy 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