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Thériault, S.* ; Holdcraft, J.A.* ; Sharipova, D.* ; Faucherre, A.* ; Debiec, R.M.* ; Peloso, G.M.* ; Al-Kassou, B.* ; Aranki, S.* ; Ashikhmina Swan, E.* ; Ballotta, A.* ; Bellino, M.* ; Björck, H.M.* ; Boureau, A.S.* ; Braund, P.S.* ; Corriveau, F.* ; Dagenais, F.* ; Folkersen, L.* ; Forte, A.* ; Francke, M.D.* ; Frigiola, A.* ; Gorbatov, S.* ; Guo, D.* ; Habchi, K.M.* ; Heydarpour, M.* ; Isselbacher, E.M.* ; Jopling, C.* ; Laporte, F.* ; Le Scouarnec, S.* ; Li, Z.* ; Lichtner, P. ; Maj, C.* ; Manikpurage, H.D.* ; Nelson, C.P.* ; Nguyen, T.B.* ; Norris, R.A.* ; Ong, C.S.* ; Pibarot, P.* ; Roychowdhury, T.* ; Sarubbi, B.* ; Simonet, F.* ; Sundt, T.* ; Surakka, I.* ; Tessler, I.* ; Willer, C.J.* ; Wittmann, S. ; Yang, B.* ; Berezovets, I.* ; Doppler, S.A.* ; Dreßen, M.* ; Knoll, K.* ; Puehler, T.* ; Schunkert, H.* ; Avierinos, J.F.* ; Bissell, M.M.* ; Bolger, A.P.* ; Bossé, Y.* ; Bossone, E.* ; Brion, M.* ; Citro, R.* ; de Vincentiis, C.* ; Deeb, G.M.* ; Della Corte, A.* ; Dina, C.* ; Durst, R.* ; Ensminger, S.* ; Eriksson, P.* ; Evangelista, A.* ; Franco-Cereceda, A.* ; Gilon, D.* ; Giusti, B.* ; Hetherington, S.L.* ; Huggins, G.S.* ; Krane, M.* ; Le Tourneau, T.* ; Limongelli, G.* ; Mathieu, P.* ; Messika-Zeitoun, D.* ; Michelena, H.I.* ; Milewicz, D.* ; Muehlschlegel, J.D.* ; Murdock, D.R.* ; Nickenig, G.* ; Nistri, S.* ; Nöthen, M.M.* ; Pluchinotta, F.* ; Prakash, S.K.* ; Samani, N.J.* ; Schott, J.J.* ; Webb, T.R.* ; Zaffran, S.* ; Abdelilah-Seyfried, S.* ; Eagle, K.* ; Schumacher, J.* ; Trenkwalder, T.* ; Body, S.*

Genome and transcriptome-wide analyses identify multiplecandidate genes and a significant polygenic contribution inbicuspid aortic valve.

Circulation 153, 1060-1076 (2026)
Postprint Research data DOI PMC
Open Access Green
BACKGROUND: 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. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 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=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Rna Sequencing ; Bicuspid Aortic Valve ; Genome-wide Association Study ; Polygenic Risk Score ; Zebrafish; Mendelian Randomization; Outflow Tract; Variants; Association; Disease; Zebrafish; Identification; Mutations; Stenosis; Insights
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Journal Circulation
Quellenangaben Volume: 153, Issue: 14, Pages: 1060-1076 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Reviewing status Peer reviewed
Institute(s) CF Genomics (CF-GEN)
Grants Canadian Institutes of Health Research
Swedish Heart-Lung Foundation
I-SITE NExT health and engineering program (cole Centrale de Nantes and Nantes University)
Centre National de la Recherche Scientifique through the IRP-GAINES program
Frderverein Deutsches Herzzentrum Mnchen
Bavarian State Ministry of Health
Bavarian State Ministry of Science and the Arts through the Deutsches Herzzentrum Mnchen-Munich Institute of Robotics and Machine Intelligence Joint Research Center
Leducq Foundation
German Heart Foundation (Deutsche Herzstiftung e.V.)
German Research Foundation as part of the Sonderforschungsbereich
Swedish Research Council
Heart Link Children's Charity
National Institute for Health Research Leicester Biomedical Research Centre
Heart and Stroke Foundation of Canada
Deutsche Forschungsgemeinschaft
Laboratory of Excellence Ion Channel Science and Therapeutics
Agence Nationale de la Recherche
British Heart Foundation Accelerator Award
British Heart Foundation Research Excellence Award
Academy of Medical Sciences
Horizon Europe Framework Programme (HORIZON) by the European Commission
National Heart, Lung, and Blood Institute
French National Research Agency
Fondation pour la Recherche Mdicale
Association Franaise contre les Myopathies (NMH-Decrypt Project)
La Fondation Leducq
Leducq Transatlantic Network of Excellence
National Institutes of Health
Assistance Publique-Hpitaux de Paris, France
German Federal Ministry of Education and Research (BMBF)
Canada Research Chair in Genomics of Heart and Lung Diseases
Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada
Instituto de Salud Carlos III
Italian Ministry of Work, Health and Social Politics
Fondation Genavie
Fondation Coeur et Recherche
Deutsche Herzstiftung