| Title: |
Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve |
| Authors: |
Thériault, Sébastien; Holdcraft, Jacob; Sharipova, Dinara; Faucherre, Adèle; Debiec, Radoslaw; Peloso, Gina; Al-Kassou, Baravan; Aranki, Sary; Ashikhmina Swan, Elena; Ballotta, Andrea; Bellino, Michele; Björck, Hanna; Boureau, Anne Sophie; Braund, Peter; Corriveau, François; Dagenais, François; Folkersen, Lasse; Forte, Amalia; Francke, Michael; Frigiola, Alessandro; Gorbatov, Svetlana; Guo, Dongchuan; Habchi, Karam; Heydarpour, Mahyar; Isselbacher, Eric; Jopling, Chris; Laporte, Fabien; Le Scouarnec, Solena; Li, Zhonglin; Lichtner, Peter; Maj, Carlo; Manikpurage, Hasanga; Nelson, Christopher; Nguyen, Thy; Norris, Russell; Ong, Chin Siang; Pibarot, Philippe; Roychowdhury, Tanmoy; Sarubbi, Berardo; Simonet, Floriane; Sundt, Thoralf; Surakka, Ida; Tessler, Idit; Willer, Cristen; Wittmann, Susanne; Yang, Bo; Berezovets, Igor; Doppler, Stefanie; Dreßen, Martina; Knoll, Katharina; Puehler, Thomas; Schunkert, Heribert; Avierinos, Jean-François; Bissell, Malenka; Bolger, Aidan; Bossé, Yohan; Bossone, Eduardo; Brion, María; Citro, Rodolfo; de Vincentiis, Carlo; Deeb, G. Michael; Della Corte, Alessandro; Dina, Christian; Durst, Ronen; Ensminger, Stephan; Eriksson, Per; Evangelista, Arturo; Franco-Cereceda, Anders; Gilon, Dan; Giusti, Betti; Hetherington, Simon; Huggins, Gordon; Krane, Markus; Le Tourneau, Thierry; Limongelli, Giuseppe; Mathieu, Patrick; Messika-Zeitoun, David; Michelena, Hector; Milewicz, Dianna; Muehlschlegel, Jochen; Murdock, David; Nickenig, Georg; Nistri, Stefano; Nöthen, Markus; Pluchinotta, Francesca; Prakash, Siddharth; Samani, Nilesh; Schott, Jean-Jacques; Webb, Tom; Zaffran, Stéphane; Abdelilah-Seyfried, Salim; Eagle, Kim; Schumacher, Johannes; Trenkwalder, Teresa; Body, Simon |
| Contributors: |
Institut Universitaire de Cardiologie et de Pneumologie de Québec; Université Laval Québec (ULaval); University of Potsdam = Universität Potsdam; Institut de Génomique Fonctionnelle (IGF); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); University of Leicester; Brigham and Women's Hospital Boston; Mayo Clinic Rochester; Centro Cardiologico Monzino Milano; Dpt di Scienze Cliniche e di Comunità Milano (DISCCO); Università degli Studi di Milano = University of Milan (UNIMI)-Università degli Studi di Milano = University of Milan (UNIMI)-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS); Università degli Studi di Salerno = University of Salerno (UNISA); Karolinska University Hospital Solna, Sweden (KUH); Institut du Thorax CHU Nantes (CHU Thorax); Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ); Università degli studi della Campania "Luigi Vanvitelli" = University of the Study of Campania Luigi Vanvitelli; University of Texas Health Science Center; The University of Texas Health Science Center at Houston (UTHealth); Hadassah Hebrew University Medical Center Jerusalem; New York Presbyterian Hospital; Massachusetts General Hospital Boston; Helmholtz Munich, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH); Philipps Universität Marburg = Philipps University of Marburg; University of Colorado Anschutz Medical Campus Aurora; Medical University of South Carolina Charleston (MUSC); Department of Neuroscience, Yale University School of Medicine; Yale School of Medicine New Haven, Connecticut (YSM); Ashoka University; Ospedale Monaldi Napoli = University Hospital Dei Colli – Monaldi Naples; Chaim Sheba Medical Center; University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH); Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel (CAU); Technische Universität Munchen = Technical University Munich = Université Technique de Munich (TUM); University Hospital LMU Munich; Ludwig Maximilian University Munich = Ludwig Maximilians Universität München (LMU); German Heart Center = Deutsches Herzzentrum München Munich, Germany (GHC); Département de Cardiologie Hôpital de la Timone - APHM; Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone CHU - APHM (TIMONE); University of Leeds; University of Naples Federico II = Università degli studi di Napoli Federico II (UNINA); Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela (IDIS); Università degli Studi del Molise = University of Molise (UNIMOL); Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.); Università degli Studi di Roma "La Sapienza" = Sapienza University Rome (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II (UNINA); Vall d'Hebron University Hospital Barcelona; Karolinska Institutet = Karolinska Institute Stockholm; Università degli Studi di Firenze = University of Florence = Université de Florence (UniFI); Tufts Medical Center Boston; University of Ottawa Heart Institute; University of Ottawa Ottawa; Johns Hopkins University School of Medicine Baltimore; Marseille medical genetics - Centre de génétique médicale de Marseille (MMG); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM); Universität Bonn = University of Bonn; University Hospital Bonn; Université du Michigan = University of Michigan Ann Arbor (UMich); Boston University Boston (BU); Fondation pour la Recherche Médicale (DPC20111123002)Association Française contre les Myopathies (NMH-Decrypt Project)Fondation Leducq (Leducq Transatlantic Network of Excellence 21CVD03–ReVAMP)Fondation Coeur et RechercheFédération Française de Cardiologie; ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010); ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011); ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016); ANR-13-BSV6-0011,CavsGen,Variation génétique, transcriptome et épigénome du rétrécissement aortique calcifié(2013); European Project: 101115381,HORIZON-EIC-2022-PATHFINDERCHALLENGES-01,HORIZON-EIC-2022-PATHFINDERCHALLENGES-01,MIRACLE(2023) |
| Source: |
ISSN: 0009-7322. |
| Publisher Information: |
CCSD; American Heart Association |
| Publication Year: |
2026 |
| Collection: |
Université de Montpellier: HAL |
| Subject Terms: |
polygenic risk score; zebrafish; bicuspid aortic valve; RNA sequencing; genome-wide association study; [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system; [SDV.BDD]Life Sciences [q-bio]/Development Biology; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41645906; info:eu-repo/grantAgreement//101115381/EU/MultiomIcs based Risk stratification of Atherosclerotic CardiovascuLar disEase/MIRACLE; PUBMED: 41645906 |
| DOI: |
10.1161/CIRCULATIONAHA.125.074752 |
| Availability: |
https://hal.science/hal-05505768; https://hal.science/hal-05505768v1/document; https://hal.science/hal-05505768v1/file/The%CC%81riault%20et%20al%202026.pdf; https://doi.org/10.1161/CIRCULATIONAHA.125.074752 |
| Rights: |
https://hal.science/licences/copyright/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.2EC8545B |
| Database: |
BASE |