Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve

作者：Sébastien Thériault, Jacob A. Holdcraft, Dinara Sharipova, Adèle Faucherre, Radosław Dębiec, Gina M. Peloso, Baravan Al‐Kassou, Sary Aranki, Elena Ashikhmina Swan, Andrea Ballotta, Michele Bellino, Hanna M. Björck, Anne Sophie Boureau, Peter S. Braund, François Corriveau, François Dagenais, Lasse Folkersen, Amalia Forte, Michael Francke, Alessandro Frigiola, Svetlana Gorbatov, Dongchuan Guo, Karam M Habchi, Mahyar Heydarpour, Eric M. Isselbacher, Chris Jopling, Fabien Laporte, Solena Le Scouarnec, Zhonglin Li, Peter Lichtner, Carlo Maj, Hasanga D. Manikpurage, Christopher P. Nelson, Thy B. Nguyen, R. Norris, Chin Siang Ong, P Pibarot, Tanmoy Roychowdhury, Berardo Sarubbi, Floriane Simonet, Sundt Tm, Ida Surakka, Idit Tessler, Cristen J. Willer, Susanne Wittmann, Bo Yang, Igor Berezovets, S. Doppler, Martina Dreßen, Katharina Knoll, T. Puehler, H Schunkert, Jean-François Aviérinos, Malenka M. Bissell, Aidan Bolger, Yohan Bossé, Eduardo Bossone, M Brion, Rodolfo Citro, Carlo De Vincentiis, G. Michael Deeb, Alessandro Della Corte, C. Dina, Ronen Durst, Stephan Ensminger, Per Eriksson, Arturo Evangelista, Anders Franco-Cereceda, Dan Gilon, Betti Giusti, Simon Hetherington, G S Huggins, Markus Krane, Thierry Le Tourneau, Giuseppe Limongelli, P. Mathieu, David Messika-Zeitoun, Hector I. Michelena, Dianna Milewicz, Jochen D. Muehlschlegel, David R. Murdock, G. Nickenig, Stefano Nistri, M Nöthen, Francesca Pluchinotta, Siddharth K. Prakash, Nilesh J. Samani, J. Schott, Tom R. Webb, Stéphane Zaffran, Salim Abdelilah-Seyfried, Kim A. Eagle, Johannes Schumacher, Teresa Trenkwalder, Simon C. Body · 发表于：Circulation · 年份：2026 · DOI：10.1161/circulationaha.125.074752 · 被引用次数：5 · 研究领域：Congenital heart defects research、Aortic Disease and Treatment Approaches、Congenital Heart Disease Studies

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 sc...