Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.
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Thériault Sébastien, Holdcraft Jacob A, Sharipova Dinara, Faucherre Adèle, Debiec Radoslaw M, Peloso Gina M, Al-Kassou Baravan, Aranki Sary, Ashikhmina Swan Elena, Ballotta Andrea, Bellino Michele, Björck Hanna M, Boureau Anne Sophie, Braund Peter S, Corriveau François, Dagenais François, Folkersen Lasse, Forte Amalia, Francke Michael D, Frigiola Alessandro, Gorbatov Svetlana, Guo Dongchuan, Habchi Karam M, Heydarpour Mahyar, Isselbacher Eric M, Jopling Chris, Laporte Fabien, Le Scouarnec Solena, Li Zhonglin, Lichtner Peter, Maj Carlo, Manikpurage Hasanga D, Nelson Christopher P, Nguyen Thy B, Norris Russell A, Ong Chin Siang, Pibarot Philippe, Roychowdhury Tanmoy, Sarubbi Berardo, Simonet Floriane, Sundt Thoralf, Surakka Ida, Tessler Idit, Willer Cristen J, Wittmann Susanne, Yang Bo, Berezovets Igor, Doppler Stefanie A, Dreßen Martina, Knoll Katharina, Puehler Thomas, Schunkert Heribert, Avierinos Jean-François, Bissell Malenka M, Bolger Aidan P, 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 L, Huggins Gordon S, Krane Markus, Le Tourneau Thierry, Limongelli Giuseppe, Mathieu Patrick, Messika-Zeitoun David, Michelena Hector I, Milewicz Dianna, Muehlschlegel Jochen D, Murdock David R, Nickenig Georg, Nistri Stefano, Nöthen Markus M, Pluchinotta Francesca, Prakash Siddharth K, Samani Nilesh J, Schott Jean-Jacques, Webb Tom R, Zaffran Stéphane, Abdelilah-Seyfried Salim, Eagle Kim, Schumacher Johannes, Trenkwalder Teresa, Body Simon C
Аннотация
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.