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Elucidation of the genetic causes of bicuspid aortic valve disease.

Cardiovascular research

Authors: Jan Gehlen, Anja Stundl, Radoslaw Debiec, Federica Fontana, Markus Krane, Dinara Sharipova, Christopher P Nelson, Baravan Al-Kassou, Ann-Sophie Giel, Jan-Malte Sinning, Christopher M H Bruenger, Carolin F Zelck, Laura L Koebbe, Peter S Braund, Thomas R Webb, Simon Hetherington, Stephan Ensminger, Buntaro Fujita, Salah A Mohamed, Malakh Shrestha, Heike Krueger, Matthias Siepe, Fabian Alexander Kari, Peter Nordbeck, Larissa Buravezky, Malte Kelm, Verena Veulemans, Matti Adam, Stephan Baldus, Karl-Ludwig Laugwitz, Yannick Haas, Matthias Karck, Uwe Mehlhorn, Lars Oliver Conzelmann, Ingo Breitenbach, Corinna Lebherz, Paul Urbanski, Won-Keun Kim, Joscha Kandels, David Ellinghaus, Ulrike Nowak-Goettl, Per Hoffmann, Felix Wirth, Stefanie Doppler, Harald Lahm, Martina Dreßen, Moritz von Scheidt, Katharina Knoll, Thorsten Kessler, Christian Hengstenberg, Heribert Schunkert, Georg Nickenig, Markus M Nöthen, Aidan P Bolger, Salim Abdelilah-Seyfried, Nilesh J Samani, Jeanette Erdmann, Teresa Trenkwalder, Johannes Schumacher

AIMS: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect.

METHODS AND RESULTS: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology.

CONCLUSION: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.

PMID: 35727948

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