Elucidation of the genetic causes of bicuspid aortic valve disease. Issue 3 (21st June 2022)

• Record Type: Journal Article
• Authors: Gehlen, Jan; Stundl, Anja; Debiec, Radoslaw; Fontana, Federica; Krane, Markus; Sharipova, Dinara; Nelson, Christopher P; Al-Kassou, Baravan; Giel, Ann-Sophie; Sinning, Jan-Malte; Bruenger, Christopher M H; Zelck, Carolin F; Koebbe, Laura L; Braund, Peter S; Webb, Thomas R; Hetherington, Simon; Ensminger, Stephan; Fujita, Buntaro; Mohamed, Salah A; Shrestha, Malakh; Krueger, Heike; Siepe, Matthias; Kari, Fabian Alexander; Nordbeck, Peter; Buravezky, Larissa; Kelm, Malte; Veulemans, Verena; Adam, Matti; Baldus, Stephan; Laugwitz, Karl-Ludwig; Haas, Yannick; Karck, Matthias; Mehlhorn, Uwe; Conzelmann, Lars Oliver; Breitenbach, Ingo; Lebherz, Corinna; Urbanski, Paul; Kim, Won-Keun; Kandels, Joscha; Ellinghaus, David; Nowak-Goettl, Ulrike; Hoffmann, Per; Wirth, Felix; Doppler, Stefanie; Lahm, Harald; Dreßen, Martina; von Scheidt, Moritz; Knoll, Katharina; Kessler, Thorsten; Hengstenberg, Christian; Schunkert, Heribert; Nickenig, Georg; Nöthen, Markus M; Bolger, Aidan P; Abdelilah-Seyfried, Salim; Samani, Nilesh J; Erdmann, Jeanette; Trenkwalder, Teresa; Schumacher, Johannes;
• Is Part Of: Cardiovascular research. Volume 119:Issue 3(2023)
• Page Start: 857
• Page End: 866
• Publication Date: 2022-06-21
• Subjects: Bicuspid aortic valve -- GWAS -- SNP-based heritability -- Foetal heart transcriptome -- Zebrafish; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac099
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: 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. Graphical Abstract: Graphical Abstract