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1. Elucidation of the genetic causes of bicuspid aortic valve disease

Author

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, Noethen, Markus M., Bolger, Aidan P., Abdelilah-Seyfried, Salim, Samani, Nilesh J., Erdmann, Jeanette, Trenkwalder, Teresa, Schumacher, Johannes, 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, Noethen, Markus M., Bolger, Aidan P., Abdelilah-Seyfried, Salim, Samani, Nilesh J., Erdmann, Jeanette, Trenkwalder, Teresa, and Schumacher, Johannes

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 x 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 x 10(-16)), GATA4 (P = 1.61 x 10(-09)), and TEX41 (P = 7.68 x 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 similar to 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.

Published
2023

2. Elucidation of the genetic causes of bicuspid aortic valve disease

Author

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, Noethen, Markus M., Bolger, Aidan P., Abdelilah-Seyfried, Salim, Samani, Nilesh J., Erdmann, Jeanette, Trenkwalder, Teresa, Schumacher, Johannes, 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, Noethen, Markus M., Bolger, Aidan P., Abdelilah-Seyfried, Salim, Samani, Nilesh J., Erdmann, Jeanette, Trenkwalder, Teresa, and Schumacher, Johannes

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 x 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 x 10(-16)), GATA4 (P = 1.61 x 10(-09)), and TEX41 (P = 7.68 x 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 similar to 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.

3. Elucidation of the genetic causes of bicuspid aortic valve disease.

Author

Gehlen J, Stundl A, Debiec R, Fontana F, Krane M, Sharipova D, Nelson CP, Al-Kassou B, Giel AS, Sinning JM, Bruenger CMH, Zelck CF, Koebbe LL, Braund PS, Webb TR, Hetherington S, Ensminger S, Fujita B, Mohamed SA, Shrestha M, Krueger H, Siepe M, Kari FA, Nordbeck P, Buravezky L, Kelm M, Veulemans V, Adam M, Baldus S, Laugwitz KL, Haas Y, Karck M, Mehlhorn U, Conzelmann LO, Breitenbach I, Lebherz C, Urbanski P, Kim WK, Kandels J, Ellinghaus D, Nowak-Goettl U, Hoffmann P, Wirth F, Doppler S, Lahm H, Dreßen M, von Scheidt M, Knoll K, Kessler T, Hengstenberg C, Schunkert H, Nickenig G, Nöthen MM, Bolger AP, Abdelilah-Seyfried S, Samani NJ, Erdmann J, Trenkwalder T, and Schumacher J

Subjects
Animals, Humans, Aortic Valve pathology, Genome-Wide Association Study, Zebrafish genetics, Endothelial Cells metabolism, Bicuspid Aortic Valve Disease metabolism, Bicuspid Aortic Valve Disease pathology, Heart Valve Diseases pathology
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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2023
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