Gehlen, Jan, Stundl, Anja, Debiec, Radoslaw ORCID: 0000-0003-2292-467X, Fontana, Federica, Krane, Markus, Sharipova, Dinara ORCID: 0000-0002-2267-831X, 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 ORCID: 0000-0002-2560-4068, 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 ORCID: 0000-0003-3326-1621, 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 . Elucidation of the genetic causes of bicuspid aortic valve disease. Cardiovasc. Res.. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gehlen, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stundl, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debiec, RadoslawUNSPECIFIEDorcid.org/0000-0003-2292-467XUNSPECIFIED
Fontana, FedericaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krane, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sharipova, DinaraUNSPECIFIEDorcid.org/0000-0002-2267-831XUNSPECIFIED
Nelson, Christopher P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al-Kassou, BaravanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giel, Ann SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinning, Jan MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruenger, Christopher M. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zelck, Carolin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koebbe, Laura L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braund, Peter S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Webb, Thomas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hetherington, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ensminger, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fujita, BuntaroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohamed, Salah A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shrestha, MalakhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siepe, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kari, Fabian AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordbeck, PeterUNSPECIFIEDorcid.org/0000-0002-2560-4068UNSPECIFIED
Buravezky, LarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kelm, MalteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veulemans, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, MattiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laugwitz, Karl LudwigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, YannickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karck, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehlhorn, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conzelmann, Lars OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Breitenbach, IngoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lebherz, CorinnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urbanski, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Won KeunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kandels, JoschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellinghaus, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nowak-Goettl, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doppler, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lahm, HaraldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dressen, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Scheidt, MoritzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knoll, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kessler, ThorstenUNSPECIFIEDorcid.org/0000-0003-3326-1621UNSPECIFIED
Hengstenberg, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schunkert, HeribertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickenig, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolger, Aidan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdelilah-Seyfried, SalimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Samani, Nilesh J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erdmann, JeanetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trenkwalder, TeresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-697701
DOI: 10.1093/cvr/cvac099
Journal or Publication Title: Cardiovasc. Res.
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1755-3245
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GATA4 MUTATIONS; HEART; VARIANTS; ASSOCIATION; CELLS; MUC4; EMTMultiple languages
Cardiac & Cardiovascular SystemsMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69770

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