University of Leicester
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Elucidation of the genetic causes of bicuspid aortic valve disease

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journal contribution
posted on 2023-11-15, 15:13 authored by J Gehlen, A Stundl, R Debiec, F Fontana, M Krane, D Sharipova, CP Nelson, B Al-Kassou, AS Giel, JM Sinning, CMH Bruenger, CF Zelck, LL Koebbe, PS Braund, TR Webb, S Hetherington, S Ensminger, B Fujita, SA Mohamed, M Shrestha, H Krueger, M Siepe, FA Kari, P Nordbeck, L Buravezky, M Kelm, V Veulemans, M Adam, S Baldus, KL Laugwitz, Y Haas, M Karck, U Mehlhorn, LO Conzelmann, I Breitenbach, C Lebherz, P Urbanski, WK Kim, J Kandels, D Ellinghaus, U Nowak-Goettl, P Hoffmann, F Wirth, S Doppler, H Lahm, M Dreßen, M von Scheidt, K Knoll, T Kessler, C Hengstenberg, H Schunkert, G Nickenig, MM Nöthen, AP Bolger, S Abdelilah-Seyfried, NJ Samani, J Erdmann, T Trenkwalder, J Schumacher


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.


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


Deutsche Forschungsgemeinschaft (DFG): TRR259, SFB958, SE2016/13-1, SE2016/17-1, NO246/17-1, KR3985/12-1, EXC 2167-390884018, INST 336/104-1, and INST 336/114-1 FUGG

NIHR Leicester Biomedical Research Centre

Leicester Biomedical Research Centre

British Heart Foundation


Author affiliation

Diabetes Research Centre, University of Leicester


  • VoR (Version of Record)

Published in

Cardiovascular Research






857 - 866


Oxford University Press (OUP)





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