“Echocardiographic screening of first-degree relatives (parents, children and siblings) of someone with a bicuspid aortic valve is important”
(Boston)—Bicuspid aortic valve (BAV) is a common congenital heart defect where the aortic valve has two leaflets ( cusps ) instead of the usual three, resulting in abnormal blood flow and development of aortic valve diseases such as aortic stenosis and incompetence. In addition, the BAV is sometimes accompanied by development of an enlarged aorta - the main artery in the body. Both the bicuspid aortic valve and an enlarged aorta often require cardiac surgery, usually after the age of 50 years. Despite this, only a limited number of genes have been associated with the disease and the molecular mechanisms remain unexplained in most cases.
In a new study aimed to further understand the genetic architecture of BAV, an international group of researchers led by Boston University Chobanian & Avedisian School of Medicine and Laval University in Quebec City, Canada, along with the Bicuspid Aortic Valve Consortium, the Genetic Aortic Network (a division of The Marfan Foundation) and participating Institutions, believe the condition is strongly influenced by the cumulative effect of variation in many different genes (polygenic contribution).
“We found that variation in 36 genetic regions increases the risk of a bicuspid aortic valve. These findings support the notion that bicuspid aortic valve disease is an inherited disease caused by a combination of many common genetic variants, not merely a single mutation in a single gene,” explains co-corresponding author Simon C. Body, MD, MPH, professor of anesthesiology at Boston University Chobanian & Avedisian School of Medicine.
From a group of 65,677 U.S., Canadian and European participants, the researchers performed a genome-wide association study (GWAS) meta-analysis on 9,631 individuals with BAV. After identifying general genetic regions through GWAS, they used RNA sequencing to study gene activity (expression levels) in specific, relevant tissues.
They observed 36 regions with genetic variants associated with a bicuspid aortic valve, four of which had been previously identified. They prioritized 55 genes in these regions based upon expression in human aortic valve tissues from individuals who had surgery, then tested the effect of changing four selected genes, upon heart development in an experimental model, demonstrating that all four altered genes had effects on development of the valve. The researchers also looked at the effect of these genes in a statistical model finding a three-fold increase in risk for a BAV in individuals in the top 10% and association with aortic aneurysmal disease, a bulge in the aortic wall that can rupture. Some of these 36 genetic regions are also involved in aortic stenosis and aortic aneurysm development, which could lead to better prediction of these complications in people with BAV and point to biological mechanisms responsible for these joint effects.
According to the researchers, while these findings support the notion that BAV is an inherited disease, the findings do not currently support genetic testing, either prenatally or later in life, for predicting a bicuspid aortic valve. “Echocardiography and other imaging modalities remain the gold standard for diagnosis. In addition, the identified heritability supports performing screening echocardiography on first-degree relatives of a person with an identified bicuspid valve,” adds Body.
These findings appear online in the journal Circulation .
S.T. was supported by the Canadian Institutes of Health Research (PJT – 162344) and by the Heart and Stroke Foundation of Canada (G-19-0026386). D.S. was supported by the Deutsche Forschungsgemeinschaft (NO246/17-1). A. Faucherre is part of the Laboratory of Excellence Ion Channel Science and Therapeutics supported by a grant from the Agence nationale de la recherche (ANR; ANR-10-INSB-04). R.M.D., A.P.B., and T.R.W. received support from the British Heart Foundation Accelerator Award (AA/18/3/34220). R.M.D., A.P.B., N.J.S., and T.R.W. are supported by a British Heart Foundation 791 Research Excellence Award (RE/24/130031). R.M.D. received support from the Academy of Medical Sciences (Award number RM61G1013/42885). The BRAVE study is supported by the National Institute for Health Research Leicester Biomedical Research Centre. The BRAVE study also received research support from the Heart Link Children’s Charity, East Midlands, UK (Charity registration number 1203709). B.A.-K., G.N., M.M.N., and J.S. were supported by the Deutsche Forschungsgemeinschaft (DFG) (TRR259). H.M.B. was supported by the Swedish Research Council and Swedish Heart- Lung Foundation (2020-01442, 2022-0136). F.L. was supported by International Research Program (IRP) - VERACITIES, an initiative under the I-SITE NExT health and engineering program (École Centrale de Nantes & Nantes University). Additional support was provided by Inserm and Centre national de la recherche scientifique (CNRS) through the IRP-GAINES program. P.P. was supported by the Canadian Institutes of Health Research (FDN-143225). M.D. was supported by Förderverein Deutsches Herzzentrum München. H.S. was supported by the framework of DigiMed Bayern (www.digimed805 bayern.de; DMB-1805–0001) by the Bavarian State Ministry of Health, Care and Prevention and the Bavarian State Ministry of Science and the Arts through the DHM807 MSRM Joint Research Center (1530/891 02), the Leducq Foundation (18CVD02), the German Heart Foundation (Deutsche Herzstiftung e.V.), the German Research Foundation (DFG) as part of the Sonderforschungsbereich SFB 1123 (B02) and the Sonderforschungsbereich SFB TRR 267 (B05), the German Federal Ministry of Economics and Energy in its scheme of ModulMax (Grant No: ZF4590201BA8, the Horizon Europe Framework Programme (HORIZON) by the European Commission (MIRACLE 101115381), the German Federal Ministry of Education and Research (BMBF) within the framework of COMMITMENT (01ZX1904A). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases and was supported by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada (MOP – 10248, MOP – 137058, PJT – 153396, PJT – 159641). M. Brion was supported by Instituto de Salud Carlos III (ISCIII) (PI22/00286). A.D.C. was supported by the Italian Ministry of Work, Health and Social Politics (GR-2009-1580434). C.D. was supported by a grant from the Fondation Genavie. P.E. was supported by the Swedish Research Council and Swedish Heart-Lung Foundation (2020-01442, 2021-0521). M.K. was supported by Deutsche Forschungsgemeinschaft (DFG) projects KR3770/7-3, and KR3770/14-1. T.L.T. was supported by Fondation Coeur et Recherche (2012), Fédération Française de Cardiologie (2018). P.M. was supported by the Canadian Institutes of Health Research (PJT-191807). The COFRASA and GENERAC studies (D.M.-Z.) are supported by a grant from Assistance Publique-Hôpitaux de Paris, France. D.M. was supported by ARTIVION. J.D.M. was supported by the NIH (R01HL149998) and by National Heart, Lung, and Blood Institute (NHLBI) (R01HL118266, R01HL150401). S.K.P. was supported by the NHLBI (R01HL137028, R21HL150383). J.J.S. was supported by the French National Research Agency (ANR: [13-BSV6-0011]), the Fondation pour la Recherche Médicale (FRM: [DCV20070409278]), and the International Research Program (IRP) - VERACITIES, an initiative under the I-SITE NExT health and engineering program (École Centrale de Nantes & Nantes University). Additional support was provided by Inserm and CNRS through the IRP-GAINES program. S.Z. was supported by “Association Française 837 contre les Myopathies” [NMH-Decrypt Project], the “Fondation pour la Recherche Médicale” [DPC20111123002], the “Institut National de la Santé et de la Recherche Médicale” and "la Fondation Leducq”. S.A.-S. was supported by Deutsche Forschungsgemeinschaft (DFG) projects SE2016/7-3, SE2016/10-1, SE2016/13-1, NO246/17-1, and the Leducq Transatlantic Network of Excellence “21CVD03 - ReVAMP”. T.T. was supported by Deutsche Herzstiftung. S.C.B was supported by the National Heart, Lung, and Blood Institute (R01HL114823, R21HL150373).
Circulation
10.1161/CIRCULATIONAHA.125.074752
Data/statistical analysis
Cells
Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve
6-Feb-2026