Highlights
- Identification of 36 genomic loci associated with Bicuspid Aortic Valve (BAV), including 32 previously undescribed loci, significantly expanding the known genetic landscape of the disease.
- Transcriptome-wide prioritization identified KANK2, ERBB4, PRDM6, and STRN as key causal candidates, with KANK2 and ERBB4 validated through human aortic valve expression data.
- Functional validation in zebrafish models confirmed that disruption of WNT4, LEF1, STRN, and KANK2 leads to significant defects in cardiac development.
- A novel Polygenic Risk Score (PRS) demonstrates a twofold increase in BAV risk per standard deviation and reveals a robust genetic correlation with thoracic aortic aneurysm and atrial fibrillation.
Background
Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect, affecting 0.5% to 2% of the general population. Characterized by the fusion of two of the three aortic valve leaflets, BAV is not merely a structural anomaly but a progressive clinical entity associated with significant morbidity, including early-onset aortic stenosis, aortic regurgitation, and a high risk of thoracic aortic aneurysms (TAA).
Despite a high estimated heritability (up to 89% in some twin studies), the genetic architecture of BAV has long remained elusive. Historically, research focused on rare, highly penetrant mutations in genes such as NOTCH1, GATA4, and SMAD6. However, these monogenic causes explain only a small fraction of cases. The clinical community has faced a significant “missing heritability” problem, which has hindered the development of effective screening tools and personalized management strategies. The study by Thériault et al. (2026) represents a paradigm shift, moving the focus toward a polygenic model where multiple common variants collectively influence the risk of disrupted heart morphogenesis.
Key Content
Methodological Framework and GWAS Meta-analysis
To address the complex genetic landscape of BAV, researchers conducted a massive genome-wide association study (GWAS) meta-analysis. The study included 9,631 BAV cases and 65,677 controls, leveraging data from diverse international cohorts and biobanks. This large-scale approach provided the statistical power necessary to identify common variants with modest effect sizes.
The analysis identified 36 independent genomic loci reaching genome-wide significance. Notably, 32 of these loci were novel. These findings suggest that BAV risk is distributed across the genome rather than concentrated in a few “master regulator” genes. The identified loci were largely located in or near genes involved in early embryonic heart development and the maintenance of vascular integrity.
Integrating the Transcriptome: Prioritizing Causal Genes
Identifying a genomic locus is only the first step; determining which specific gene at that locus drives the disease is a major challenge in human genetics. Thériault et al. utilized transcriptomic data from relevant human tissues, including fetal and adult aortic valves (n=484), the aorta (n=326), and the left ventricle (n=326).
Through a combination of colocalization and Mendelian randomization (MR) based on gene expression, several key candidates were prioritized:
- KANK2 and ERBB4: Prioritized based on expression profiles in human aortic valves. ERBB4 is a member of the epidermal growth factor receptor family and is crucial for cardiac cushion formation.
- PRDM6: Linked to aortic tissue expression. PRDM6 is known to regulate smooth muscle cell differentiation, a key factor in aortic wall stability.
- STRN: Prioritized based on left ventricular tissue expression, suggesting a possible link between valve development and broader myocardial architecture.
Functional Validation in Zebrafish Models
To move from statistical association to biological causation, the researchers employed in vivo zebrafish models. They targeted four candidate genes: WNT4, LEF1, STRN, and KANK2.
The knockdown or knockout of these genes consistently resulted in cardiac developmental defects. Specifically, disruption of the Wnt signaling pathway (via WNT4 and LEF1) resulted in impaired looping of the heart tube and abnormal valve leaflet formation. These findings reinforce the hypothesis that BAV results from subtle disturbances in the fundamental signaling pathways that guide cardiogenesis during the first trimester.
Clinical Application: Polygenic Risk Scores (PRS)
The study developed a PRS to aggregate the risk conferred by common variants. When tested in an independent cohort, the PRS was highly predictive, with an odds ratio (OR) of 2.07 (95% CI, 1.90-2.25) per standard deviation.
Beyond BAV itself, the researchers utilized the UK Biobank (n=355,618) to perform a phenome-wide association study (PheWAS). The BAV PRS was significantly associated with:
- Thoracic Aortic Aneurysm (TAA): Confirming a shared genetic basis between the valve phenotype and the associated aortopathy.
- Atrial Fibrillation (AF): Suggesting that the genetic risk for BAV may also predispose individuals to conduction abnormalities or structural remodeling of the atria.
Expert Commentary
The transition from a monogenic to a polygenic understanding of BAV has profound implications for clinical practice. For decades, clinicians have struggled with the variable penetrance and expressivity seen in BAV families. The polygenic model explains why two individuals with the same high-risk variant might have vastly different clinical outcomes: the total “genetic burden”—as captured by a PRS—modulates the phenotypic expression.
From a biological perspective, the involvement of the Wnt and ERBB4 pathways highlights the importance of the epithelial-to-mesenchymal transition (EMT) in valve development. Disruptions in these pathways likely prevent the proper remodeling of the cardiac cushions into thin, flexible valve leaflets.
However, limitations remain. While the PRS is a powerful research tool, its integration into routine clinical care requires further validation. We must determine whether a high PRS in a patient with a normally functioning tricuspid valve warrants increased surveillance for aortic aneurysms. Furthermore, the current study was predominantly conducted in populations of European ancestry; expanding this research to more diverse global populations is essential to ensure equitable clinical benefits.
Conclusion
The work of Thériault et al. provides the most comprehensive genetic map of Bicuspid Aortic Valve to date. By identifying 36 genomic loci and validating the roles of genes like KANK2 and ERBB4, the study clarifies the molecular mechanisms underlying this common defect. The successful development of a polygenic risk score paves the way for a more personalized approach to cardiovascular medicine, where genetic data may eventually assist in early diagnosis and the prevention of life-threatening complications like aortic dissection. Future research should focus on the interaction between polygenic risk and environmental factors, such as maternal health during pregnancy, to further refine our understanding of BAV etiology.
References
- Thériault S, et al. Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve. Circulation. 2026 Feb 6. doi: 10.1161/CIRCULATIONAHA.125.074752. PMID: 41645906.
- Braverman AC, et al. The Bicuspid Aortic Valve and Associated Aortopathy. In: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 12th ed. 2022.
- Fedak PWM, et al. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation. 2002;106(8):900-904. PMID: 12186790.