Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve.
Summary
A meta-GWAS of 9,631 cases identified 36 loci (32 novel) for BAV, with transcriptomics-based prioritization and zebrafish knockdown/knockout confirming roles of candidate genes in cardiac development. A polygenic risk score predicted BAV and showed phenome-wide associations, underscoring a strong polygenic component driving abnormal aortic valve morphogenesis.
Key Findings
- Meta-analysis identified 36 genomic loci for BAV susceptibility, including 32 novel loci.
- Transcriptome-based prioritization in fetal and adult valve tissues highlighted candidate genes for morphogenesis.
- Knockdown/knockout of 4 candidates in zebrafish perturbed cardiac development, supporting causality.
- A polygenic risk score predicted BAV in independent cohorts and showed broad phenotypic associations in UK Biobank.
Clinical Implications
Polygenic risk and gene prioritization could inform early identification and surveillance strategies in at-risk individuals and guide mechanistic studies for targeted therapies in BAV and associated aortopathy.
Why It Matters
This is the most comprehensive genetic analysis of BAV to date integrating GWAS, tissue transcriptomics, in vivo functional validation, and polygenic risk modeling, redefining disease architecture and enabling precision risk stratification.
Limitations
- Causal mechanisms for many loci remain to be defined at the variant-to-function level.
- Polygenic risk translation to individual clinical decision-making requires prospective validation.
Future Directions
Fine-mapping and CRISPR-based functional dissection of top loci, integration with single-cell multi-omics of valve development, and prospective evaluation of polygenic risk in screening programs.
Study Information
- Study Type
- Case-control
- Research Domain
- Diagnosis
- Evidence Level
- III - Genetic case-control meta-analysis with functional validation
- Study Design
- OTHER