Unveiling the Genetic Landscape of Coronary Artery Disease Through Common and Rare Structural Variants.

Summary

Leveraging high-coverage WGS from TOPMed, the authors tested 58,706 structural variants in 11,556 CAD cases and 42,907 controls and found a genome‑wide significant common intergenic duplication at 6q21, with additional rare SV burden signals by sliding‑window aggregation. Findings broaden CAD genetics beyond SNVs and implicate SVs in disease susceptibility.

Key Findings

• Analyzed 58,706 structural variants using high-coverage WGS in 11,556 CAD cases and 42,907 controls from TOPMed.
• Identified a genome-wide significant association for a common biallelic intergenic duplication at chromosome 6q21.
• Rare SV burden signals were detected using sliding-window aggregation, supporting roles for both common and rare SVs in CAD risk.

Clinical Implications

Immediate clinical action is limited, but incorporating SVs into genetic architectures may refine CAD risk models and prioritize functional targets for therapeutics.

Limitations

• Functional validation of implicated SVs is not presented.
• Independent replication and precise effect estimation are needed; potential residual stratification cannot be fully excluded.

Future Directions

Replicate in independent ancestries; map SV breakpoints and target genes; integrate with eQTL/epigenomics; evaluate incremental predictive value over SNV-based polygenic scores.