Ultra-rare variants (minor allele frequency ≤ 0.1%) with low linkage disequilibrium contribute approximately 50% to the estimated 34.3% heritability of coronary artery disease.
Observational (n=22,443)
Yes
Ultra-rare genetic variants with low linkage disequilibrium explain approximately half of the heritability of coronary artery disease, highlighting the importance of rare non-coding variants in CAD genetic risk.
Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk. Whole genome sequences enable discovery of rare variants which may help to explain the heritability of common diseases. Here the authors find that ultra-rare variants explain ~50% of coronary artery disease (CAD) heritability and highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.
Rocheleau et al. (2024) conducted an observational in Coronary artery disease (n=22,443). Ultra-rare genetic variants (MAF ≤ 0.1%) vs. Other genetic variants was evaluated on Coronary artery disease heritability on the liability scale. Ultra-rare variants (minor allele frequency ≤ 0.1%) with low linkage disequilibrium contribute approximately 50% to the estimated 34.3% heritability of coronary artery disease.