Rare variant contribution to the heritability of coronary artery disease

Nat Commun. 2024 Oct 9;15(1):8741. doi: 10.1038/s41467-024-52939-6.

Abstract

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.

MeSH terms

  • Case-Control Studies
  • Coronary Artery Disease* / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • White People / genetics
  • Whole Genome Sequencing