Faculty, Staff and Student Publications
Publication Date
10-9-2024
Journal
Nature Communications
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.
Keywords
Humans, Coronary Artery Disease, Genetic Predisposition to Disease, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Male, Female, Gene Frequency, Genome-Wide Association Study, White People, Case-Control Studies, Whole Genome Sequencing, Genetic Variation, Middle Aged, Genetics, Functional genomics
DOI
10.1038/s41467-024-52939-6
PMID
39384761
PMCID
PMC11464707
PubMedCentral® Posted Date
10-9-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes