Faculty, Staff and Student Publications
Language
English
Publication Date
10-9-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-52939-6
PMID
39384761
PMCID
PMC11464707
PubMedCentral® Posted Date
10-9-2024
PubMedCentral® Full Text Version
Post-print
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
Published Open-Access
yes
Recommended Citation
Rocheleau, Ghislain; Clarke, Shoa L; Auguste, Gaëlle; et al., "Rare Variant Contribution to the Heritability of Coronary Artery Disease" (2024). Faculty, Staff and Student Publications. 635.
https://digitalcommons.library.tmc.edu/uthsph_docs/635