Rare variant contribution to the heritability of coronary artery disease.
Journal
Nature communications
Series/Report No.
Nature Communications
Journal Volume
15
Journal Issue
1
Start Page
Art. No. 4417
ISSN
2041-1723
Date Issued
2024-10-09
Author(s)
Rocheleau, Ghislain
Clarke, Shoa L
Auguste, Gaëlle
Hasbani, Natalie R
Morrison, Alanna C
Heath, Adam S
Bielak, Lawrence F
Iyer, Kruthika R
Young, Erica P
Stitziel, Nathan O
Jun, Goo
Laurie, Cecelia
Broome, Jai G
Khan, Alyna T
Arnett, Donna K
Becker, Lewis C
Bis, Joshua C
Boerwinkle, Eric
Bowden, Donald W
Carson, April P
Ellinor, Patrick T
Fornage, Myriam
Franceschini, Nora
Freedman, Barry I
Heard-Costa, Nancy L
Hou, Lifang
Chen, Yii-Der Ida
Kenny, Eimear E
Kooperberg, Charles
Kral, Brian G
Loos, Ruth J F
Lutz, Sharon M
Manson, JoAnn E
Martin, Lisa W
Mitchell, Braxton D
Nassir, Rami
Palmer, Nicholette D
Post, Wendy S
Preuss, Michael H
Psaty, Bruce M
Raffield, Laura M
Regan, Elizabeth A
Rich, Stephen S
Smith, Jennifer A
Taylor, Kent D
Yanek, Lisa R
Young, Kendra A
Hilliard, Austin T
Tcheandjieu, Catherine
Peyser, Patricia A
Vasan, Ramachandran S
Rotter, Jerome I
Miller, Clint L
Assimes, Themistocles L
de Vries, Paul S
Do, Ron
et. al
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.
SDGs
Publisher
Nature Research
Type
journal article