Rare variant contribution to the heritability of coronary artery disease

Ghislain Rocheleau, Shoa L. Clarke, Gaëlle Auguste, Natalie R. Hasbani, Alanna C. Morrison, Adam S. Heath, Lawrence F. Bielak, Kruthika R. Iyer, Erica P. Young, Nathan O. Stitziel, Goo Jun, Cecelia Laurie, Jai G. Broome, Alyna T. Khan, Donna K. Arnett, Lewis C. Becker, Joshua C. Bis, Eric Boerwinkle, Donald W. Bowden, April P. Carson, Patrick T. Ellinor, Myriam Fornage, Nora Franceschini, Barry I. Freedman, Nancy L. Heard-Costa, Lifang Hou, Yii- Der Ida Chen, Eimear E. Kenny, Charles Kooperberg, Brian G. Kral, Ruth J. F. Loos, Sharon M. Lutz, JoAnn E. Manson, Lisa W. Martin, Braxton D. Mitchell, Rami Nassir, Nicholette D. Palmer, Wendy S. Post, Michael H. Preuss, Bruce M. Psaty, Laura M. Raffield, Elizabeth A. Regan, Stephen S. Rich, Jennifer A. Smith, Kent D. Taylor, Lisa R. Yanek, Kendra A. Young, Austin T. Hilliard, Catherine Tcheandjieu, Patricia A. Peyser, Ramachandran S. Vasan, Jerome I. Rotter, Clint L. Miller, Themistocles L. Assimes, Paul S. Vries and Ron Do ()
Additional contact information
Ghislain Rocheleau: Icahn School of Medicine at Mount Sinai
Shoa L. Clarke: Stanford University School of Medicine
Gaëlle Auguste: University of Virginia
Natalie R. Hasbani: The University of Texas Health Science Center at Houston
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Adam S. Heath: The University of Texas Health Science Center at Houston
Lawrence F. Bielak: University of Michigan
Kruthika R. Iyer: Stanford University School of Medicine
Erica P. Young: Washington University School of Medicine
Nathan O. Stitziel: Washington University School of Medicine
Goo Jun: The University of Texas Health Science Center at Houston
Cecelia Laurie: University of Washington
Jai G. Broome: University of Washington
Alyna T. Khan: University of Washington
Donna K. Arnett: University of Kentucky
Lewis C. Becker: Johns Hopkins University School of Medicine
Joshua C. Bis: University of Washington
Eric Boerwinkle: The University of Texas Health Science Center at Houston
Donald W. Bowden: Wake Forest University School of Medicine
April P. Carson: University of Mississippi Medical Center
Patrick T. Ellinor: Massachusetts General Hospital
Myriam Fornage: The University of Texas Health Science Center at Houston
Nora Franceschini: University of North Carolina
Barry I. Freedman: Wake Forest University School of Medicine
Nancy L. Heard-Costa: and Blood Institute and Boston University’s Framingham Heart Study
Lifang Hou: Northwestern University Feinberg School of Medicine
Yii- Der Ida Chen: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Charles Kooperberg: Fred Hutchinson Cancer Center
Brian G. Kral: Johns Hopkins University School of Medicine
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Sharon M. Lutz: Harvard Pilgrim Health Care
JoAnn E. Manson: Harvard Medical School
Lisa W. Martin: George Washington University
Braxton D. Mitchell: University of Maryland School of Medicine
Rami Nassir: Umm Al-Qura University
Nicholette D. Palmer: Wake Forest University School of Medicine
Wendy S. Post: Johns Hopkins University School of Medicine
Michael H. Preuss: Icahn School of Medicine at Mount Sinai
Bruce M. Psaty: University of Washington
Laura M. Raffield: University of North Carolina at Chapel Hill
Elizabeth A. Regan: National Jewish Health
Stephen S. Rich: University of Virginia
Jennifer A. Smith: University of Michigan
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Lisa R. Yanek: Johns Hopkins University School of Medicine
Kendra A. Young: University of Colorado Anschutz Medical Campus
Austin T. Hilliard: VA Palo Alto Health Care System
Catherine Tcheandjieu: Stanford University School of Medicine
Patricia A. Peyser: University of Michigan
Ramachandran S. Vasan: and Blood Institute and Boston University’s Framingham Heart Study
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Clint L. Miller: University of Virginia
Themistocles L. Assimes: Stanford University School of Medicine
Paul S. Vries: The University of Texas Health Science Center at Houston
Ron Do: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52939-6

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