Rare variant contribution to the heritability of coronary artery disease

Ghislain Rocheleau, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Shoa L. Clarke, Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
Gaëlle Auguste, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Natalie R. Hasbani, Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Alanna C. Morrison, Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Adam S. Heath, Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Lawrence F. Bielak, Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Kruthika R. Iyer, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Erica P. Young, Department of Medicine, Division of Cardiology, Washington University School of Medicine, Saint Louis, MO, USA.
Nathan O. Stitziel, Department of Medicine, Division of Cardiology, Washington University School of Medicine, Saint Louis, MO, USA.
Goo Jun, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Cecelia Laurie, Department of Biostatistics, University of Washington, Seattle, WA, USA.
Jai G. Broome, Department of Biostatistics, University of Washington, Seattle, WA, USA.
Alyna T. Khan, Department of Biostatistics, University of Washington, Seattle, WA, USA.
Donna K. Arnett, College of Public Health, University of Kentucky, Lexington, KY, USA.
Lewis C. Becker, GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Joshua C. Bis, Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
Eric Boerwinkle, Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Donald W. Bowden, Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
April P. Carson, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Patrick T. Ellinor, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Myriam Fornage, Department of Epidemiology, Human Genetics, and Environmental Sciences, Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nora Franceschini, Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
Barry I. Freedman, Department of Internal Medicine, Section on Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Nancy L. Heard-Costa, National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham, MA, USA.
Lifang Hou, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Yii-Der Ida Chen, Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Eimear E. Kenny, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Charles Kooperberg, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Brian G. Kral, GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ruth J. Loos, The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sharon M. Lutz, Department of Population Medicine, Harvard Pilgrim Health Care, Boston, MA, USA.

Document Type

Journal Article

Publication Date

10-9-2024

Journal

Nature communications

Volume

15

Issue

1

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.

Department

Medicine

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