Rare variant contribution to the heritability of coronary artery disease

Authors

• 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.

APA Citation

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.; and Lutz, Sharon M., "Rare variant contribution to the heritability of coronary artery disease" (2024). GW Authored Works. Paper 5858.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/5858

Department

Medicine