An integrated germline and somatic genomic model for coronary artery disease
Year: 2026
Type: article
Abstract: Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.
Source: Nature Communications
Authors: Xiong Yang, Min Seo Kim, Xinyu Zhu, Md Mesbah Uddin, Tetsushi Nakao, So Mi Jemma Cho, Satoshi Koyama, Tingfeng Xu, Laurens F. Reeskamp, Rufan Zhang, Zhaoqi Liu, Yunga A, Paul S. de Vries, Ramachandran S. Vasan, Eric Boerwinkle, Alanna C. Morrison, Bruce M. Psaty, Russell P. Tracy, Susan R. Heckbert, Michael H. Cho, Jeong H. Yun, Nicholette D. Palmer, Donald W. Bowden, Joanne M. Murabito, Daniel Levy, Nancy L. Heard-Costa, George T. O’Connor, Lewis C. Becker, Brian G. Kral, Lisa R. Yanek, Laura M. Raffield, Bertha Hidalgo, Jerome I. Rotter, Stephen S. Rich, Kent D. Taylor, Wendy S. Post, Charles Kooperberg, Alexander P. Reiner, Braxton D. Mitchell, Sharon L. R. Kardia, Jennifer A. Smith, Patricia A. Peyser, Lawrence F. Bielak, Dong Keon Yon, Hong-Hee Won, Donna K. Arnett, Albert V. Smith, Stacey B. Gabriel, Patrick T. Ellinor, Pradeep Natarajan, Minxian Wang, Akl C. Fahed
Institutions: Chinese Academy of Sciences, Beijing Institute of Genomics, Institute of Vertebrate Paleontology and Paleoanthropology, Broad Institute, Massachusetts General Hospital, University of Chinese Academy of Sciences, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Amsterdam UMC Location University of Amsterdam, OLVG, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, University of Amsterdam, The University of Texas Health Science Center at Houston, Boston University, The University of Texas at San Antonio, University of Washington, University of Vermont, Harvard University, Wake Forest University, Boston Medical Center, National Heart, Lung, and Blood Institute, Framingham Heart Study, Johns Hopkins University, Johns Hopkins Medicine, University of North Carolina at Chapel Hill, University of Alabama at Birmingham, Center for Clinical and Translational Science, The Lundquist Institute, Harbor–UCLA Medical Center, University of Virginia, Fred Hutch Cancer Center, University of Maryland, Baltimore, University of Michigan, Kyung Hee University, Kyung Hee University Medical Center, Samsung Medical Center, Sungkyunkwan University, University of South Carolina, Zhongnan Hospital of Wuhan University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Coronary plaque changes with statin and colchicine among people with high polygenic risk- a mechanistic pilot study, G5160451519, Integration of novel contextual and genomic blood pressure measures to enhance cardiovascular disease prediction and management in young adults, Infrastructure for mentored access to CHS data and specimens, Integrating genomic and nongenomic risk for coronary artery disease
OpenAlex ID: W7140513001