Epigenome-wide DNA methylation association study of CHIP provides insight into perturbed gene regulation

Sara Kirmani, Tianxiao Huan (), Joseph C. Amburg, Roby Joehanes, Md Mesbah Uddin, Ngoc Quynh H. Nguyen, Bing Yu, Jennifer A. Brody, Myriam Fornage, Jan Bressler, Nona Sotoodehnia, David A. Ong, Fabio Puddu, James S. Floyd, Christie M. Ballantyne, Bruce M. Psaty, Laura M. Raffield, Pradeep Natarajan, Karen N. Conneely, Joshua S. Weinstock, April P. Carson, Leslie A. Lange, Kendra Ferrier, Nancy L. Heard-Costa, Joanne Murabito, Alexander G. Bick () and Daniel Levy ()
Additional contact information
Sara Kirmani: Framingham Heart Study
Tianxiao Huan: Framingham Heart Study
Joseph C. Amburg: Vanderbilt University Medical Center
Roby Joehanes: Framingham Heart Study
Md Mesbah Uddin: Broad Institute of Harvard and MIT
Ngoc Quynh H. Nguyen: The University of Texas Health Science Center at Houston
Bing Yu: The University of Texas Health Science Center at Houston
Jennifer A. Brody: University of Washington
Myriam Fornage: University of Texas Health Science Center at Houston
Jan Bressler: The University of Texas Health Science Center at Houston
Nona Sotoodehnia: University of Washington
David A. Ong: Vanderbilt University Medical Center
Fabio Puddu: Chesterford Research Park
James S. Floyd: University of Washington
Christie M. Ballantyne: Baylor College of Medicine
Bruce M. Psaty: University of Washington
Laura M. Raffield: University of North Carolina
Pradeep Natarajan: Broad Institute of Harvard and MIT
Karen N. Conneely: Emory University School of Medicine
Joshua S. Weinstock: Emory University School of Medicine
April P. Carson: University of Mississippi Medical Center
Leslie A. Lange: University of Colorado at Denver
Kendra Ferrier: University of Colorado at Denver
Nancy L. Heard-Costa: Framingham Heart Study
Joanne Murabito: Framingham Heart Study
Alexander G. Bick: Vanderbilt University Medical Center
Daniel Levy: Framingham Heart Study

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract With age, hematopoietic stem cells can acquire somatic mutations in leukemogenic genes that confer a proliferative advantage in a phenomenon termed CHIP. How these mutations result in increased risk for numerous age-related diseases remains poorly understood. We conduct a multiracial meta-analysis of EWAS of CHIP in the Framingham Heart Study, Jackson Heart Study, Cardiovascular Health Study, and Atherosclerosis Risk in Communities cohorts (N = 8196) to elucidate the molecular mechanisms underlying CHIP and illuminate how these changes influence cardiovascular disease risk. We functionally validate the EWAS findings using human hematopoietic stem cell models of CHIP. We then use expression quantitative trait methylation analysis to identify transcriptomic changes associated with CHIP-associated CpGs. Causal inference analyses reveal 261 CHIP-associated CpGs associated with cardiovascular traits and all-cause mortality (FDR adjusted p-value

Date: 2025
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DOI: 10.1038/s41467-025-59333-w

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