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

Author

Listed:
  • Sara Kirmani

    (Framingham Heart Study
    National Institutes of Health)

  • Tianxiao Huan

    (Framingham Heart Study
    National Institutes of Health)

  • Joseph C. Amburg

    (Vanderbilt University Medical Center)

  • Roby Joehanes

    (Framingham Heart Study
    National Institutes of Health)

  • Md Mesbah Uddin

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital)

  • 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
    University of Texas Health Science Center at Houston)

  • Jan Bressler

    (The University of Texas Health Science Center at Houston
    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
    University of Washington)

  • Christie M. Ballantyne

    (Baylor College of Medicine)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington)

  • Laura M. Raffield

    (University of North Carolina)

  • Pradeep Natarajan

    (Broad Institute of Harvard and MIT
    Massachusetts General Hospital
    Harvard Medical School)

  • 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
    Boston University School of Medicine)

  • Joanne Murabito

    (Framingham Heart Study
    Boston University School of Medicine and Boston Medical Center)

  • Alexander G. Bick

    (Vanderbilt University Medical Center)

  • Daniel Levy

    (Framingham Heart Study
    National Institutes of Health)

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

Suggested Citation

  • 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, 2025. "Epigenome-wide DNA methylation association study of CHIP provides insight into perturbed gene regulation," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59333-w
    DOI: 10.1038/s41467-025-59333-w
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