Genetic determinants and genomic consequences of non-leukemogenic somatic point mutations

Joshua S. Weinstock (), Sharjeel A. Chaudhry, Maria Ioannou, Maria Viskadourou, Paula Reventun, Yasminka A. Jakubek, L. Alexander Liggett, Cecelia Laurie, Jai G. Broome, Alyna Khan, Kent D. Taylor, Xiuqing Guo, Patricia A. Peyser, Eric Boerwinkle, Nathalie Chami, Eimear E. Kenny, Ruth J. Loos, Bruce M. Psaty, Russell P. Tracy, Jennifer A. Brody, Jeong H. Yun, Michael H. Cho, Ramachandran S. Vasan, Sharon L. Kardia, Jennifer A. Smith, Laura M. Raffield, Aurelian Bidulescu, Emily C. O’Brien, Mariza Andrade, Jerome I. Rotter, Stephen S. Rich, Russell P. Tracy, Yii Der Ida Chen, C. Charles. Gu, Chao A. Hsiung, Charles Kooperberg, Bernhard Haring, Rami Nassir, Rasika Mathias, Alex Reiner, Vijay G. Sankaran, Charles J. Lowenstein, Thomas W. Blackwell, Goncalo R. Abecasis, Albert V. Smith, Hyun M. Kang, Pradeep Natarajan, Siddhartha Jaiswal, Alexander Bick, Wendy S. Post, Paul Scheet, Paul Auer, Theodoros Karantanos, Alexis Battle () and Marios Arvanitis ()
Additional contact information
Joshua S. Weinstock: Emory University
Sharjeel A. Chaudhry: Johns Hopkins University
Maria Ioannou: Johns Hopkins University School of Medicine
Maria Viskadourou: Johns Hopkins University
Paula Reventun: Johns Hopkins University
Yasminka A. Jakubek: University of Kentucky
L. Alexander Liggett: Harvard Medical School
Cecelia Laurie: University of Washington
Jai G. Broome: University of Washington
Alyna Khan: University of Washington
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Xiuqing Guo: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Patricia A. Peyser: University of Michigan
Eric Boerwinkle: Baylor College of Medicine
Nathalie Chami: The Charles Bronfman Institute of Personalized Medicine
Eimear E. Kenny: Institute for Genomic Health
Ruth J. Loos: The Charles Bronfman Institute of Personalized Medicine
Bruce M. Psaty: University of Washington
Russell P. Tracy: Larner College of Medicine at the University of Vermont
Jennifer A. Brody: University of Washington
Jeong H. Yun: Brigham and Women’s Hospital
Michael H. Cho: Brigham and Women’s Hospital
Ramachandran S. Vasan: Boston University’s Framingham Heart Study
Sharon L. Kardia: University of Michigan
Jennifer A. Smith: University of Michigan
Laura M. Raffield: University of North Carolina
Aurelian Bidulescu: Indiana University School of Public Health – Bloomington
Emily C. O’Brien: Duke Clinical Research Institute
Mariza Andrade: Department of Health Sciences Research
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Stephen S. Rich: University of Virginia
Russell P. Tracy: Larner College of Medicine at the University of Vermont
Yii Der Ida Chen: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
C. Charles. Gu: Washington University
Chao A. Hsiung: Taipei Taiwan
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Bernhard Haring: University of Würzburg
Rami Nassir: University of California Davis
Rasika Mathias: Johns Hopkins University School of Medicine
Alex Reiner: Fred Hutchinson Cancer Research Center
Vijay G. Sankaran: Harvard Medical School
Charles J. Lowenstein: Johns Hopkins University
Thomas W. Blackwell: University of Michigan School of Public Health
Goncalo R. Abecasis: University of Michigan School of Public Health
Albert V. Smith: University of Michigan School of Public Health
Hyun M. Kang: University of Michigan School of Public Health
Pradeep Natarajan: Massachusetts General Hospital
Siddhartha Jaiswal: Stanford University
Alexander Bick: Vanderbilt University
Wendy S. Post: Johns Hopkins University
Paul Scheet: University of Texas M.D. Anderson Cancer Center
Paul Auer: Medical College of Wisconsin
Theodoros Karantanos: Johns Hopkins University School of Medicine
Alexis Battle: Johns Hopkins University
Marios Arvanitis: Johns Hopkins University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as leukemogenic point mutations or mosaic chromosomal alterations (mCAs), are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we use 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantify CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we develop a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We perform a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. We identify seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1).Functional analyses of SMC4 and NRIP1 implicated altered hematopoietic stem cell self-renewal and proliferation as the primary mediator of mutation burden in blood. We then perform comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we perform phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Date: 2025
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DOI: 10.1038/s41467-025-64236-x

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