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

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.

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Nature Communications
Published
2025-10-16
DOI
https://doi.org/10.1038/s41467-025-64236-x
Citations
1
Primary Topic
Cancer Genomics and Diagnostics
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article
Field-Weighted Citation Impact
0.94

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article

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

Cecelia Laurie, Bruce M. Psaty, Marios Arvanitis, Vijay G. Sankaran et al.
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Genetic determinants and genomic consequences of non-leukemogenic somatic point mutations

Cecelia Laurie, Bruce M. Psaty, Marios Arvanitis, Vijay G. Sankaran, Charles Kooperberg, Patricia A. Peyser, Ramachandran Srini Vasan, Hyun Min Kang, Alexander G. Bick, Ruth J. F. Loos, Michael H. Cho, Charles J. Lowenstein, Jeong H. Yun, Aurelian Bidulescu, Bernhard Haring, Mariza de Andrade, Theodoros Karantanos, Jerome I. Rotter, L. Alexander Liggett, Laura M. Raffield, Alyna Khan, Eimear E. Kenny, Wendy S. Post, Pradeep Natarajan, Nathalie Chami, Paul Scheet, Joshua S. Weinstock, Jennifer A. Smith, Paul Livermore Auer, Alexis Battle, Rasika A. Mathias, Jennifer A. Brody, Stephen S. Rich, Yasminka A. Jakubek, Paula Reventún, Siddhartha Jaiswal, Gonçalo R. Abecasis, Alex P. Reiner, Rami Nassir, Μαρία Ιωάννου, Emily C. O’Brien, Xiuqing Guo, Maria Viskadourou, Yii‐Der Ida Chen, C. Charles Gu, Jai Broome, Albert V. Smith, Kent D. Taylor, Eric Boerwinkle, Thomas W. Blackwell, Sharon L. R. Kardia, Russell P. Tracy, Sharjeel A. Chaudhry
article en
1 citations

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.

Nature CommunicationsVol. 16(1)
Broad Institute (US), University of Vermont (US), University of North Carolina at Chapel Hill (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), Albert Einstein College of Medicine (US), Beth Israel Deaconess Medical Center (US), The University of Texas MD Anderson Cancer Center (US), Howard Hughes Medical Institute (US), Harvard University (US), University of Kentucky (US), Johns Hopkins University (US), Emory University (US), Baylor College of Medicine (US), Regeneron (United States) (US), Vanderbilt University (US), University of Washington (US), Medical College of Wisconsin (US), Washington University in St. Louis (US), University of Würzburg (DE), University of Michigan (US), Johns Hopkins Medicine (US), UCLA Medical Center (US), University of Washington Medical Center (US), Taipei Veterans General Hospital (TW), Office of Public Health Genomics (US), Massachusetts General Hospital (US), Clinical Research Institute (US), Fred Hutch Cancer Center (US), National Heart, Lung, and Blood Institute (US), Child Health and Development Institute (US), Dana-Farber Cancer Institute (US), Indiana University Bloomington (US), Framingham Heart Study (US), Universitätsklinikum Würzburg (DE), Mayo Clinic in Florida (US), New York Genome Center (US), Genomic Health (United States) (US), Sidney Kimmel Comprehensive Cancer Center (US), Harbor–UCLA Medical Center (US), University of Virginia (US), University of California, Davis (US), Saarland University (DE), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Health and Human Services, American Heart Association, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences
Openalex Percentile: Top 19%
Cancer Genomics and Diagnostics
0.94
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