Evidence map›Paper›PMID 41102182›Full record

ArticleNature communications2025

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 and 45 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Genetic influences on haematopoiesis.Nature reviews. Genetics · 2026
    Review
  2. Article
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  5. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

55 authors.

Joshua S WeinstockDepartment of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA. josh.weinstock@emory.edu.ORCID http://orcid.org/0000-0001-7013-1899
Sharjeel A ChaudhryDivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-8701-3979
Maria IoannouDivision of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Maria ViskadourouDivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Paula ReventunDivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6221-8780
Yasminka A JakubekDepartment of Internal Medicine, University of Kentucky, Lexington, KY, USA.
L Alexander LiggettDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Cecelia LaurieDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-6569-2501
Jai G BroomeDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-7638-0749
Alyna KhanDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0002-5264-5068
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-9717-8459
Eric BoerwinkleHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Nathalie ChamiThe Charles Bronfman Institute of Personalized Medicine, New York, NY, USA.ORCID http://orcid.org/0000-0002-8547-6424
Eimear E KennyInstitute for Genomic Health, York, NY, USA.
Ruth J LoosThe Charles Bronfman Institute of Personalized Medicine, New York, NY, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7278-2190
Russell P TracyDepartment of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-8509-148X
Jeong H YunChanning Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4361-8295
Michael H ChoChanning Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4907-1657
Ramachandran S VasanNational Heart Lung and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA, USA.ORCID http://orcid.org/0000-0001-7357-5970
Sharon L KardiaDepartment of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
Jennifer A SmithDepartment of Epidemiology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-3575-5468
Laura M RaffieldDepartment of Genetics, University of North Carolina, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-7892-193X
Aurelian BidulescuDepartment of Epidemiology and Biostatistics, Indiana University School of Public Health - Bloomington, Bloomington, IN, USA.
Emily C O'BrienDuke Clinical Research Institute, Durham, NC, USA.
Mariza de AndradeMayo Clinic, Department of Health Sciences Research, Rochester, MN, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0001-7191-1723
Stephen S RichDepartment of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-3872-7793
Russell P TracyDepartment of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA.
Yii Der Ida ChenThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0003-1741-3517
C Charles GuCenter for Biostatistics and Data Sciences, Washington University, St. Louis, MO, USA.ORCID http://orcid.org/0000-0002-8527-8145
Chao A HsiungDepartment of Medicine, Taipei Veterans General Hospital, Taipei Taiwan, Taipei, Taiwan.ORCID http://orcid.org/0000-0002-8209-9627
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7986-8560
Bernhard HaringDepartment of Medicine III, Saarland University Hospital, Homburg, Saarland, Germany; Department of Medicine I, University of Würzburg, Würzburg, Bavaria, Germany.
Rami NassirUniversity of California Davis, Davis, CA, USA.ORCID http://orcid.org/0000-0001-9914-7851
Rasika MathiasDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alex ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-1427-4470
Vijay G SankaranDivision of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0044-443X
Charles J LowensteinDepartment of Medicine, Cardiology Division, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-0485-7514
Thomas W BlackwellCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Goncalo R AbecasisCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Albert V SmithCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0003-1942-5845
Hyun M KangCenter for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-3631-3979
Pradeep NatarajanCenter for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8402-7435
Siddhartha JaiswalDepartment of Pathology, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-9597-0477
Alexander BickDivision of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.ORCID http://orcid.org/0000-0001-5824-9595
Wendy S PostDepartment of Medicine, Cardiology Division, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-8655-5204
Paul ScheetDepartment of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-5173-7497
Paul AuerDepartment of Biostatistics, Medical College of Wisconsin, Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.ORCID http://orcid.org/0000-0003-1735-8044
Theodoros KarantanosDivision of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alexis BattleDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA. ajbattle@jhu.edu.ORCID http://orcid.org/0000-0002-5287-627X
Marios ArvanitisDivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. marvani1@jhmi.edu.

Funding

Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
Rare variants and NHLBI traits in deeply phenotyped cohortsU01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2017 to 2018
$5.6M
Modeling the dynamicimpact of rare and common genetic variation on gene expression anddiseaseR35GM139580 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI BATTLE, ALEXIS · 2021 to 2025
$3.1M
Infrastructure for mentored access to CHS data and specimensR01HL172803 · NHLBI · UNIVERSITY OF WASHINGTON · PI James S Floyd, Michelle Christina Odden · 2025 to 2026
$2.7M
From genotype to phenotype in a GWAS locus: the role of REST in atherosclerosisK08HL166690 · NHLBI · OHIO STATE UNIVERSITY · PI Marios Arvanitis · 2023 to 2026
$681k
NHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS K08 HL166690NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL172803NHLBI NIH HHS U01 HL120393NIGMS NIH HHS R35 GM139580
6 · The paper itself

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.

Indexed as

Clonal HematopoiesisPoint MutationGenome-Wide Association StudyGenomicsGerm-Line MutationHumans

Identifiers

PMID41102182
PMCPMC12532822

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.