The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Autor:	Weinstock JS; Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, USA., Chaudhry SA; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Surgery, Division of Vascular and Endovascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., Ioannou M; Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine., Viskadourou M; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD., Reventun P; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD., Jakubek YA; Department of Internal Medicine, University of Kentucky., Liggett LA; Division of Hematology/Oncology, Boston Childrens Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Laurie C; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA., Broome JG; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA., Khan A; Department of Biostatistics, University of Washington, Seattle, WA 98195, USA., Taylor KD; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Guo X; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Peyser PA; Department of Epidemiology, School of Public Health, Boston University, Boxton, MA USA., Boerwinkle E; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Chami N; The Charles Bronfman Institute of Personalized Medicine.; The Mindich Child Health and Developlement Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kenny EE; Institute for Genomic Health., Loos RJ; The Charles Bronfman Institute of Personalized Medicine.; The Mindich Child Health and Developlement Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, WA, USA.; Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA., Russell TP; Department of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA., Brody JA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Yun JH; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA USA., Cho MH; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA USA., Vasan RS; National Heart Lung and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA, USA., Kardia SL; Department of Epidemiology, University of Michigan, Ann Arbor, MI., Smith JA; Department of Epidemiology, University of Michigan, Ann Arbor, MI.; Survey Research Center, Institute for Social Research, University of Michgian, Ann Arbor, MI., Raffield LM; Department of Genetics, University of North Carolina, Chapel Hill, NC, 27514., Bidulescu A; Department of Epidemiology and Biostatistics, Indiana University School of Public Health Bloomington, Bloomington, IN, USA., O'Brien E; Duke Clinical Research Institute, Durham, NC, USA., de Andrade M; Mayo Clinic, Department of Health Sciences Research, Rochester, MN, USA., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Rich SS; Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA., Tracy RP; Department of Pathology & Laboratory Medicine and Biochemistry, Larner College of Medicine at the University of Vermont, Colchester, VT, USA., Chen YI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA USA., Gu CC; Center for Biostatistics and Data Sciences, Washington University, St. Louis, MO USA., Hsiung CA; Department of Medicine, Taipei Veterans General Hospital, Taipei Taiwan - 201 Shi-Pai Rd. Sec. 2, Taipei Taiwan., Kooperberg C; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Haring B; Department of Medicine III, Saarland University Hospital, Homburg, Saarland, Germany - Department of Medicine I, University of Wrzburg, Wrzburg, Bavaria, Germany.; Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, USA. Electronic address., Nassir R; University of California Davis, Davis, CA, USA., Mathias R; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Reiner A; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Sankaran V; Division of Hematology/Oncology, Boston Childrens Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Lowenstein CJ; Department of Medicine, Cardiology Division, Johns Hopkins University., Blackwell TW; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA., Abecasis GR; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.; Regeneron Pharmaceuticals, Tarrytown, NY, USA., Smith AV; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA., Kang HM; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA., Natarajan P; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics, Broad Institute of Harvard & MIT, Cambridge, MA.; Department of Medicine, Harvard Medical School, Boston, MA., Jaiswal S; Department of Pathology, Stanford University, Stanford, CA, USA., Bick A; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA., Post WS; Department of Medicine, Cardiology Division, Johns Hopkins University., Scheet P; Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA., Auer P; Department of Biostatistics, Medical College of WisconsinDivision of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA., Karantanos T; Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine., Battle A; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.; Malone Center for Engineering in Healthcare, Johns Hopkins University, Baltimore, MD.; Department of Computer Science, Johns Hopkins University, Baltimore, MD., Arvanitis M; Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD.; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 26. Date of Electronic Publication: 2024 Aug 26.
DOI:	10.1101/2024.08.22.24312319
Abstrakt:	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 point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, 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 used 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 quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed 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 performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg ( TCL1A, TERT, SMC4, NRIP1, PRDM16 , MSRA , SCARB1 ), and one locus associated with a sex-associated mutation pathway ( SRGAP2C) . We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg. Competing Interests: Competing Interests Declaration L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat). B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. J.Y. reports grant support from Bayer. M.C. reports grant support from Bayer and GSK, Consulting and speaking fees from Illumina and AstraZeneca. A.G.B., P.N, and S.J. are cofounders, equity holders, and on the scientific advisory board of TenSixteen Bio. G.R.A. is an employee of Regeneron Pharmaceuticals and receives salary, stock and stock options as compensation.
Databáze:	MEDLINE
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