The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Joshua S Weinstock; Cecelia A Laurie; Jai G Broome; Kent D Taylor; Xiuqing Guo; Alan R Shuldiner; Jeffrey R O'Connell; Joshua P Lewis; Eric Boerwinkle; Kathleen C Barnes; Nathalie Chami; Eimear E Kenny; Ruth J F Loos; Myriam Fornage; Susan Redline; Brian E Cade; Frank D Gilliland; Zhanghua Chen; W James Gauderman; Rajesh Kumar; Leslie Grammer; Robert P Schleimer; Bruce M Psaty; Joshua C Bis; Jennifer A Brody; Edwin K Silverman; Jeong H Yun; Dandi Qiao; Scott T Weiss; Jessica Lasky-Su; Dawn L DeMeo; Nicholette D Palmer; Barry I Freedman; Donald W Bowden; Michael H Cho; Ramachandran S Vasan; Andrew D Johnson; Lisa R Yanek; Lewis C Becker; Sharon Kardia; Jiang He; Robert Kaplan; Susan R Heckbert; Nicholas L Smith; Kerri L Wiggins; Donna K Arnett; Marguerite R Irvin; Hemant Tiwari; Adolfo Correa; Laura M Raffield; Yan Gao; Mariza de Andrade; Jerome I Rotter; Stephen S Rich; Ani W Manichaikul; Barbara A Konkle; Jill M Johnsen; Marsha M Wheeler; Brian S Custer; Ravindranath Duggirala; Joanne E Curran; John Blangero; Hongsheng Gui; Shujie Xiao; L Keoki Williams; Deborah A Meyers; Xingnan Li; Victor Ortega; Stephen McGarvey; C Charles Gu; Yii-Der Ida Chen; Wen-Jane Lee; M Benjamin Shoemaker; Dawood Darbar; Dan Roden; Christine Albert; Charles Kooperberg; Pinkal Desai; Thomas W Blackwell; Goncalo R Abecasis; Albert V Smith; Hyun M Kang; Rasika Mathias; Pradeep Natarajan; Siddhartha Jaiswal; Alexander P Reiner; Alexander G Bick; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1126/sciadv.abm4945

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Sci Adv. 2023 Apr 28;9(17):eabm4945. doi: 10.1126/sciadv.abm4945. Epub 2023 Apr 26.

Authors

Joshua S Weinstock¹, Cecelia A Laurie², Jai G Broome^{2

3}, Kent D Taylor⁴, Xiuqing Guo⁴, Alan R Shuldiner⁵, Jeffrey R O'Connell⁵, Joshua P Lewis⁵, Eric Boerwinkle⁶, Kathleen C Barnes⁷, Nathalie Chami^{8

9}, Eimear E Kenny¹⁰, Ruth J F Loos^{8

9}, Myriam Fornage¹¹, Susan Redline^{12

13}, Brian E Cade^{12

13

14}, Frank D Gilliland¹⁵, Zhanghua Chen¹⁵, W James Gauderman¹⁵, Rajesh Kumar^{16

17}, Leslie Grammer¹⁷, Robert P Schleimer¹⁷, Bruce M Psaty^{18

19

20}, Joshua C Bis¹⁸, Jennifer A Brody¹⁸, Edwin K Silverman²¹, Jeong H Yun²¹, Dandi Qiao²¹, Scott T Weiss^{12

21}, Jessica Lasky-Su^{12

21}, Dawn L DeMeo^{12

21}, Nicholette D Palmer²², Barry I Freedman²³, Donald W Bowden²², Michael H Cho²⁴, Ramachandran S Vasan²⁵, Andrew D Johnson^{25

26}, Lisa R Yanek²⁷, Lewis C Becker²⁷, Sharon Kardia²⁸, Jiang He²⁹, Robert Kaplan³⁰, Susan R Heckbert^{19

31}, Nicholas L Smith^{19

31

32}, Kerri L Wiggins³³, Donna K Arnett³⁴, Marguerite R Irvin³⁵, Hemant Tiwari³⁵, Adolfo Correa³⁶, Laura M Raffield³⁷, Yan Gao³⁸, Mariza de Andrade³⁹, Jerome I Rotter⁴, Stephen S Rich⁴⁰, Ani W Manichaikul⁴⁰, Barbara A Konkle²⁰, Jill M Johnsen^{20

41}, Marsha M Wheeler⁴², Brian S Custer⁴³, Ravindranath Duggirala^{44

45}, Joanne E Curran^{44

45}, John Blangero^{44

45}, Hongsheng Gui^{46

47}, Shujie Xiao^{46

47}, L Keoki Williams^{46

47}, Deborah A Meyers⁴⁸, Xingnan Li⁴⁹, Victor Ortega⁵⁰, Stephen McGarvey⁵¹, C Charles Gu⁵², Yii-Der Ida Chen⁴, Wen-Jane Lee⁵³, M Benjamin Shoemaker⁵⁴, Dawood Darbar⁵⁵, Dan Roden⁵⁶, Christine Albert⁵⁷, Charles Kooperberg⁵⁸, Pinkal Desai^{59

60}, Thomas W Blackwell¹, Goncalo R Abecasis^{1

61}, Albert V Smith¹, Hyun M Kang¹, Rasika Mathias²⁷, Pradeep Natarajan^{14

62

63}, Siddhartha Jaiswal⁶⁴, Alexander P Reiner^{58

19}, Alexander G Bick⁶⁵; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Affiliations

¹ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
² Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
³ Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁵ Department of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, USA.
⁶ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
⁸ The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁰ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ Harvard Medical School, Boston, MA 02115, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁵ Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90089, USA.
¹⁶ Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
¹⁷ Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
¹⁹ Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
²⁰ Department of Medicine, University of Washington, Seattle, WA 98195, USA.
²¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
²² Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
²³ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.
²⁴ Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁵ National Heart, Lung, and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA 01701, USA.
²⁶ National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, MA 01701, USA.
²⁷ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
²⁸ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
²⁹ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
³⁰ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
³¹ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA 98101, USA.
³² Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA 98108, USA.
³³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
³⁴ Dean's Office, College of Public Health, University of Kentucky, Lexington, KY 40506, USA.
³⁵ University of Alabama at Birmingham, Birmingham, AL 35294, USA.
³⁶ Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³⁸ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
³⁹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
⁴⁰ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
⁴¹ Research Institute, Bloodworks Northwest, Seattle, WA 98102, USA.
⁴² Genome Science, University of Washington, Seattle, WA 98195, USA.
⁴³ Vitalant Research Institute, San Francisco, CA 94105, USA.
⁴⁴ Department of Human Genetics, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
⁴⁵ South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX 78520, USA.
⁴⁶ Center for Individualized and Genomic Medicine Research (CIGMA), Henry Ford Health System, Detroit, MI 48202, USA.
⁴⁷ Department of Medicine, Henry Ford Health System, Detroit, MI 48202, USA.
⁴⁸ Division of Genetics, Genomics, and Precision Medicine, University of Arizona, Tucson, AZ 85721, USA.
⁴⁹ Department of Medicine, University of Arizona, Tucson, AZ 85721, USA.
⁵⁰ Wake Forest University School of Medicine, Winston-Salem, NC 27101, USA.
⁵¹ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI 02903, USA.
⁵² Division of Biostatistics, Washington University School of Medicine, Campus Box 8067, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
⁵³ Department of Medical Research, Taichung Veterans General Hospital, 1650, Sec. 4, Taiwan Boulevard, Taichung City, Taiwan.
⁵⁴ Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁵⁵ Division of Cardiology, University of Illinois at Chicago, Chicago, IL 60607, USA.
⁵⁶ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁵⁷ Department of Cardiology, Cedars-Sinai, Los Angeles, CA 90048, USA.
⁵⁸ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
⁵⁹ Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
⁶⁰ Englander Institute of Precision Medicine, Weill Cornell Medicine, New York 10065, NY, USA.
⁶¹ Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA.
⁶² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁶⁴ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
⁶⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.

Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

MeSH terms

Germ-Line Mutation*
Hematopoiesis*
Humans
Middle Aged
Mutation
Mutation, Missense
Phenotype

Abstract

MeSH terms

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