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

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.

PMID: 37126548
PMCID: PMC10132750
DOI: 10.1126/sciadv.abm4945

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

Joshua S Weinstock et al. Sci Adv. 2023.

. 2023 Apr 28;9(17):eabm4945.

doi: 10.1126/sciadv.abm4945. Epub 2023 Apr 26.

Authors

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.

PMID: 37126548
PMCID: PMC10132750
DOI: 10.1126/sciadv.abm4945

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.

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Figures

**Fig. 1.. Identification of recurrent somatic mutations from TOPMed whole genomes.**
(A) Identification of RNMSMs. (B) The allele frequency spectrum of somatic mutations. These represent the frequency of sets of variants with the given allele count. (C) The average number of RNMSMs stratified across age bins with 95% CIs. (D) The histogram of the slopes of the individual RNMSMs with age. (E) Enrichments of chromHMM annotations across blood epigenomes from Roadmap Epigenomics. Enrichments are defined as the log odds ratio (OR) multiplied by the −log₁₀ (P value) from the Fisher’s exact test. T_reg, regulatory T cell; TH, T helper cell; IL-17pp, interleukin-17pp; PMA, phorbol 12-myristate 13-acetate; MACS, magnetic-activated cell sorting; Tmem, T memory.

**Fig. 2.. Somatic genotype PCs are associated with genetic ancestry.**
(A) Global ancestry labels, as estimated from RFMix, are regressed on the first five sPCs in a multinomial regression with a study indicator included as a covariate. The ORs are estimated with East Asian ancestry as the reference level. (B) A scatterplot of sPC4 and sPC5, with colors indicated by the RFMix global ancestry label. (C) A circular genome plot where the angle indicates genomic position, and the radius within a given track indicates the allele frequency, which ranges from 0 to 0.12. A separate track is plotted for the allele frequencies computed separately in European, Sub-Saharan African, and East Asian genomes, respectively, which are colored by the legend indicated in (B). The size of points indicates the fixation index (Fst) estimate, where larger points have larger Fst values.

**Fig. 3.. Germline determinants of RNMSM burden.**
(A) Manhattan plot from GWAS of RNMSM burden, computed using SAIGE. Germline variants included had a minor allele count ≥ 600 and were distinct from the set of RNMSMs. (B) Genetic determinants of individual RNMSMs are primarily in “cis,” where cis is defined as within 2 Mb of the RNMSM. Genomic coordinates of the associated linkage disequilibrium (LD)-clumped germline variants are plotted on the x axis, and coordinates of the RNMSMs are plotted on the y axis. Points falling along the diagonal indicate cis associations. Tick marks along the y axis indicate positions of the RNMSMs from the LD-clumped associations.

**Fig. 4.. RNMSMs associate with blood cell traits.**
Associations between eight RNMSMs (q values < 0.05) with harmonized blood cell traits in 2996 individuals. Units correspond to an increase of an SD of the phenotype associated with an increase in the VAF value of an RNMSM by 0.10. WBC, white blood cell; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources