. 2020 Oct;586(7831):763-768.

doi: 10.1038/s41586-020-2819-2. Epub 2020 Oct 14.

Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Alexander G Bick^#^{1

2

3

4}, Joshua S Weinstock^#⁵, Satish K Nandakumar^{2

6}, Charles P Fulco^{2

7}, Erik L Bao^{2

6

8}, Seyedeh M Zekavat^{2

9}, Mindy D Szeto^{10

11}, Xiaotian Liao^{2

6}, Matthew J Leventhal², Joseph Nasser², Kyle Chang¹², Cecelia Laurie¹³, Bala Bharathi Burugula¹⁴, Christopher J Gibson¹⁵, Amy E Lin¹⁶, Margaret A Taub¹⁷, Francois Aguet², Kristin Ardlie², Braxton D Mitchell^{18

19}, Kathleen C Barnes^{10

20}, Arden Moscati²¹, Myriam Fornage^{22

23}, Susan Redline^{3

24

25}, Bruce M Psaty^{26

27

28

29}, Edwin K Silverman^{3

30}, Scott T Weiss^{3

30}, Nicholette D Palmer³¹, Ramachandran S Vasan³², Esteban G Burchard^{33

34}, Sharon L R Kardia³⁵, Jiang He^{36

37}, Robert C Kaplan^{38

39}, Nicholas L Smith^{27

29

40}, Donna K Arnett⁴¹, David A Schwartz⁴², Adolfo Correa⁴³, Mariza de Andrade⁴⁴, Xiuqing Guo⁴⁵, Barbara A Konkle^{46

47}, Brian Custer^{48

49}, Juan M Peralta⁵⁰, Hongsheng Gui⁵¹, Deborah A Meyers⁵², Stephen T McGarvey⁵³, Ida Yii-Der Chen⁵⁴, M Benjamin Shoemaker⁵⁵, Patricia A Peyser³⁵, Jai G Broome¹³, Stephanie M Gogarten¹³, Fei Fei Wang¹³, Quenna Wong¹³, May E Montasser¹⁸, Michelle Daya¹⁰, Eimear E Kenny⁵⁶, Kari E North⁵⁷, Lenore J Launer⁵⁸, Brian E Cade^{24

59}, Joshua C Bis²⁶, Michael H Cho^{3

30}, Jessica Lasky-Su^{3

30}, Donald W Bowden³¹, L Adrienne Cupples⁶⁰, Angel C Y Mak³³, Lewis C Becker⁶¹, Jennifer A Smith^{35

62}, Tanika N Kelly^{36

37}, Stella Aslibekyan⁶³, Susan R Heckbert^{27

29}, Hemant K Tiwari⁶⁴, Ivana V Yang⁴², John A Heit⁶⁵, Steven A Lubitz^{2

3

66}, Jill M Johnsen^{46

47}, Joanne E Curran⁵⁰, Sally E Wenzel⁶⁷, Daniel E Weeks⁶⁸, Dabeeru C Rao⁶⁹, Dawood Darbar⁷⁰, Jee-Young Moon³⁸, Russell P Tracy⁷¹, Erin J Buth¹³, Nicholas Rafaels²⁰, Ruth J F Loos^{21

72}, Peter Durda⁷¹, Yongmei Liu⁷³, Lifang Hou⁷⁴, Jiwon Lee²⁴, Priyadarshini Kachroo^{3

30}, Barry I Freedman⁷⁵, Daniel Levy^{76

77}, Lawrence F Bielak³⁵, James E Hixson⁷⁸, James S Floyd^{26

27

47}, Eric A Whitsel^{79

80}, Patrick T Ellinor^{2

3

66}, Marguerite R Irvin⁶³, Tasha E Fingerlin⁸¹, Laura M Raffield⁸², Sebastian M Armasu⁴⁴, Marsha M Wheeler⁸³, Ester C Sabino⁸⁴, John Blangero⁵⁰, L Keoki Williams⁵¹, Bruce D Levy^{3

85}, Wayne Huey-Herng Sheu⁸⁶, Dan M Roden^{87

88

89}, Eric Boerwinkle^{89

90}, JoAnn E Manson^{3

91

92}, Rasika A Mathias⁶¹, Pinkal Desai⁹³, Kent D Taylor^{94

95}, Andrew D Johnson^{76

77}; NHLBI Trans-Omics for Precision Medicine Consortium; Paul L Auer⁹⁶, Charles Kooperberg⁹⁷, Cathy C Laurie¹³, Thomas W Blackwell⁵, Albert V Smith⁵, Hongyu Zhao^{98

99}, Ethan Lange¹⁰, Leslie Lange¹⁰, Stephen S Rich¹⁰⁰, Jerome I Rotter^{94

95}, James G Wilson^{101

102}, Paul Scheet¹², Jacob O Kitzman^{14

103}, Eric S Lander^{2

7

104}, Jesse M Engreitz^{2

105}, Benjamin L Ebert^{2

3

15

106}, Alexander P Reiner^{27

97}, Siddhartha Jaiswal¹⁰⁷, Gonçalo Abecasis^{5

108}, Vijay G Sankaran^{2

3

6}, Sekar Kathiresan^{109

110

111

112}, Pradeep Natarajan^{113

114

115}

Collaborators, Affiliations

Collaborators

NHLBI Trans-Omics for Precision Medicine Consortium:
Namiko Abe, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Dimitrios Avramopoulos, John Barnard, R Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Panagiotis Benos, Marcos Bezerra, Larry Bielak, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Karen Bunting, Carlos Bustamante, Jonathan Cardwell, Vincent Carey, Cara Carty, Richard Casaburi, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Elaine Cornell, Carolyn Crandall, James Crapo, Jeffrey Curtis, Coleen Damcott, Sayantan Das, Sean David, Colleen Davis, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Qing Duan, Ravi Duggirala, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Leslie Emery, Serpil Erzurum, Charles Farber, Matthew Flickinger, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi Priscilla Geng, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Da-Wei Gong, Harald Goring, Sharon Graw, Daniel Grine, C Charles Gu, Yue Guan, Namrata Gupta, Jeff Haessler, Michael Hall, Daniel Harris, Nicola L Hawley, Ben Heavner, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A Jhun, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Shannon Kelly, Michael Kessler, Alyna Khan, Wonji Kim, Greg Kinney, Holly Kramer, Christoph Lange, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Keng Han Lin, Xihong Lin, Simin Liu, Yu Liu, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, Lauren Margolin, Lisa Martin, Susan Mathai, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Daniel McGoldrick, Caitlin McHugh, Hao Mei, Luisa Mestroni, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, Matt Moll, Courtney Montgomery, Solomon Musani, Stanford Mwasongwe, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C Nelson, Bonnie Neltner, Deborah Nickerson, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, David Paik, James Pankow, George Papanicolaou, Afshin Parsa, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Laura Rasmussen-Torvik, Aakrosh Ratan, Robert Reed, Elizabeth Regan, Muagututi'a Sefuiva Reupena, Ken Rice, Carolina Roselli, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Danish Saleheen, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Christopher Scheller, Ellen Schmidt, Karen Schwander, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Stephanie L Sherman, Amol Shetty, Aniket Shetty, Brian Silver, Josh Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Heming Wang, Karol Watson, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, Carla Wilson, Joseph Wu, Huichun Xu, Lisa Yanek, Rongze Yang, Norann Zaghloul, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Degui Zhi, Xiang Zhou, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁸ Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
⁹ Yale School of Medicine, New Haven, CT, USA.
¹⁰ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹² Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁴ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁸ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁹ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
²⁰ Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
²¹ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁴ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁷ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁸ Department of Health Services, University of Washington, Seattle, WA, USA.
²⁹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³¹ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³² Departments of Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.
³³ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
³⁶ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³⁷ Tulane University Translational Science Institute, New Orleans, LA, USA.
³⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
³⁹ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
⁴⁰ Seattle Epidemiologic Information and Research Center, Department of Veterans Affairs, Office of Research and Development, Seattle, WA, USA.
⁴¹ College of Public Health, University of Kentucky, Lexington, KY, USA.
⁴² Department of Medicine, University of Colorado, Aurora, CO, USA.
⁴³ Departments of Medicine and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁴ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴⁵ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴⁶ Bloodworks Northwest, Seattle, WA, USA.
⁴⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴⁸ Vitalant Research Institute, San Francisco, CA, USA.
⁴⁹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵⁰ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
⁵¹ Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵² Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
⁵³ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁵⁴ Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA.
⁵⁵ Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁵⁸ Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
⁵⁹ Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁶⁰ Departments of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁶¹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁶² Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁶³ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁴ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁵ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
⁶⁶ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷ Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁸ Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁹ Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
⁷⁰ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁷¹ Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁷² Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷³ Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁷⁴ Department of Preventive Medicine, Northwestern Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷⁵ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷⁶ Framingham Heart Study, Framingham, MA, USA.
⁷⁷ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷⁸ Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
⁷⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
⁸⁰ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁸¹ Center for Genes Environment and Health, National Jewish Health, Denver, CO, USA.
⁸² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁸³ Department of Genome Science, University of Washington, Seattle, WA, USA.
⁸⁴ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁸⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸⁶ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁸⁷ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁸ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁹¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹² Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
⁹³ Department of Medicine, Weill Cornell Medical School, New York, NY, USA.
⁹⁴ Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁵ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁶ Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
⁹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁸ Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA.
⁹⁹ Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
¹⁰⁰ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰¹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁰² Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁴ Department of Biology, MIT, Cambridge, MA, USA.
¹⁰⁵ Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
¹⁰⁶ Howard Hughes Medical Institute, Boston, MA, USA.
¹⁰⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰⁸ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
¹⁰⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹⁰ Harvard Medical School, Boston, MA, USA. sekar@broadinstitute.org.
¹¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. sekar@broadinstitute.org.
¹¹² Verve Therapeutics, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. pradeep@broadinstitute.org.
¹¹⁴ Harvard Medical School, Boston, MA, USA. pradeep@broadinstitute.org.
¹¹⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. pradeep@broadinstitute.org.

^# Contributed equally.

PMID: 33057201
PMCID: PMC7944936
DOI: 10.1038/s41586-020-2819-2

Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Alexander G Bick et al. Nature. 2020 Oct.

. 2020 Oct;586(7831):763-768.

doi: 10.1038/s41586-020-2819-2. Epub 2020 Oct 14.

Authors

Collaborators

NHLBI Trans-Omics for Precision Medicine Consortium:
Namiko Abe, Christine Albert, Laura Almasy, Alvaro Alonso, Seth Ament, Peter Anderson, Pramod Anugu, Deborah Applebaum-Bowden, Dan Arking, Allison Ashley-Koch, Stella Aslibekyan, Tim Assimes, Dimitrios Avramopoulos, John Barnard, R Graham Barr, Emily Barron-Casella, Lucas Barwick, Terri Beaty, Gerald Beck, Diane Becker, Rebecca Beer, Amber Beitelshees, Emelia Benjamin, Panagiotis Benos, Marcos Bezerra, Larry Bielak, Russell Bowler, Jennifer Brody, Ulrich Broeckel, Karen Bunting, Carlos Bustamante, Jonathan Cardwell, Vincent Carey, Cara Carty, Richard Casaburi, James Casella, Peter Castaldi, Mark Chaffin, Christy Chang, Yi-Cheng Chang, Daniel Chasman, Sameer Chavan, Bo-Juen Chen, Wei-Min Chen, Seung Hoan Choi, Lee-Ming Chuang, Mina Chung, Ren-Hua Chung, Clary Clish, Suzy Comhair, Elaine Cornell, Carolyn Crandall, James Crapo, Jeffrey Curtis, Coleen Damcott, Sayantan Das, Sean David, Colleen Davis, Michael DeBaun, Ranjan Deka, Dawn DeMeo, Scott Devine, Qing Duan, Ravi Duggirala, Susan Dutcher, Charles Eaton, Lynette Ekunwe, Adel El Boueiz, Leslie Emery, Serpil Erzurum, Charles Farber, Matthew Flickinger, Nora Franceschini, Chris Frazar, Mao Fu, Stephanie M Fullerton, Lucinda Fulton, Stacey Gabriel, Weiniu Gan, Shanshan Gao, Yan Gao, Margery Gass, Bruce Gelb, Xiaoqi Priscilla Geng, Mark Geraci, Soren Germer, Robert Gerszten, Auyon Ghosh, Richard Gibbs, Chris Gignoux, Mark Gladwin, David Glahn, Da-Wei Gong, Harald Goring, Sharon Graw, Daniel Grine, C Charles Gu, Yue Guan, Namrata Gupta, Jeff Haessler, Michael Hall, Daniel Harris, Nicola L Hawley, Ben Heavner, Ryan Hernandez, David Herrington, Craig Hersh, Bertha Hidalgo, Brian Hobbs, John Hokanson, Elliott Hong, Karin Hoth, Chao Agnes Hsiung, Yi-Jen Hung, Haley Huston, Chii Min Hwu, Rebecca Jackson, Deepti Jain, Cashell Jaquish, Min A Jhun, Craig Johnson, Rich Johnston, Kimberly Jones, Hyun Min Kang, Shannon Kelly, Michael Kessler, Alyna Khan, Wonji Kim, Greg Kinney, Holly Kramer, Christoph Lange, Meryl LeBoff, Seunggeun Shawn Lee, Wen-Jane Lee, Jonathon LeFaive, David Levine, Joshua Lewis, Xiaohui Li, Yun Li, Henry Lin, Honghuang Lin, Keng Han Lin, Xihong Lin, Simin Liu, Yu Liu, Kathryn Lunetta, James Luo, Michael Mahaney, Barry Make, Ani Manichaikul, Lauren Margolin, Lisa Martin, Susan Mathai, Susanne May, Patrick McArdle, Merry-Lynn McDonald, Sean McFarland, Daniel McGoldrick, Caitlin McHugh, Hao Mei, Luisa Mestroni, Julie Mikulla, Nancy Min, Mollie Minear, Ryan L Minster, Matt Moll, Courtney Montgomery, Solomon Musani, Stanford Mwasongwe, Josyf C Mychaleckyj, Girish Nadkarni, Rakhi Naik, Take Naseri, Sergei Nekhai, Sarah C Nelson, Bonnie Neltner, Deborah Nickerson, Jeff O'Connell, Tim O'Connor, Heather Ochs-Balcom, David Paik, James Pankow, George Papanicolaou, Afshin Parsa, Marco Perez, James Perry, Ulrike Peters, Patricia Peyser, Lawrence S Phillips, Toni Pollin, Wendy Post, Julia Powers Becker, Meher Preethi Boorgula, Michael Preuss, Pankaj Qasba, Dandi Qiao, Zhaohui Qin, Laura Rasmussen-Torvik, Aakrosh Ratan, Robert Reed, Elizabeth Regan, Muagututi'a Sefuiva Reupena, Ken Rice, Carolina Roselli, Ingo Ruczinski, Pamela Russell, Sarah Ruuska, Kathleen Ryan, Danish Saleheen, Shabnam Salimi, Steven Salzberg, Kevin Sandow, Christopher Scheller, Ellen Schmidt, Karen Schwander, Frank Sciurba, Christine Seidman, Jonathan Seidman, Vivien Sheehan, Stephanie L Sherman, Amol Shetty, Aniket Shetty, Brian Silver, Josh Smith, Tanja Smith, Sylvia Smoller, Beverly Snively, Michael Snyder, Tamar Sofer, Nona Sotoodehnia, Adrienne M Stilp, Garrett Storm, Elizabeth Streeten, Jessica Lasky Su, Yun Ju Sung, Jody Sylvia, Adam Szpiro, Carole Sztalryd, Daniel Taliun, Hua Tang, Matthew Taylor, Simeon Taylor, Marilyn Telen, Timothy A Thornton, Machiko Threlkeld, Lesley Tinker, David Tirschwell, Sarah Tishkoff, Hemant Tiwari, Catherine Tong, Michael Tsai, Dhananjay Vaidya, David Van Den Berg, Peter VandeHaar, Scott Vrieze, Tarik Walker, Robert Wallace, Avram Walts, Heming Wang, Karol Watson, Bruce Weir, Lu-Chen Weng, Jennifer Wessel, Cristen Willer, Kayleen Williams, Carla Wilson, Joseph Wu, Huichun Xu, Lisa Yanek, Rongze Yang, Norann Zaghloul, Yingze Zhang, Snow Xueyan Zhao, Wei Zhao, Degui Zhi, Xiang Zhou, Xiaofeng Zhu, Michael Zody, Sebastian Zoellner

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Harvard Medical School, Boston, MA, USA.
⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶ Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁸ Health Sciences and Technology Program, Harvard Medical School, Boston, MA, USA.
⁹ Yale School of Medicine, New Haven, CT, USA.
¹⁰ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹¹ Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹² Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Biostatistics, University of Washington, Seattle, WA, USA.
¹⁴ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁸ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁹ Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD, USA.
²⁰ Colorado Center for Personalized Medicine, School of Medicine, University of Colorado, Aurora, CO, USA.
²¹ Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
²³ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
²⁴ Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁷ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁸ Department of Health Services, University of Washington, Seattle, WA, USA.
²⁹ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁰ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
³¹ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³² Departments of Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.
³³ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
³⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, USA.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
³⁶ Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
³⁷ Tulane University Translational Science Institute, New Orleans, LA, USA.
³⁸ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
³⁹ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
⁴⁰ Seattle Epidemiologic Information and Research Center, Department of Veterans Affairs, Office of Research and Development, Seattle, WA, USA.
⁴¹ College of Public Health, University of Kentucky, Lexington, KY, USA.
⁴² Department of Medicine, University of Colorado, Aurora, CO, USA.
⁴³ Departments of Medicine and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁴⁴ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴⁵ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴⁶ Bloodworks Northwest, Seattle, WA, USA.
⁴⁷ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴⁸ Vitalant Research Institute, San Francisco, CA, USA.
⁴⁹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵⁰ Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
⁵¹ Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
⁵² Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, AZ, USA.
⁵³ Department of Epidemiology and International Health Institute, Brown University School of Public Health, Providence, RI, USA.
⁵⁴ Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA.
⁵⁵ Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁵⁶ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
⁵⁸ Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
⁵⁹ Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
⁶⁰ Departments of Biostatistics and Epidemiology, Boston University School of Public Health, Boston, MA, USA.
⁶¹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁶² Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁶³ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁴ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
⁶⁵ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
⁶⁶ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁶⁷ Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁸ Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁹ Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
⁷⁰ Division of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
⁷¹ Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
⁷² Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷³ Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
⁷⁴ Department of Preventive Medicine, Northwestern Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁷⁵ Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
⁷⁶ Framingham Heart Study, Framingham, MA, USA.
⁷⁷ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁷⁸ Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA.
⁷⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
⁸⁰ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁸¹ Center for Genes Environment and Health, National Jewish Health, Denver, CO, USA.
⁸² Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁸³ Department of Genome Science, University of Washington, Seattle, WA, USA.
⁸⁴ Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁸⁵ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁸⁶ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁸⁷ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁸ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹⁰ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
⁹¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁹² Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
⁹³ Department of Medicine, Weill Cornell Medical School, New York, NY, USA.
⁹⁴ Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁵ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁹⁶ Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
⁹⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁹⁸ Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA.
⁹⁹ Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
¹⁰⁰ Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
¹⁰¹ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
¹⁰² Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁰³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁰⁴ Department of Biology, MIT, Cambridge, MA, USA.
¹⁰⁵ Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
¹⁰⁶ Howard Hughes Medical Institute, Boston, MA, USA.
¹⁰⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰⁸ Regeneron Pharmaceuticals, Tarrytown, NY, USA.
¹⁰⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹⁰ Harvard Medical School, Boston, MA, USA. sekar@broadinstitute.org.
¹¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. sekar@broadinstitute.org.
¹¹² Verve Therapeutics, Cambridge, MA, USA. sekar@broadinstitute.org.
¹¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. pradeep@broadinstitute.org.
¹¹⁴ Harvard Medical School, Boston, MA, USA. pradeep@broadinstitute.org.
¹¹⁵ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. pradeep@broadinstitute.org.

^# Contributed equally.

PMID: 33057201
PMCID: PMC7944936
DOI: 10.1038/s41586-020-2819-2

Erratum in

Author Correction: Inherited causes of clonal haematopoiesis in 97,691 whole genomes.
Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL, Zekavat SM, Szeto MD, Liao X, Leventhal MJ, Nasser J, Chang K, Laurie C, Burugula BB, Gibson CJ, Niroula A, Lin AE, Taub MA, Aguet F, Ardlie K, Mitchell BD, Barnes KC, Moscati A, Fornage M, Redline S, Psaty BM, Silverman EK, Weiss ST, Palmer ND, Vasan RS, Burchard EG, Kardia SLR, He J, Kaplan RC, Smith NL, Arnett DK, Schwartz DA, Correa A, de Andrade M, Guo X, Konkle BA, Custer B, Peralta JM, Gui H, Meyers DA, McGarvey ST, Chen IY, Shoemaker MB, Peyser PA, Broome JG, Gogarten SM, Wang FF, Wong Q, Montasser ME, Daya M, Kenny EE, North KE, Launer LJ, Cade BE, Bis JC, Cho MH, Lasky-Su J, Bowden DW, Cupples LA, Mak ACY, Becker LC, Smith JA, Kelly TN, Aslibekyan S, Heckbert SR, Tiwari HK, Yang IV, Heit JA, Lubitz SA, Johnsen JM, Curran JE, Wenzel SE, Weeks DE, Rao DC, Darbar D, Moon JY, Tracy RP, Buth EJ, Rafaels N, Loos RJF, Durda P, Liu Y, Hou L, Lee J, Kachroo P, Freedman BI, Levy D, Bielak LF, Hixson JE, Floyd JS, Whitsel EA, Ellinor PT, Irvin MR, Fingerlin TE, Raffield LM, Armasu SM, Wheeler MM, Sabino EC, Blangero J, Williams LK, Levy BD, Sheu WH, Roden DM, Boerwinkle E, Manson JE, Mathias RA, Desai P, Taylor KD, Johnson AD;… See abstract for full author list ➔ Bick AG, et al. Nature. 2021 Mar;591(7851):E27. doi: 10.1038/s41586-021-03280-1. Nature. 2021. PMID: 33707633 No abstract available.

Abstract

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown¹. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer^2-4 and coronary heart disease⁵-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)⁶. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

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Figures

**Extended Data Fig. 1|. Characterizing TOPMed CHIP.**
a, There was marked heterogeneity of CHIP clone size as measured by variant allele fraction by CHIP driver gene. Violin plot spanning minimum and maximum values calculated on full dataset (Supplementary Table 3). Sample size for each element in violin plot displayed in Fig. 1, b, 90% of individuals with CHIP had only one CHIP driver mutation identified c, CHIP prevalence with age was highly concordant across sequenced cohorts. CHIP prevalence was estimated from a logistic mixed model with spline-transformed age, sex, and cohort included as predictors. The cohort was included as a random intercept. Sample size for each cohort listed in Supplementary Table 1. d, CHIP prevalence with age in this study (blue triangles, N=82,807) was highly consistent with previously observed CHIP prevalence (dots represent mean point prevalence with shaded area represents 95% confidence interval; N_Genovese=12,380; N_Jaiswal = 17,182; N_Xie = 2,728).

**Extended Data Fig. 2|. CHIP age association by mutational mechanism, gene and overlap with somatic chromosomal mosaicism.**
a, cumulative density plot of CHIP incidence with age stratified by single nucleotide variant (SNV) vs frameshift mutations. SNVs were observed in younger individuals than Frameshift mutations (N=4,939; two-sided wilcox rank sum test p=0.01). b, cumulative density plot of CHIP incidence with age stratified by driver gene. c, 855 elderly WHI individuals (mean age: 70) with both whole genome and the array genotyping data available were interrogated for large-scale mosaic chromosomal rearrangements. The two somatic events did not co-occur more than would be expected by chance (hypergeometric p=0.25).

**Extended Data Fig. 3|. CHIP associates with Blood, Lipid, and Inflammatory traits.**
a, CHIP consistently associated with increased Red Cell Distribution Width (RDW). *JAK2*, *SF3B1* and *SRSF2* showed driver gene specific effects on blood traits (see Supplementary Table S5) b, CHIP status was not consistently associated with lipid traits, other than *JAK2* CHIP which was associated with decreased total cholesterol and a trend towards decreased LDL (see Supplementary Table S6) c, CHIP status is associated with inflammatory markers, however notable heterogeneity existed across CHIP mutations (see Supplementary Table S7). Associations utilized a two-sided t-test from a multivariate general linear model including age, smoking, race and gender and study center and were not adjusted for multiple comparisons. Sample sizes and exact p-values for each phenotype are listed in Supplementary Tables 5–7.

**Extended Data Fig. 4|. CHIP passenger somatic mutation spectrum.**
a, Singleton mutation counts by nucleotide context in CHIP Cases and Controls. b, Signature contribution in CHIP cases and controls identified differential enrichment

**Extended Data Fig. 5|. CHIP Single variant association regional association plots.**
a, TERT locus b, TRIM59/KPNA4 locus c, TET2 locus. Two-sided association testing performed using SAIGE (N=65,405 individuals, see methods)

**Extended Data Fig. 6|. CHIP transcriptome-wide association study (TWAS) results across 48 tissues identified 7 significant loci.**
UTMOST algorithm applied to CHIP genome wide association study results from n=65,405 individuals (see methods). Genomic coordinates listed on x-axis. P-value from generalized Berk-Jones test on Y axis. Multiple hypothesis corrected threshold, p<2.9 × 10⁻⁶ displayed as dotted red line.

**Extended Data Fig. 7|. Tissue-specific results from the top 9 overall UTMOST-significant genes.**
UTMOST algorithm applied to CHIP genome wide association study results from n=65,405 individuals. P-value from generalized Berk-Jones test. eQTL z-scores for associations with P<0.05 are displayed in each bar. GTEX eQTL tissue listed on Y-axis.

**Extended Data Fig. 8 |. CRISPR/Cas9 editing efficiency of TET2 Enhancer deletion in primary CD34+ HSPCs.**
a, Schematic showing the position of the two sgRNAs used to delete the TET2 enhancer (512bp) containing rs79901204. B, Gel electrophoresis image of PCR products from genomic DNA of edited HSPCs indicating unedited (WT) and deletion bands at sgRNA target site. Percentages of deletion alleles determined by band intensity and is shown below each lane. The experiment contains 3 biological replicates and was performed once.

**Extended Data Fig. 9 |. rs79901204 associated with genome wide differential methylation signal,**
Methylation Quantitative Trait association results of rs79901204 variant with cpg methylation probes identify an altered peripheral leukocyte methylation profile genome wide in N = 1747 individuals. The strongest signal is at the chr4 TET2 locus. P-values on Y-axis derived from two-sided linear mixed effects model (see methods). To account for multiple hypothesis testing, a Bonferroni threshold of p < 5.8 × 10⁻⁸ was used to establish statistical significance.

**Extended Data Fig. 10 |. Sensitivity of CHIP detection at various VAFs across sequencing depths.**
A set of 30 samples from a previously published CHIP cohort (Gibbons et al, 2017) were computationally down sampled to 30x, 40x, 50x, 100x and 400x sequencing depth. TOPMed WGS data was typically in the 40x depth range across CHIP genes. WGS data has excellent sensitivity to detect CHIP clones with VAF >10%, and ~50% sensitivity to detect CHIP VAF 5–10%, with minimal ability to detect CHIP clones <5%.

**Fig. 1|. Identifying CHIP in TOPMed Genomes.**
CHIP was identified in 97,631 whole genome sequenced peripheral blood samples through the curation of somatic driver mutations. Counts for 8 most common driver genes plotted. **inset**, CHIP prevalence increased with age. Center line represents general additive model spline, 95% confidence interval is shaded (n=82,807 individuals; two-sided t-test: p<10⁻³⁰⁰).

**Fig. 2|. Genetic Determinants of CHIP.**
Single variant genetic association analyses of CHIP identified three genome wide significant loci. Two-sided association testing performed using SAIGE (n=65,405 individuals, see methods)

**Fig. 3|. African ancestry specific *TET2* locus risk variant disrupts hematopoietic stem cell *TET2* enhancer decreasing TET2 expression and increasing self-renewal.**
a, the TET2 locus with fine-mapped risk variants, Activity-by-Contact (ABC) hematopoietic stem and progenitor cell (HSPC) enhancers, DNase-Seq CD34+ HSPC and RefSeq genes. ABC model predicts that rs79901204 disrupts a TET2 enhancer resulting in decreased TET2 expression (see methods). b, expanded view of TET2 enhancer element. c, rs79901204 disrupts a GATA motif/E-Box motif. d, rs79901204 is associated with decreased TET2 expression in human peripheral blood RNA-seq (N_A/A=230, N_A/T=16, N_T/T=1, two-sided linear mixed model p=0.012). TPM, transcripts per million. Boxplot displays median, 25^th and 75^th percentiles, mean (diamond symbol) and outlier observations (black dots) e, luciferase assay in CD34+ primary cells demonstrates four-fold attenuation of enhancer activity by the rs79901204 T risk allele relative to the A reference allele (N=3, two-sided t-test p=0.007). f, deleting the TET2 enhancer (ENH) in CD34+ primary cells results in decreased TET2 expression relative to deletion of control locus AAVS1 (N=3, two-sided t-test, p=0.04). g, Human HSPCs were electroporated with Cas9 targeting a coding region of TET2 and AAVS1 (a control locus) and plated for primary and secondary colony-forming assays. h, two TET2 guides had differential editing efficiency. i, TET2 coding disruption leads to expanded secondary colony formation compared to AAVS1 controls (N=3, two-sided t-test p=0.01, p=0.002 for g1 and g2 respectively, with greater expansion identified in the TET2 guide with greater editing efficiency (two-sided t-test p=0.04). Mean and standard deviation of number of each colony type plotted. CFU-M, colony forming unit-macrophage; CFU-GM, granulocyte macrophage; CFU-GEMM, granulocyte erythrocyte macrophage megakaryocyte; CFU-G, granulocyte; BFU-E, burst forming unit-erythroid. In e, f, h, points represent independent replicates, mean values and error bars represent standard error are plotted.

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Inherited causes of clonal haematopoiesis in 97,691 whole genomes

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