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Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Author

Listed:
  • Alexander G. Bick

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Harvard Medical School
    Vanderbilt University Medical Center)

  • Joshua S. Weinstock

    (University of Michigan School of Public Health)

  • Satish K. Nandakumar

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Charles P. Fulco

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Erik L. Bao

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Seyedeh M. Zekavat

    (Broad Institute of MIT and Harvard
    Yale School of Medicine)

  • Mindy D. Szeto

    (University of Colorado Anschutz Medical Campus
    University of Colorado Anschutz Medical Campus)

  • Xiaotian Liao

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Matthew J. Leventhal

    (Broad Institute of MIT and Harvard)

  • Joseph Nasser

    (Broad Institute of MIT and Harvard)

  • Kyle Chang

    (The University of Texas MD Anderson Cancer Center)

  • Cecelia Laurie

    (University of Washington)

  • Bala Bharathi Burugula

    (University of Michigan)

  • Christopher J. Gibson

    (Dana-Farber Cancer Institute)

  • Abhishek Niroula

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Amy E. Lin

    (Brigham and Women’s Hospital)

  • Margaret A. Taub

    (Johns Hopkins Bloomberg School of Public Health)

  • Francois Aguet

    (Broad Institute of MIT and Harvard)

  • Kristin Ardlie

    (Broad Institute of MIT and Harvard)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine
    Baltimore Veterans Administration Medical Center)

  • Kathleen C. Barnes

    (University of Colorado Anschutz Medical Campus
    University of Colorado)

  • Arden Moscati

    (Icahn School of Medicine at Mount Sinai)

  • Myriam Fornage

    (University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston)

  • Susan Redline

    (Harvard Medical School
    Brigham and Women’s Hospital
    Beth Israel Deaconess Medical Center)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Edwin K. Silverman

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Scott T. Weiss

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Nicholette D. Palmer

    (Wake Forest School of Medicine)

  • Ramachandran S. Vasan

    (Boston University School of Medicine)

  • Esteban G. Burchard

    (University of California, San Francisco
    University of California)

  • Sharon L. R. Kardia

    (University of Michigan)

  • Jiang He

    (Tulane University School of Public Health and Tropical Medicine
    Tulane University Translational Science Institute)

  • Robert C. Kaplan

    (Albert Einstein College of Medicine
    Division of Public Health Sciences)

  • Nicholas L. Smith

    (University of Washington
    Kaiser Permanente Washington Health Research Institute
    Office of Research and Development)

  • Donna K. Arnett

    (University of Kentucky)

  • David A. Schwartz

    (University of Colorado)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Mariza Andrade

    (Mayo Clinic)

  • Xiuqing Guo

    (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • Barbara A. Konkle

    (Bloodworks Northwest
    University of Washington)

  • Brian Custer

    (Vitalant Research Institute
    University of California, San Francisco)

  • Juan M. Peralta

    (University of Texas Rio Grande Valley School of Medicine)

  • Hongsheng Gui

    (Henry Ford Health System)

  • Deborah A. Meyers

    (University of Arizona)

  • Stephen T. McGarvey

    (Brown University School of Public Health)

  • Ida Yii-Der Chen

    (Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center)

  • M. Benjamin Shoemaker

    (Vanderbilt University Medical Center)

  • Patricia A. Peyser

    (University of Michigan)

  • Jai G. Broome

    (University of Washington)

  • Stephanie M. Gogarten

    (University of Washington)

  • Fei Fei Wang

    (University of Washington)

  • Quenna Wong

    (University of Washington)

  • May E. Montasser

    (University of Maryland School of Medicine)

  • Michelle Daya

    (University of Colorado Anschutz Medical Campus)

  • Eimear E. Kenny

    (Icahn School of Medicine at Mount Sinai)

  • Kari E. North

    (University of North Carolina)

  • Lenore J. Launer

    (Intramural Research Program, National Institute on Aging)

  • Brian E. Cade

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Joshua C. Bis

    (University of Washington)

  • Michael H. Cho

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Jessica Lasky-Su

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Donald W. Bowden

    (Wake Forest School of Medicine)

  • L. Adrienne Cupples

    (Boston University School of Public Health)

  • Angel C. Y. Mak

    (University of California, San Francisco)

  • Lewis C. Becker

    (Johns Hopkins School of Medicine)

  • Jennifer A. Smith

    (University of Michigan
    University of Michigan)

  • Tanika N. Kelly

    (Tulane University School of Public Health and Tropical Medicine
    Tulane University Translational Science Institute)

  • Stella Aslibekyan

    (University of Alabama at Birmingham)

  • Susan R. Heckbert

    (University of Washington
    Kaiser Permanente Washington Health Research Institute)

  • Hemant K. Tiwari

    (University of Alabama at Birmingham)

  • Ivana V. Yang

    (University of Colorado)

  • John A. Heit

    (Division of Cardiovascular Diseases, Mayo Clinic)

  • Steven A. Lubitz

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Jill M. Johnsen

    (Bloodworks Northwest
    University of Washington)

  • Joanne E. Curran

    (University of Texas Rio Grande Valley School of Medicine)

  • Sally E. Wenzel

    (University of Pittsburgh)

  • Daniel E. Weeks

    (University of Pittsburgh)

  • Dabeeru C. Rao

    (Washington University School of Medicine)

  • Dawood Darbar

    (University of Illinois at Chicago)

  • Jee-Young Moon

    (Albert Einstein College of Medicine)

  • Russell P. Tracy

    (University of Vermont)

  • Erin J. Buth

    (University of Washington)

  • Nicholas Rafaels

    (University of Colorado)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Peter Durda

    (University of Vermont)

  • Yongmei Liu

    (Duke University Medical Center)

  • Lifang Hou

    (Northwestern University)

  • Jiwon Lee

    (Brigham and Women’s Hospital)

  • Priyadarshini Kachroo

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Barry I. Freedman

    (Section on Nephrology, Wake Forest School of Medicine)

  • Daniel Levy

    (Framingham Heart Study
    National Institutes of Health)

  • Lawrence F. Bielak

    (University of Michigan)

  • James E. Hixson

    (University of Texas Health Science Center at Houston School of Public Health)

  • James S. Floyd

    (University of Washington
    University of Washington
    University of Washington)

  • Eric A. Whitsel

    (University of North Carolina
    University of North Carolina)

  • Patrick T. Ellinor

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Marguerite R. Irvin

    (University of Alabama at Birmingham)

  • Tasha E. Fingerlin

    (National Jewish Health)

  • Laura M. Raffield

    (University of North Carolina)

  • Sebastian M. Armasu

    (Mayo Clinic)

  • Marsha M. Wheeler

    (University of Washington)

  • Ester C. Sabino

    (Faculdade de Medicina da Universidade de São Paulo)

  • John Blangero

    (University of Texas Rio Grande Valley School of Medicine)

  • L. Keoki Williams

    (Henry Ford Health System)

  • Bruce D. Levy

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Wayne Huey-Herng Sheu

    (Taichung Veterans General Hospital)

  • Dan M. Roden

    (Vanderbilt University Medical Center
    Vanderbilt University Medical Center
    Vanderbilt University Medical Center)

  • Eric Boerwinkle

    (Vanderbilt University Medical Center
    Baylor College of Medicine)

  • JoAnn E. Manson

    (Harvard Medical School
    Brigham and Women’s Hospital
    Harvard School of Public Health)

  • Rasika A. Mathias

    (Johns Hopkins School of Medicine)

  • Pinkal Desai

    (Weill Cornell Medical School)

  • Kent D. Taylor

    (Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
    Harbor-UCLA Medical Center)

  • Andrew D. Johnson

    (Framingham Heart Study
    National Institutes of Health)

  • Paul L. Auer

    (University of Wisconsin-Milwaukee)

  • Charles Kooperberg

    (Fred Hutchinson Cancer Research Center)

  • Cathy C. Laurie

    (University of Washington)

  • Thomas W. Blackwell

    (University of Michigan School of Public Health)

  • Albert V. Smith

    (University of Michigan School of Public Health)

  • Hongyu Zhao

    (Yale University
    Yale University)

  • Ethan Lange

    (University of Colorado Anschutz Medical Campus)

  • Leslie Lange

    (University of Colorado Anschutz Medical Campus)

  • Stephen S. Rich

    (University of Virginia)

  • Jerome I. Rotter

    (Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
    Harbor-UCLA Medical Center)

  • James G. Wilson

    (University of Mississippi Medical Center
    Beth Israel Deaconess Medical Center)

  • Paul Scheet

    (The University of Texas MD Anderson Cancer Center)

  • Jacob O. Kitzman

    (University of Michigan
    University of Michigan)

  • Eric S. Lander

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    MIT)

  • Jesse M. Engreitz

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Benjamin L. Ebert

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

  • Alexander P. Reiner

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • Siddhartha Jaiswal

    (Stanford University School of Medicine)

  • Gonçalo Abecasis

    (University of Michigan School of Public Health
    Regeneron Pharmaceuticals)

  • Vijay G. Sankaran

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Sekar Kathiresan

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital
    Verve Therapeutics)

  • Pradeep Natarajan

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

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 cancer2–4 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.

Suggested Citation

  • Alexander G. Bick & Joshua S. Weinstock & Satish K. Nandakumar & Charles P. Fulco & Erik L. Bao & Seyedeh M. Zekavat & Mindy D. Szeto & Xiaotian Liao & Matthew J. Leventhal & Joseph Nasser & Kyle Chan, 2020. "Inherited causes of clonal haematopoiesis in 97,691 whole genomes," Nature, Nature, vol. 586(7831), pages 763-768, October.
    • Handle: RePEc:nat:nature:v:586:y:2020:i:7831:d:10.1038_s41586-020-2819-2
    DOI: 10.1038/s41586-020-2819-2
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    Citations

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    Cited by:

    1. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. M d Mesbah Uddin & Ngoc Quynh H. Nguyen & Bing Yu & Jennifer A. Brody & Akhil Pampana & Tetsushi Nakao & Myriam Fornage & Jan Bressler & Nona Sotoodehnia & Joshua S. Weinstock & Michael C. Honigberg &, 2022. "Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. J. McClatchy & R. Strogantsev & E. Wolfe & H. Y. Lin & M. Mohammadhosseini & B. A. Davis & C. Eden & D. Goldman & W. H. Fleming & P. Conley & G. Wu & L. Cimmino & H. Mohammed & A. Agarwal, 2023. "Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Yash Pershad & Taralynn Mack & Hannah Poisner & Yasminka A. Jakubek & Adrienne M. Stilp & Braxton D. Mitchell & Joshua P. Lewis & Eric Boerwinkle & Ruth J. F. Loos & Nathalie Chami & Zhe Wang & Kathle, 2024. "Determinants of mosaic chromosomal alteration fitness," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    5. Kelly L. Bolton & Youngil Koh & Michael B. Foote & Hogune Im & Justin Jee & Choong Hyun Sun & Anton Safonov & Ryan Ptashkin & Joon Ho Moon & Ji Yeon Lee & Jongtak Jung & Chang Kyung Kang & Kyoung-Ho S, 2021. "Clonal hematopoiesis is associated with risk of severe Covid-19," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    6. Romain O. Georges & Hugo Sepulveda & J. Carlos Angel & Eric Johnson & Susan Palomino & Roberta B. Nowak & Arshad Desai & Isaac F. López-Moyado & Anjana Rao, 2022. "Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Md Mesbah Uddin & Seyedmohammad Saadatagah & Abhishek Niroula & Bing Yu & Whitney E. Hornsby & Shriienidhie Ganesh & Kim Lannery & Art Schuermans & Michael C. Honigberg & Alexander G. Bick & Peter Lib, 2024. "Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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