Inherited causes of clonal haematopoiesis in 97,691 whole genomes


Alexander G. Bick, Massachusetts General Hospital
Joshua S. Weinstock, University of Michigan School of Public Health
Satish K. Nandakumar, Broad Institute
Charles P. Fulco, Broad Institute
Erik L. Bao, Broad Institute
Seyedeh M. Zekavat, Broad Institute
Mindy D. Szeto, University of Colorado Anschutz Medical Campus
Xiaotian Liao, Broad Institute
Matthew J. Leventhal, Broad Institute
Joseph Nasser, Broad Institute
Kyle Chang, University of Texas MD Anderson Cancer Center
Cecelia Laurie, University of Washington, Seattle
Bala Bharathi Burugula, University of Michigan, Ann Arbor
Christopher J. Gibson, 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
Kristin Ardlie, Broad Institute
Braxton D. Mitchell, University of Maryland School of Medicine
Kathleen C. Barnes, University of Colorado Anschutz Medical Campus
Arden Moscati, Icahn School of Medicine at Mount Sinai
Myriam Fornage, University of Texas Health Science Center at Houston
Susan Redline, Harvard Medical School
Bruce M. Psaty, University of Washington School of Medicine
Edwin K. Silverman, Harvard Medical School
Scott T. Weiss, Harvard Medical School
Nicholette D. Palmer, Wake Forest School of Medicine
Ramachandran S. Vasan, Boston University School of Medicine
Esteban G. Burchard, University of California, San Francisco
Sharon L.R. Kardia, University of Michigan, Ann Arbor
Jiang He, Tulane University School of Public Health and Tropical Medicine
Robert C. Kaplan, Albert Einstein College of Medicine of Yeshiva University

Document Type

Journal Article

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© 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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.