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.
Bibliographical noteFunding Information:
Competing interests B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. E.K.S. and M.H.C. received grant support from GlaxoSmithKlein and Bayer. S.T.W. received royalties from UpToDate. S.A. reports employment and equity in 23andMe. B.I.F. is a consultant for RenalytixAI and AstraZeneca Pharmaceuticals. M.E.M. reports funding from Regeneron Pharmaceuticals, unrelated to this project. M.H.C. has received grant support from GlaxoSmithKlein and Bayer and consulting or speaking fees from AstraZeneca and Illumina. J.S.F. has consulted for Shionogi. B.D.L. is a co-founder of Nocion Therapeutics; receives grant support from Pieris Pharmaceuticals, Sanofi and Samsung Research America; and has served as a consultant for Bayer, Entrinsic Health, Gossamer Bio, NControl, Novartis, Teva and Thetis Pharmaceuticals. E.S.L. serves on the board of directors for Codiak BioSciences and serves on the scientific advisory board of F-Prime Capital Partners and Third Rock Ventures. B.L.E. reports grant support from Celgene and Deerfield. P.T.E. has received grant support from Bayer AG and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. G.A. is an employee of Regeneron Pharmaceuticals and owns stock and stock options for Regeneron Pharmaceuticals. S.J. is a scientific advisor to Grail. S.L. receives sponsored research support from Bristol Myers Squibb, Pfizer, Bayer AG, Boehringer Ingelheim and Fitbit; has consulted for Bristol Myers Squibb, Pfizer and Bayer AG; and participates in a research collaboration with IBM. P.N. reports grants support from Amgen, Apple and Boston Scientific, and is a scientific advisor to Apple. S.K. is an employee of Verve Therapeutics, and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis and San Therapeutics; is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; and has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest and Medscape. The other authors declare no competing interests.
Acknowledgements Investigators who conducted this research report individual research support from R35 HL135818 (S.R.), P01 HL132825 (S.T.W.), R01 HL091357 and R01 HL055673 (D.K.A.), W81 XWH-17-1-0597 (D.A.S.), K01 HL135405 (B.E.C.), P01 HL132825 (J.L.-S.), K01HL136700 (S.A.), R01 HL113323 (J.E.C.), R01HL1333040 (D.E.W.), R01 HL138737 (D.D.), P01 HL132825 (P.K.), T32 HL129982 (L.M.R.), R01 HL113323 (J.B.), HHS-N268201800002I (T.W.B. and A.V.S.), U54 GM115428 (J.G.W.), R01 HL148565 and R01 HL148050 (P.N.), F30 HL149180 (S.M.Z.), R01 HL139731 and AHA-18SFRN34250007 (S.L.), DP5 OD029586 (A.G.B.), Claudia Adams Barr Program for Innovative Cancer Research (V.G.S.), R01 142711, MGH Hassenfeld Scholar Award (P.N.), Fondation Leducq TNE-18CVD04 (A.G.B., B.L.E., S.J., P.N. and S.K.), Burroughs Wellcome Foundation (A.G.B. and S.J.), Ludwig Cancer Center (S.J.) and UM1-HG008895 (S.K.). WGS for the Trans-Omics in Precision Medicine (TOPMed) programme was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services.
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