Inherited causes of clonal haematopoiesis in 97,691 whole genomes

doi:10.1038/s41586-020-2819-2

Inherited causes of clonal haematopoiesis in 97,691 whole genomes

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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.

Original language	English
Pages (from-to)	763-768
Number of pages	6
Journal	Nature
Volume	586
Issue number	7831
DOIs	https://doi.org/10.1038/s41586-020-2819-2
State	Published - Oct 29 2020

Bibliographical note

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

Funding

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.

Funders	Funder number
Boehringer Ingelheim and Fitbit
GlaxoSmithKlein
Ludwig Center for Cancer Immunotherapy	UM1-HG008895
Pieris Pharmaceuticals
Samsung Research America
Thetis Pharmaceuticals
National Heart, Lung, and Blood Institute (NHLBI)	K01HL136700, R35HL135818
National Heart, Lung, and Blood Institute (NHLBI)
Burroughs Wellcome Fund
Bristol-Myers Squibb
International Business Machines Corporation
Pfizer
Bayer AG
Novartis
Sanofi
Massachusetts General Hospital
Teva Pharmaceutical Industries Ltd.
Quest Diagnostics Incorporated
MyoKardia
Fondation Leducq	TNE-18CVD04
Fondation Leducq

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41586-020-2819-2

Cite this

@article{44c6aa62425942b5a6b0b342d36761ef,

title = "Inherited causes of clonal haematopoiesis in 97,691 whole genomes",

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.",

author = "Bick, {Alexander G.} and Weinstock, {Joshua S.} and Nandakumar, {Satish K.} and Fulco, {Charles P.} and Bao, {Erik L.} and Zekavat, {Seyedeh M.} and Szeto, {Mindy D.} and Xiaotian Liao and Leventhal, {Matthew J.} and Joseph Nasser and Kyle Chang and Cecelia Laurie and Burugula, {Bala Bharathi} and Gibson, {Christopher J.} and Lin, {Amy E.} and Taub, {Margaret A.} and Francois Aguet and Kristin Ardlie and Mitchell, {Braxton D.} and Barnes, {Kathleen C.} and Arden Moscati and Myriam Fornage and Susan Redline and Psaty, {Bruce M.} and Silverman, {Edwin K.} and Weiss, {Scott T.} and Palmer, {Nicholette D.} and Vasan, {Ramachandran S.} and Burchard, {Esteban G.} and Kardia, {Sharon L.R.} and Jiang He and Kaplan, {Robert C.} and Smith, {Nicholas L.} and Arnett, {Donna K.} and Schwartz, {David A.} and Adolfo Correa and {de Andrade}, Mariza and Xiuqing Guo and Konkle, {Barbara A.} and Brian Custer and Peralta, {Juan M.} and Hongsheng Gui and Meyers, {Deborah A.} and McGarvey, {Stephen T.} and Chen, {Ida Yii Der} and Shoemaker, {M. Benjamin} and Peyser, {Patricia A.} and Broome, {Jai G.} and Gogarten, {Stephanie M.} and Wang, {Fei Fei}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = oct,

day = "29",

doi = "10.1038/s41586-020-2819-2",

language = "English",

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number = "7831",

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AU - Bick, Alexander G.

AU - Weinstock, Joshua S.

AU - Nandakumar, Satish K.

AU - Fulco, Charles P.

AU - Bao, Erik L.

AU - Zekavat, Seyedeh M.

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AU - Liao, Xiaotian

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AU - Chang, Kyle

AU - Laurie, Cecelia

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AU - Aguet, Francois

AU - Ardlie, Kristin

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AU - Barnes, Kathleen C.

AU - Moscati, Arden

AU - Fornage, Myriam

AU - Redline, Susan

AU - Psaty, Bruce M.

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AU - Weiss, Scott T.

AU - Palmer, Nicholette D.

AU - Vasan, Ramachandran S.

AU - Burchard, Esteban G.

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AU - He, Jiang

AU - Kaplan, Robert C.

AU - Smith, Nicholas L.

AU - Arnett, Donna K.

AU - Schwartz, David A.

AU - Correa, Adolfo

AU - de Andrade, Mariza

AU - Guo, Xiuqing

AU - Konkle, Barbara A.

AU - Custer, Brian

AU - Peralta, Juan M.

AU - Gui, Hongsheng

AU - Meyers, Deborah A.

AU - McGarvey, Stephen T.

AU - Chen, Ida Yii Der

AU - Shoemaker, M. Benjamin

AU - Peyser, Patricia A.

AU - Broome, Jai G.

AU - Gogarten, Stephanie M.

AU - Wang, Fei Fei

PY - 2020/10/29

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N2 - 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.

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Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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