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Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Publication ,  Journal Article
Bick, AG; Weinstock, JS; Nandakumar, SK; Fulco, CP; Bao, EL; Zekavat, SM; Szeto, MD; Liao, X; Leventhal, MJ; Nasser, J; Chang, K; Laurie, C ...
Published in: Nature
October 2020

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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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

October 2020

Volume

586

Issue

7831

Start / End Page

763 / 768

Location

England

Related Subject Headings

  • alpha Karyopherins
  • Whole Genome Sequencing
  • United States
  • Tripartite Motif Proteins
  • Proto-Oncogene Proteins
  • Precision Medicine
  • Phenotype
  • National Heart, Lung, and Blood Institute (U.S.)
  • Middle Aged
  • Male
 

Citation

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Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., … Natarajan, P. (2020). Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature, 586(7831), 763–768. https://doi.org/10.1038/s41586-020-2819-2
Bick, Alexander G., Joshua S. Weinstock, Satish K. Nandakumar, Charles P. Fulco, Erik L. Bao, Seyedeh M. Zekavat, Mindy D. Szeto, et al. “Inherited causes of clonal haematopoiesis in 97,691 whole genomes.Nature 586, no. 7831 (October 2020): 763–68. https://doi.org/10.1038/s41586-020-2819-2.
Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL, Zekavat SM, et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature. 2020 Oct;586(7831):763–8.
Bick, Alexander G., et al. “Inherited causes of clonal haematopoiesis in 97,691 whole genomes.Nature, vol. 586, no. 7831, Oct. 2020, pp. 763–68. Pubmed, doi:10.1038/s41586-020-2819-2.
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, 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-D, 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 J-Y, 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-H, Roden DM, Boerwinkle E, Manson JE, Mathias RA, Desai P, Taylor KD, Johnson AD, NHLBI Trans-Omics for Precision Medicine Consortium, Auer PL, Kooperberg C, Laurie CC, Blackwell TW, Smith AV, Zhao H, Lange E, Lange L, Rich SS, Rotter JI, Wilson JG, Scheet P, Kitzman JO, Lander ES, Engreitz JM, Ebert BL, Reiner AP, Jaiswal S, Abecasis G, Sankaran VG, Kathiresan S, Natarajan P. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature. 2020 Oct;586(7831):763–768.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

October 2020

Volume

586

Issue

7831

Start / End Page

763 / 768

Location

England

Related Subject Headings

  • alpha Karyopherins
  • Whole Genome Sequencing
  • United States
  • Tripartite Motif Proteins
  • Proto-Oncogene Proteins
  • Precision Medicine
  • Phenotype
  • National Heart, Lung, and Blood Institute (U.S.)
  • Middle Aged
  • Male