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

TitleInherited causes of clonal haematopoiesis in 97,691 whole genomes.
Publication TypeJournal Article
Year of Publication2020
AuthorsBick, AG, Weinstock, JS, Nandakumar, SK, Fulco, CP, Bao, EL, Zekavat, SM, Szeto, MD, Liao, X, Leventhal, MJ, Nasser, J, Chang, K, Laurie, C, Burugula, BBharathi, 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, M Shoemaker, B, Peyser, PA, Broome, JG, Gogarten, SM, Wang, FFei, Wong, Q, Montasser, ME, Daya, M, Kenny, EE, North, KE, Launer, LJ, Cade, BE, Bis, JC, Cho, MH, Lasky-Su, J, Bowden, DW, Cupples, AL, C Y Mak, A, 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, L Williams, K, Levy, BD, Sheu, WHuey-Herng, Roden, DM, Boerwinkle, E, Manson, JAE, Mathias, RA, Desai, P, Taylor, KD, Johnson, AD, 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
Corporate/Institutional AuthorsNHLBI Trans-Omics for Precision Medicine Consortium
Date Published2020 10
Abstract<p>Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. 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 and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). 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.</p>
Alternate JournalNature
PubMed ID33057201
Grant ListDP5 OD029586 / OD / NIH HHS / United States
R01 HL139731 / HL / NHLBI NIH HHS / United States
U54 GM115428 / GM / NIGMS NIH HHS / United States
R01 HL133040 / HL / NHLBI NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
R01 HL148050 / HL / NHLBI NIH HHS / United States
R01 HL113323 / HL / NHLBI NIH HHS / United States
R01 HL091357 / HL / NHLBI NIH HHS / United States
R01 HL055673 / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
F30 HL149180 / HL / NHLBI NIH HHS / United States
K01 HL136700 / HL / NHLBI NIH HHS / United States
R01 HL148565 / HL / NHLBI NIH HHS / United States
P01 HL132825 / HL / NHLBI NIH HHS / United States
R01 HL138737 / HL / NHLBI NIH HHS / United States
R35 HL135818 / HL / NHLBI NIH HHS / United States
UM1 HG008895 / HG / NHGRI NIH HHS / United States
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