The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.

TitleThe genetic determinants of recurrent somatic mutations in 43,693 blood genomes.
Publication TypeJournal Article
Year of Publication2023
AuthorsWeinstock, JS, Laurie, CA, Broome, JG, Taylor, KD, Guo, X, Shuldiner, AR, O'Connell, JR, Lewis, JP, Boerwinkle, E, Barnes, KC, Chami, N, Kenny, EE, Loos, RJF, Fornage, M, Redline, S, Cade, BE, Gilliland, FD, Chen, Z, W Gauderman, J, Kumar, R, Grammer, L, Schleimer, RP, Psaty, BM, Bis, JC, Brody, JA, Silverman, EK, Yun, JH, Qiao, D, Weiss, ST, Lasky-Su, J, DeMeo, DL, Palmer, ND, Freedman, BI, Bowden, DW, Cho, MH, Vasan, RS, Johnson, AD, Yanek, LR, Becker, LC, Kardia, S, He, J, Kaplan, R, Heckbert, SR, Smith, NL, Wiggins, KL, Arnett, DK, Irvin, MR, Tiwari, H, Correa, A, Raffield, LM, Gao, Y, de Andrade, M, Rotter, JI, Rich, SS, Manichaikul, AW, Konkle, BA, Johnsen, JM, Wheeler, MM, Custer, BS, Duggirala, R, Curran, JE, Blangero, J, Gui, H, Xiao, S, L Williams, K, Meyers, DA, Li, X, Ortega, V, McGarvey, S, C Gu, C, Chen, Y-DIda, Lee, W-J, M Shoemaker, B, Darbar, D, Roden, D, Albert, C, Kooperberg, C, Desai, P, Blackwell, TW, Abecasis, GR, Smith, AV, Kang, HM, Mathias, R, Natarajan, P, Jaiswal, S, Reiner, AP, Bick, AG
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalSci Adv
Volume9
Issue17
Paginationeabm4945
Date Published2023 Apr 28
ISSN2375-2548
KeywordsGerm-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype
Abstract

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

DOI10.1126/sciadv.abm4945
Alternate JournalSci Adv
PubMed ID37126548
PubMed Central IDPMC10132750
Grant ListR01 HL153805 / HL / NHLBI NIH HHS / United States
DP2 HL157540 / HL / NHLBI NIH HHS / United States
P01 HL132825 / HL / NHLBI NIH HHS / United States
K08 HL146972 / HL / NHLBI NIH HHS / United States
P01 CA196569 / CA / NCI NIH HHS / United States

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