| Title | The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Weinstock 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 Authors | NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium |
| Journal | Sci Adv |
| Volume | 9 |
| Issue | 17 |
| Pagination | eabm4945 |
| Date Published | 2023 Apr 28 |
| ISSN | 2375-2548 |
| Keywords | Germ-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. |
| DOI | 10.1126/sciadv.abm4945 |
| Alternate Journal | Sci Adv |
| PubMed ID | 37126548 |
| PubMed Central ID | PMC10132750 |
| Grant List | DP2 HL157540 / HL / NHLBI NIH HHS / United States P01 CA196569 / CA / NCI NIH HHS / United States R01 HL153805 / HL / NHLBI NIH HHS / United States |