The genetic determinants of recurrent somatic mutations in 43,693 blood genomes
Joshua S. Weinstock, Cecelia Laurie, Jai Broome, Kent D. Taylor, Xiuqing Guo, Alan R. Shuldiner, Jeffrey R. O’Connell, Joshua P. Lewis, Eric Boerwinkle, Kathleen C. Barnes, Nathalie Chami, Eimear E. Kenny, Ruth J. F. Loos, Myriam Fornage, Susan Redline, Brian E. Cade, Frank D. Gilliland, Zhanghua Chen, W. James Gauderman, Rajesh Kumar, Leslie C. Grammer, Robert P. Schleimer, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Dandi Qiao, Scott T. Weiss, Jessica Lasky‐Su, Dawn L. DeMeo, Nicholette D. Palmer, Barry I. Freedman, Donald W. Bowden, Michael H. Cho, Ramachandran S. Vasan, Andrew D. Johnson, Lisa R. Yanek, Lewis C. Becker, Sharon L.R. Kardia, Jiang He, Robert C. Kaplan, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Donna K. Arnett, Marguerite R. Irvin, Hemant K. Tiwari, Adolfo Correa, Laura M. Raffield, Yan Gao, Mariza de Andrade, Jerome I. Rotter, Stephen S. Rich, Ani Manichaikul, Barbara A. Konkle, Jill M. Johnsen, Marsha M. Wheeler, Brian Custer, Ravindranath Duggirala, Joanne E. Curran, John Blangero, Hongsheng Gui, Shujie Xiao, L. Keoki Williams, Deborah A. Meyers, Xingnan Li, Victor E. Ortega, Stephen T. McGarvey, C. Charles Gu, Yii‐Der Ida Chen, Wen‐Jane Lee, M. Benjamin Shoemaker, Dawood Darbar, Dan M. Roden, Christine M. Albert, Charles Kooperberg, Pinkal Desai, Thomas W. Blackwell, Gonçalo R. Abecasis, Albert V. Smith, Hyun Min Kang, Rasika A. Mathias, Pradeep Natarajan, Siddhartha Jaiswal, Alex P. Reiner, Alexander G. Bick
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.