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.
Original language | English |
---|---|
Article number | eabm4945 |
Journal | Science Advances |
Volume | 9 |
Issue number | 17 |
DOIs | |
State | Published - Apr 2023 |
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In: Science Advances, Vol. 9, No. 17, eabm4945, 04.2023.
Research output: Contribution to journal › Review article › peer-review
TY - JOUR
T1 - The genetic determinants of recurrent somatic mutations in 43,693 blood genomes
AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
AU - Weinstock, Joshua S.
AU - Laurie, Cecelia A.
AU - Broome, Jai G.
AU - Taylor, Kent D.
AU - Guo, Xiuqing
AU - Shuldiner, Alan R.
AU - O'Connell, Jeffrey R.
AU - Lewis, Joshua P.
AU - Boerwinkle, Eric
AU - Barnes, Kathleen C.
AU - Chami, Nathalie
AU - Kenny, Eimear E.
AU - Loos, Ruth J.F.
AU - Fornage, Myriam
AU - Redline, Susan
AU - Cade, Brian E.
AU - Gilliland, Frank D.
AU - Chen, Zhanghua
AU - Gauderman, W. James
AU - Kumar, Rajesh
AU - Grammer, Leslie
AU - Schleimer, Robert P.
AU - Psaty, Bruce M.
AU - Bis, Joshua C.
AU - Brody, Jennifer A.
AU - Silverman, Edwin K.
AU - Yun, Jeong H.
AU - Qiao, Dandi
AU - Weiss, Scott T.
AU - Lasky-Su, Jessica
AU - DeMeo, Dawn L.
AU - Palmer, Nicholette D.
AU - Freedman, Barry I.
AU - Bowden, Donald W.
AU - Cho, Michael H.
AU - Vasan, Ramachandran S.
AU - Johnson, Andrew D.
AU - Yanek, Lisa R.
AU - Becker, Lewis C.
AU - Kardia, Sharon
AU - He, Jiang
AU - Kaplan, Robert
AU - Heckbert, Susan R.
AU - Smith, Nicholas L.
AU - Wiggins, Kerri L.
AU - Arnett, Donna K.
AU - Irvin, Marguerite R.
AU - Tiwari, Hemant
AU - Correa, Adolfo
AU - Raffield, Laura M.
AU - Gao, Yan
AU - de Andrade, Mariza
AU - Rotter, Jerome I.
AU - Rich, Stephen S.
AU - Manichaikul, Ani W.
AU - Konkle, Barbara A.
AU - Johnsen, Jill M.
AU - Wheeler, Marsha M.
AU - Custer, Brian S.
AU - Duggirala, Ravindranath
AU - Curran, Joanne E.
AU - Blangero, John
AU - Gui, Hongsheng
AU - Xiao, Shujie
AU - Williams, L. Keoki
AU - Meyers, Deborah A.
AU - Li, Xingnan
AU - Ortega, Victor
AU - McGarvey, Stephen
AU - Gu, C. Charles
AU - Chen, Yii Der Ida
AU - Lee, Wen Jane
AU - Shoemaker, M. Benjamin
AU - Darbar, Dawood
AU - Roden, Dan
AU - Albert, Christine
AU - Kooperberg, Charles
AU - Desai, Pinkal
AU - Blackwell, Thomas W.
AU - Abecasis, Goncalo R.
AU - Smith, Albert V.
AU - Kang, Hyun M.
AU - Mathias, Rasika
AU - Natarajan, Pradeep
AU - Jaiswal, Siddhartha
AU - Reiner, Alexander P.
AU - Bick, Alexander G.
N1 - Funding Information: Acknowledgments:WGSfortheTr ans-Omics inPrecisionMedicine(TOPMed)progr am was supportedbytheNationalHeart,Lung,andBloodInstitute(NHLBI).SeetheSupplementary Materialsforstudyomicssupportinformation.Centralizedreadmappingandgenotypecalling, alongwithvariantqualitymetricsandfiltering,werepro vided bytheTOPMedInformatics ResearchCenter(3R01HL-117626-02S1;contractHHSN268201800002I).Phenotype harmonization,datamanagement,sampleidentityqualitycontrol,andgeneralstudy coordinationwerepro vided bytheTOPMedDataCoordinatingCenter(R01HL-120393;U01HL-120393;contractHHSN268201800001I).W ethankthestudiesandparticipantswhoprovided biologicalsamplesanddataforTOPMed.Thefullstudy-specificacknowledgmentsareincluded intheSupplementaryMaterials.Theviewsexpressedinthismanuscriptarethoseoftheauthors anddonotnecessarilyrepresenttheviewsoftheNationalHeart,Lung,andBloodInstitute;the NationalInstitutesofHealth;ortheU.S.DepartmentofHealthandHumanServices.W ewishto acknowledgethecontributionsoftheconsortiumworkingonthedevelopmentoftheNHLBI BioDataCatalystecosystem.Funding:ThisworkwassupportedbyNationalInstitutesofHealth grant3R01HL-117626-02S1,NationalInstitutesofHealthcontractHHSN268201800002I, NationalInstitutesofHealthgrantR01HL-120393,NationalInstitutesofHealthgrantU01HL-120393,NationalInstitutesofHealthcontractHHSN268201800001I,NationalInstitutesof HealthgrantDP5-OD029586(A.G.B.),BurroughsW ellcome FoundationCareerA wardfor MedicalScientists(A.G.B.andS.J.),andNHLBIBioDataCatalystFellowship(J.S.W).Author contributions:Conceptualization:J.S.W .andA.G.B.Methodology:J.S.W ., T .W .B., G.R.A.,A.V .S., H.M.K.,andA.G.B.Investigation:J.S.W .Projectadministration:C.A.L.,J.G.B.,andJ.A.B.Sample andfundingacquisition:K.D.T ., X.G.,A.R.S.,J.R.O.,J.P .L., E.B.,K.C.B.,N.C.,E.E.K.,R.J.F .L., M.F ., S.R., B.E.C.,F .D.G., Z.C.,W .J.G., R.K.,L.G.,R.P .S., B.M.P ., J.C.B.,E.K.S.,J.H.Y ., D.Q.,S.T .W ., J.L.-S.,D.L.D., N.D.P ., B.I.F ., D.W .B., M.H.C.,R.S.V ., A.D.J.,R.M.,L.R.Y ., L.C.B.,S.K.,J.H.,R.K.,S.R.H.,N.L.S.,K.L.W ., D.K.A.,M.R.I.,H.T ., A.C.,L.M.R.,Y .G., M.d.A.,J.I.R.,S.S.R.,A.W .M., B.A.K.,J.M.J.,M.M.W ., B.S.C.,R.D., J.E.C.,J.B.,H.G.,S.X.,L.K.W ., D.A.M.,X.L.,V .O., S.M.,C.C.G.,Y .-D.I.C., W .-J.L., M.B.S.,D.D.,D.R.,C.A., C.K.,P .D., andA.P .R. Supervision:T .W .B., G.R.A.,A.V .S., H.M.K.,A.J.,R.M.,P .N., S.J.,A.P .R., andA.G.B. Writing—originaldraft:J.S.W .andA.G.B.Writing—reviewandediting::K.D.T ., X.G.,A.R.S.,J.R.O., J.P .L., E.B.,K.C.B.,N.C.,E.E.K.,R.J.F .L., M.F ., S.R.,B.E.C.,F .D.G., Z.C.,W .J.G., R.K.,L.G.,R.P .S., B.M.P ., J.C.B.,E.K.S.,J.H.Y ., D.Q.,C.A.L.,J.G.B.,J.A.B.,S.T .W ., J.L.-S.,D.L.D.,N.D.P ., B.I.F ., D.W .B., M.H.C.,R.S.V ., A.D.J.,R.A.M.,L.R.Y ., L.C.B.,S.K.,J.H.,R.K.,S.R.H.,N.L.S.,K.L.W ., D.K.A.,M.R.I.,H.T ., A.C.,L.M.R.,Y .G., M.d.A.,J.I.R.,S.S.R.,A.W .M., B.A.K.,J.M.J.,M.M.W ., B.S.C.,R.D.,J.E.C.,J.B.,H.G.,S.X.,L.K.W ., D.A.M., X.L.,V .O., S.M.,C.C.G.,Y .-D.I.C., W .-J.L., M.B.S.,D.D.,D.R.,C.A.,C.K.,P .D., A.P .R., T .W .B., G.R.A.,A.V .S., H.M.K., A.D.J., R.M., P .N., S.J., and A.P .R. Competing interests: P .N. has received grants from Amgen, Apple, Boston Scientific, and Novartis; has received consulting income from Apple, BlackstoneLifeSciences,Novartis,ForesiteLabs,andGenentech;andhasspousalemployment atVertex,allunrelatedtothepresentwork.R.K.isaconsultantforRegeneron.J.H.Y .isa consultantforBridgeBiotherapeutics.L.M.R.isaconsultantfortheTOPMedAdministrative CoordinatingCenter(throughW eSta t).S.J.,A.G.B.,andP .N. arecofounders,equityholders,and onthescientificadvisoryboardofT enSixteen Bio.H.M.K.andG.R.A.areemployeesof RegeneronPharmaceuticalsandownsstockandstockoptionsforRegeneronPharmaceuticals. M.H.C. has received grant support from Bayer. All other authors declare that they hav e no competinginterests.Dataandmaterialsavailability:AllTOPMedWGSdatausedinthis analysis are available to researchers for purposes of reproducing or extending the analysis via thedbGaPaccessionnumberslistedintableS1.Alldataneededtoevaluatetheconclusionsin thepaperarepresentinthepaperand/ortheSupplementaryMaterials. Publisher Copyright: Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85158054335&partnerID=8YFLogxK
U2 - 10.1126/SCIADV.ABM4945
DO - 10.1126/SCIADV.ABM4945
M3 - Review article
C2 - 37126548
AN - SCOPUS:85158054335
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 17
M1 - eabm4945
ER -