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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1126/SCIADV.ABM4945

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

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journal › Review article › peer-review

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	https://doi.org/10.1126/SCIADV.ABM4945
State	Published - Apr 2023

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10.1126/SCIADV.ABM4945

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@article{c89895f94a5c4c9d9a3048bbcc4b2c8b,

title = "The genetic determinants of recurrent somatic mutations in 43,693 blood genomes",

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.",

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

note = "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 {\textcopyright} 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).",

year = "2023",

month = apr,

doi = "10.1126/SCIADV.ABM4945",

language = "English",

volume = "9",

journal = "Science Advances",

issn = "2375-2548",

number = "17",

}

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 -

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

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