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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.

SUBMITTER: Weinstock JS

PROVIDER: S-EPMC10132750 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Weinstock Joshua S JS Laurie Cecelia A CA Broome Jai G JG Taylor Kent D KD Guo Xiuqing X Shuldiner Alan R AR O'Connell Jeffrey R JR Lewis Joshua P JP Boerwinkle Eric E Barnes Kathleen C KC Chami Nathalie N Kenny Eimear E EE Loos Ruth J F RJF Fornage Myriam M Redline Susan S Cade Brian E BE Gilliland Frank D FD Chen Zhanghua Z Gauderman W James WJ Kumar Rajesh R Grammer Leslie L Schleimer Robert P RP Psaty Bruce M BM Bis Joshua C JC Brody Jennifer A JA Silverman Edwin K EK Yun Jeong H JH Qiao Dandi D Weiss Scott T ST Lasky-Su Jessica J DeMeo Dawn L DL Palmer Nicholette D ND Freedman Barry I BI Bowden Donald W DW Cho Michael H MH Vasan Ramachandran S RS Johnson Andrew D AD Yanek Lisa R LR Becker Lewis C LC Kardia Sharon S He Jiang J Kaplan Robert R Heckbert Susan R SR Smith Nicholas L NL Wiggins Kerri L KL Arnett Donna K DK Irvin Marguerite R MR Tiwari Hemant H Correa Adolfo A Raffield Laura M LM Gao Yan Y de Andrade Mariza M Rotter Jerome I JI Rich Stephen S SS Manichaikul Ani W AW Konkle Barbara A BA Johnsen Jill M JM Wheeler Marsha M MM Custer Brian S BS Duggirala Ravindranath R Curran Joanne E JE Blangero John J Gui Hongsheng H Xiao Shujie S Williams L Keoki LK Meyers Deborah A DA Li Xingnan X Ortega Victor V McGarvey Stephen S Gu C Charles CC Chen Yii-Der Ida YI Lee Wen-Jane WJ Shoemaker M Benjamin MB Darbar Dawood D Roden Dan D Albert Christine C Kooperberg Charles C Desai Pinkal P Blackwell Thomas W TW Abecasis Goncalo R GR Smith Albert V AV Kang Hyun M HM Mathias Rasika R Natarajan Pradeep P Jaiswal Siddhartha S Reiner Alexander P AP Bick Alexander G AG

Science advances 20230426 17

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 wit ...[more]

PMID: 37126548

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Project description:Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Dataset Information

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

Publications

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

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