Shared and distinct genetic etiologies for different types of clonal hematopoiesis
Abstract Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH r...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41315-5 |
| _version_ | 1797558383050489856 |
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| author | Derek W. Brown Liam D. Cato Yajie Zhao Satish K. Nandakumar Erik L. Bao Eugene J. Gardner Aubrey K. Hubbard Alexander DePaulis Thomas Rehling Lei Song Kai Yu Stephen J. Chanock John R. B. Perry Vijay G. Sankaran Mitchell J. Machiela |
| author_facet | Derek W. Brown Liam D. Cato Yajie Zhao Satish K. Nandakumar Erik L. Bao Eugene J. Gardner Aubrey K. Hubbard Alexander DePaulis Thomas Rehling Lei Song Kai Yu Stephen J. Chanock John R. B. Perry Vijay G. Sankaran Mitchell J. Machiela |
| author_sort | Derek W. Brown |
| collection | DOAJ |
| description | Abstract Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk. |
| first_indexed | 2024-03-10T17:29:45Z |
| format | Article |
| id | doaj.art-77165817170e4e85a1c42338d2c3eefb |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:29:45Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-77165817170e4e85a1c42338d2c3eefb2023-11-20T10:03:32ZengNature PortfolioNature Communications2041-17232023-09-0114111310.1038/s41467-023-41315-5Shared and distinct genetic etiologies for different types of clonal hematopoiesisDerek W. Brown0Liam D. Cato1Yajie Zhao2Satish K. Nandakumar3Erik L. Bao4Eugene J. Gardner5Aubrey K. Hubbard6Alexander DePaulis7Thomas Rehling8Lei Song9Kai Yu10Stephen J. Chanock11John R. B. Perry12Vijay G. Sankaran13Mitchell J. Machiela14Division of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolMRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDivision of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDivision of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolMRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteDivision of Cancer Epidemiology and Genetics, National Cancer InstituteMRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge School of Clinical MedicineDivision of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDivision of Cancer Epidemiology and Genetics, National Cancer InstituteAbstract Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.https://doi.org/10.1038/s41467-023-41315-5 |
| spellingShingle | Derek W. Brown Liam D. Cato Yajie Zhao Satish K. Nandakumar Erik L. Bao Eugene J. Gardner Aubrey K. Hubbard Alexander DePaulis Thomas Rehling Lei Song Kai Yu Stephen J. Chanock John R. B. Perry Vijay G. Sankaran Mitchell J. Machiela Shared and distinct genetic etiologies for different types of clonal hematopoiesis Nature Communications |
| title | Shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| title_full | Shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| title_fullStr | Shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| title_full_unstemmed | Shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| title_short | Shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| title_sort | shared and distinct genetic etiologies for different types of clonal hematopoiesis |
| url | https://doi.org/10.1038/s41467-023-41315-5 |
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