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1811071263325552640
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MIT
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© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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2024-09-23T08:48:24Z
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Article
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mit-1721.1/133476
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Massachusetts Institute of Technology
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| language |
English
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2024-09-23T08:48:24Z
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2021
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Springer Science and Business Media LLC
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dspace
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| spelling |
mit-1721.1/1334762022-04-01T17:20:50Z Inherited causes of clonal haematopoiesis in 97,691 whole genomes © 2020, The Author(s), under exclusive licence to Springer Nature Limited. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues. 2021-10-27T19:53:03Z 2021-10-27T19:53:03Z 2020 2021-07-20T17:39:20Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133476 en 10.1038/s41586-020-2819-2 Nature Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC
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| spellingShingle |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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| title |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
|
| title_full |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
|
| title_fullStr |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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| title_full_unstemmed |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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| title_short |
Inherited causes of clonal haematopoiesis in 97,691 whole genomes
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| title_sort |
inherited causes of clonal haematopoiesis in 97 691 whole genomes
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| url |
https://hdl.handle.net/1721.1/133476
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