Repository logo
 

Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Gu, Muxin 
Jiang, Tao 
Mitchell, Jonathan 

Abstract

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

Description

Funder: British Heart Foundation

Keywords

Cell Transformation, Neoplastic, Clonal Hematopoiesis, Genetic Predisposition to Disease, Genome-Wide Association Study, Hematopoiesis, Humans, Mutation, Risk Factors

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

54

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Cancer Research UK (23015)
Leukemia & Lymphoma Society (RTF6006-19)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
British Heart Foundation (None)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (MC_UU_00002/7)