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

Summary

This large-scale genetic analysis of 200,453 UK Biobank participants substantially expanded the known landscape of inherited genetic predisposition to clonal hematopoiesis, identifying 10 novel germline loci beyond previously reported associations. The findings implicate DNA damage repair, haematopoietic stem cell biology, and myeloid oncogenesis pathways, with notably subtype-specific effects at TCL1A and CD164 for the two most common CH driver mutations. Mendelian randomisation evidence indicates that smoking and telomere length are causal risk factors for CH development, and that genetic predisposition to CH causally influences risks of haematological and non-haematological malignancies and cardiovascular disease.

UK applicability

Since the study was conducted exclusively in UK Biobank participants of European ancestry, the findings are directly applicable to UK clinical and population health contexts. The identification of modifiable risk factors (smoking) alongside genetic predisposition may inform UK public health messaging and screening strategies, though the clinical utility of genetic profiling for CH risk prediction in routine UK practice remains to be established.

Key measures

Germline genetic variants associated with clonal hematopoiesis; CH-subtype-specific associations; causal risk factors (smoking, leukocyte telomere length); disease outcomes (myeloproliferative neoplasia, malignancies, atrial fibrillation, epigenetic ageing)

Outcomes reported

The study identified 14 germline genetic loci associated with clonal hematopoiesis (CH) in European-ancestry populations, implicating genes involved in DNA damage repair, stem cell migration, and myeloid oncogenesis. Mendelian randomisation analyses demonstrated causal relationships between smoking, leukocyte telomere length, and CH; and between genetic CH predisposition and risks of myeloproliferative neoplasia, non-haematological malignancies, atrial fibrillation, and blood epigenetic ageing.

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