Abstract
Clonal hematopoiesis (CH) – age-related expansion of mutated hematopoietic clones – can differ in frequency and cellular fitness. Descriptive studies have identified a spectrum of events (coding mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs) and loss of sex chromosomes), some of which have been associated with disease risk. Co-existence of different CH events raises key questions as to their origin, selection, and impact. Analyses of sequence and genotype array data in up to 482,378 individuals from UK Biobank revealed shared genetic architecture across different types of CH. We observed co-occurrence of CHIP and mCAs with co-localization at TET2, DNMT3A and JAK2, in which CHIP precedes mCA acquisition. CH types are associated with cellular differentiation, DNA repair, and cell cycle regulation pathways, which can drive clonal expansion and reduce telomere length. Insights into the shared architecture of CH could improve detection and prevention of CH-related outcomes.
Competing Interest Statement
V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma, and Cellarity, all unrelated to the present work. All other authors declare no relevant competing interests.
Footnotes
↵^ These authors jointly supervised this work
