Shared and distinct genetic etiologies for different types of clonal hematopoiesis

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). Co-existence of different CH events raises key questions as to their origin, selection, and impact. Here, we report analyses of sequence and genotype array data in up to 482,378 individuals from UK Biobank, demonstrating shared genetic architecture across different types of CH. These data highlighted evidence for a cellular evolutionary trade-off between different forms of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. Furthermore, we observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Individuals carrying these overlapping somatic mutations had a large increase in risk of future hematological malignancy (HR=17.31, 95% CI=9.80-30.58, P=8.94x10-23), which is significantly elevated compared to individuals with non-overlapping CHIP and autosomal mCAs (Pheterogeneity=8.83x10-3). Finally, we leverage the shared genetic architecture of these CH traits to identify 15 novel loci associated with blood cancer risk.