Somatic passenger mutation burden is associated with hematologic malignancy and mortality in large genomic cohortsGenetic markers linked to blood cancer and higher mortality risk

Clonal hematopoiesis (CH), an aging-related expansion of hematopoietic stem cell (HSC) clones, is associated with hematologic malignancy, cardiovascular disease, and mortality. Most clonal expansions, however, occur in the absence of known driver mutations. Passenger mutations reveal positive selection in HSCs and provide a quantitative, driver-agnostic phenotype that increases statistical power over dichotomized driver-based definitions. We used somatic passenger mutation burden as a quantitative phenotype to map the genetic, phenotypic, and geographic correlates of CH across 791,067 blood whole-genome sequences from UK Biobank (UKB) and the All of Us Research Program (AoU). Multi-ancestry meta-analysis of genome-wide association studies in both cohorts identified 81 loci associated with passenger mutation burden, including 42 novel loci. Rare-variant analyses additionally implicated MBD2, PRKACB, PUF60, and related epigenetic and transcriptional regulators of clonal fitness. Together, common and rare germline associations converged with canonical CH drivers on shared pathways regulating DNA methylation, chromatin, RNA splicing, and genome maintenance. Sex and ancestry stratified analyses revealed the shared and population-specific determinants of CH, including loci undetected in the pooled analysis. Associated variants were concentrated in regulatory elements active in hematopoietic stem and progenitor cells, linking germline associations to relevant cell states and lineages. Phenome-wide analyses revealed distinct consequences of inherited CH liability and observed passenger burden, with passenger burden strongly associated with incident hematologic malignancy and mortality and germline risk showing additional nonhematologic associations. Finally, spatial modelling of passenger mutation burden across U.S. regions revealed persistent geographic heterogeneity incompletely explained by income, air quality, or chemotherapy prevalence, pointing to additional unmeasured environmental exposures. Overall, through parallel analyses of two population-scale biobanks, we characterize the multi-ancestry genetic architecture of CH and reveal convergence of germline and somatic variation on shared pathways governing clonal expansion in aging blood.