Germline genomic and phenomic landscape of clonal hematopoiesis in 323,112 individuals

Abstract With age, acquired mutations can cause clonal expansion of hematopoietic stem cells (HSC). This clonal hematopoiesis of indeterminate potential (CHIP) leads to an increased predisposition to numerous diseases including blood cancer and cardiovascular disease. Here, we report multi- ancestry genome-wide association meta-analyses of CHIP among 323,112 individuals (19.5% non-European; 5.3% have CHIP). We identify 15 genome-wide significant regions and nominate additional loci through multi-trait analyses, and highlight variants in genes involved in self- renewal and proliferation of HSC, telomere maintenance, and DNA damage response pathways. We then use Mendelian randomization to establish a causal relationship between CHIP and coronary artery disease. Next, we systematically profile consequences of CHIP across the phenome, which revealed strong associations with hematopoietic, neoplastic, and circulatory conditions corroborated by polygenic enrichment of CHIP loci in immune cells and cardiomyocytes. These findings expand the genomic and phenomic landscape of CHIP.