Large-scale genetic studies have enhanced the understanding of germline causes of clonal hematopoiesis. Using exome-sequencing data from 628,388 individuals in the UK Biobank and the Geisinger MyCode Community Health Initiative, Kessler et al. identified 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using common-variant genome-wide association analyses, they identified 24 loci that contained variants associated with CHIP, 21 of which were newly identified associations. In addition, rare variant and gene burden exome-wide association analyses identified new rare variant associations with clonal hematopoiesis and telomere length. Cross-sectional association analyses of 5,041 traits in the UK Biobank revealed relationships between CHIP and a wide range of traits such as COVID-19 infection, cardiovascular disease and hematological malignancy. Mendelian randomization analyses showed an increased risk of developing solid cancers such as lung cancer among CHIP carriers. Overall, the study provides a valuable compendium of common and rare variant associations with CHIP and other clonal hematopoiesis phenotypes, which may facilitate further research on disease mechanisms and potential therapeutic agents.

Original reference: Nature 612, 301–309 (2022)