Population-Based Identification of Clonal Hematopoiesis Using Peripheral Blood Whole-Genome Sequencing in Japan

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition whose population-level characteristics and clinical concordance in Japan remain incompletely defined. We analyzed whole-genome sequencing data from 49,982 participants in the Tohoku Medical Megabank (TMM) cohort to characterize the prevalence, mutational spectrum, age dependency, and clinical relevance of CHIP. CHIP mutations were detected in 1234 individuals (2.5%), comprising 1413 variants across 1015 loci. DNMT3A and TET2 were the most frequently mutated genes, whereas ASXL1 and PPM1D mutations were less prevalent than reported in Western cohorts. Four recurrent CHIP candidate loci (ZNF318, SMC3, CBL, and GNAS) were identified, most of which were predicted to be oncogenic. Comparison with TOPMed and UK Biobank datasets demonstrated overall concordance in variant prevalence, with differences observed for selected driver mutations. dN/dS analysis indicated positive selection in the majority of CHIP-associated genes. Concordance with clonal hematopoiesis (CH) mutations detected in cancer patients was evaluated using data from the MONSTAR-SCREEN-2 study with paired leukocyte sequencing. When focusing on genes in which CHIP mutations have been reported, 66% were confirmed as CH, yielding a positive predictive value of 66% and a negative predictive value of 76%. CHIP prevalence increased significantly with age, exceeding 5% in individuals aged ≥ 70 years, with an estimated 3.4% increase per additional year of age. Higher variant allele frequency mutations showed a slightly stronger age association. These findings define the landscape of CHIP in the Japanese population and clarify its relationship to CH detected by cancer-focused liquid biopsy assays.