Mutational Architecture of Clonal Hematopoiesis of Indeterminate Potential in 29,596 Chinese Individuals

Clonal hematopoiesis of indeterminate potential (CHIP) an age-related expansion of hematopoietic clones with somatic mutations, associated with hematologic malignancies and cardiovascular disease, but remains poorly characterized beyond European-ancestry populations. Here, we analyzed high-depth sequencing data from 29,596 individuals, including a discovery cohort of 13,445 and an independent replication cohort of 16,151, representing the largest systematic investigation of CHIP across diverse Chinese ethnic groups to date. We estimated an overall CHIP prevalence of ~4.5%, slightly lower than reported in Europeans (~5.7%). While DNMT3A and TET2 were the most frequently mutated genes, the relative contributions of other genes, including KMT2D and ASXL1, varied across populations. Interestingly, population differentiation at AICDA were consistent with a potential contribution to the higher frequency of KMT2D-associated CHIP in Chinese populations. Our findings suggest that current CHIP whitelists, being largely derived from European samples, should be applied cautiously and refined through broader population representation and ancestry-informed validation. Together, these results delineate the population-scale mutational landscape of CHIP in Chinese cohorts and provide a reference framework for studies of somatic hematopoiesis in East Asian populations.