Genomic and phenomic landscape of clonal hematopoiesis in over a million ancestrally diverse participants

Uddin, M. M., Yu, Z., Weinstock, J. S., Niroula, A., Vlasschaert, C., Koyama, S., Nakao, T., Urbut, S. M., Zekavat, S. M., Paruchuri, K., Truong, B., Silver, A. J., Mack, T. M., Wong, M. Y., Haidermota, S. M., Bhattacharya, R., Doroodgar Jorshery, S., Raddatz, M. A., Honigberg, M. C., Hornsby, W. E., Zhang, M. J., Dron, J., Heimlich, J. B., Sankaran, V. G., Griffin, G. K., Gibson, C. J., Adegboye, H. A., Cho, K., Sun, Y. V., Pyarajan, S., Wilson, P. W., Veterans Affairs Million Veteran Program, , Genovese, G., Xu, Y., Savona, M. R., Chen, Y.-D. I., Sheu, W. H.-H., Hung, Y.-J., Raffield, L. M.

Broad Institute · medrxiv

Paper

Abstract

With aging, somatic mutations in hematopoietic stem and progenitor cells (HSPC) can give rise to clonal hematopoiesis of indeterminate potential (CHIP), a premalignant state associated with diverse age-related diseases. Here we report the largest multi-ancestry genome-wide analysis of CHIP to date (N = 1,018,305), including individuals of African (N = 85,978), Admixed American (N = 191,371), East Asian (N = 13,532), European (N = 694,015), and South Asian (N = 13,193) ancestry. Multi-ancestry meta-analyses identified 72 genome-wide significant loci, including 44 novel associations implicating genes such as AFF1, ATF7IP, ATP8B4, BCL2, CEBPA, CYRIA, DNM2, ELF1, NKX2-3, PIK3CB, PRDM16, RPN1, TERC, and TRIM4. Notably, variants at MECOM and PHF20L1 showed opposite allelic effects between DNMT3A- and non-DNMT3A-driven CHIP, highlighting driver-specific germline influences. Implicated loci converge on pathways regulating telomere maintenance, cell-cycle control, hematopoietic transcription, DNA damage response and immune signaling. These findings support a model in which germline variation both expands the HSPC pool and biases clonal selection in a driver-dependent manner, providing a mechanistic basis for inter-individual heterogeneity in CHIP. Phenome-wide association analyses further linked CHIP to hematologic, neoplastic, and circulatory traits, with enrichment across hematopoietic and non-hematopoietic cell types. Together, this work expands the genomic and phenomic landscape of CHIP and reveals germline-somatic interactions that shape clonal evolution during aging.

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Research summary

The paper identifies genetic loci associated with clonal hematopoiesis that may influence aging and age-related diseases. The study provides insights into the genetic underpinnings of clonal evolution in hematopoietic cells, which is relevant to understanding mechanisms of aging and potential interventions.

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