Fig. 5: Genetic determinants of incident CHIP.

Association of prevalent clonal hematopoiesis of indeterminate potential (CHIP) with incident CHIP: a, b polygenic risk score (PRS) and c germline variants analysis. a Distribution of PRS in ARIC AA and EA participants. b Ancestry-stratified PRS was calculated using 21 independent variants (P < 5E−8; Supplementary Data 5) from Kessler et al.¹⁵. Logistic regression was performed, adjusting for age, sex, smoking status, top five principal components of ancestry, and batch effect. Data are presented as odds ratio (OR) with a 95% confidence interval (CI) and uncorrected P-value from a two-sided Z-test. The results show a strong association between prevalent CHIP PRS and incident CHIP. c Forest plot of odds ratio with 95% CI from inverse variant-weighted fixed-effect meta-analyses of single-variant associations for incident overall CHIP, incident DNMT3A CHIP, and incident TET2 CHIP in ARIC AA (n = 637) and ARIC EA (n = 2378) participants. Uncorrected P-values are from two-sided Z-tests. Single-variant association adjusted for age, age², sex, top ten principal components of ancestry, and batch effect, followed by multi-ancestry meta-analysis, was conducted to investigate the association of genome-wide significant (P < 5E−8) prevalent CHIP-associated variants¹⁵ and incident CHIP at a significant level of P < 0.05. This figure presents the lead variant(s) from each locus, and the full list is available in Supplementary Data 6–8. Several germline variants previously associated with prevalent CHIP were found to be associated with incident CHIP, indicating a shared genetic basis between prevalent and incident CHIP. ARIC AA the Atherosclerosis Risk in Communities Study African American; ARIC EA European American; EA effect allele; EAF effect allele frequency; SNV single nucleotide variant.