Fig. 4: GWAS and ExWAS of all CH and gene-specific CH in the MCPS.

a, Manhattan plot representing the common germline variants with MAF ≥ 1% included for CH GWAS. Unadjusted two-sided P values on the y axis were derived from Firth logistic regression implemented using REGENIE software. One new association at the TCL1A-TCL1B locus from MCPS (red) was identified as genome-wide significant (P < 5 × 10⁻⁸), with the nearest gene of the leading genetic polymorphism annotated. One previously reported association from the European population at the TERT locus is indicated in blue. b, rs187319135 identified as genome-wide significant from overall CH, and TET2-CH and SF3B1+SRSF2-CH. Overall and gene-specific CH risk estimates conferred by the minor allele (T) are shown here for 136,401 MCPS participants. ORs and unadjusted two-sided P values were derived from Firth logistic regression implemented using REGENIE software. Risk estimates are shown when both CH or gene-specific CH cases and controls have minor allele count (MAC) ≥ 1. Risk estimates for UKB were not included owing to the absence of risk allele (MAC = 0) in CH individuals. Measures of center represent the ORs; error bars, lower and upper bounds of the 95% confidence intervals of the ORs. Full circles represent significant associations (P < 0.05); hollow circles represent non-significant associations (P ≥ 0.05). c, Manhattan plot representing the rare (MAF < 1%) and common germline variants included for TET2-CH ExWAS. P values on the y axis were derived from Firth logistic regression implemented using REGENIE software. Rare TCL1B promoter variant rs774615666 (red) was identified as exome-wide significant (P < 1 × 10⁻⁸). Common TERT variant indicated in blue. d, rs774615666 identified as exome-wide significant from TET2-CH and SF3B1+SRSF2-CH. Overall and gene-specific CH risk estimates conferred by the minor allele (T) are shown here for 136,149 MCPS and 416,118 UKB participants. Risk estimates are shown when both CH or gene-specific CH cases and controls have MAC ≥ 1. ORs and unadjusted two-sided P values were derived from Firth logistic regression implemented using REGENIE software for MCPS and Fisher’s exact test for UKB. Measures of center represent the ORs; error bars, lower and upper bound of the 95% confidence interval of the ORs. Full circles represent significant associations (P < 0.05); hollow circles represent non-significant associations (P ≥ 0.05).