Comparative analysis of 136,401 Admixed Americans and 419,228 Europeans reveals ancestry-specific genetic determinants of clonal haematopoiesis

The development of clonal haematopoiesis (CH), the age-related expansion of mutated haematopoietic stem cell (HSC) clones, is influenced by genetic and non-genetic factors. To date, large-scale studies of CH have focused on individuals of European descent, such that the impact of genetic ancestry on CH development remains incompletely understood. Here, we investigate this by studying CH in 136,401 admixed participants from the Mexico City Prospective Study (MCPS) and 419,228 European participants from the UK Biobank (UKB). We observe that CH was significantly less common in MCPS compared to UKB (adjusted odds ratio (OR) = 0.56 [95% Cl = 0.55-0.59], P = 1.60 x 10-206), a difference that persisted when comparing MCPS participants whose genomes were >50% ancestrally Indigenous American to those whose genomes were >50% ancestrally European (adjusted OR = 0.76 [0.70-0.83], P = 1.78 x 10-10). Genome- and exome-wide association analyses in MCPS participants identified two novel loci associated with CH (CSGALNACT1 and DIAPH3), and ancestry-specific variants in the TCL1B locus with opposing effect on DNMT3A-versus non-DNMT3A-CH. Meta-analysis of the MCPS and UKB cohorts identified another five novel loci associated with overall or gene specific CH, including polymorphisms at PAPR11/CCND2, MEIS1 and UBE2G1/SPNS3. Our CH study, the largest in a non-European population to date, demonstrates the profound impact of ancestry on CH development and reveals the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis and advance health equity amongst different human populations.