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. ### Competing Interest Statement S.W., F.H., A.N., I.T., S.V.V.D., H.T., K.S., K.C., D.P.L., O.S.B., R.S.D., S.W., Q.W., S.P., M.A.F., A.R.H., J.M. are current employees and/or stockholders of AstraZeneca. R.C. is the chair of the data monitoring committee of the PROMINENT trial and the deputy chair of a not-for-profit clinical trial company (PROTAS) unrelated to this work. ### Funding Statement The generation of the UKB data was funded by the UKB Exome Sequencing Consortium (UKB-ESC) members: AbbVie, Alnylam Pharmaceuticals, AstraZeneca, Biogen, Bristol-Myers Squibb, Pfizer, Regeneron, and Takeda. The MCPS has received funding from the Mexican Health Ministry, the National Council of Science and Technology for Mexico, the Wellcome Trust (058299/Z/99), Cancer Research UK, British Heart Foundation, and the UK Medical Research Council (MC\_UU\_00017/2). The generation of the MCPS data was funded through an academic partnership among the National Autonomous University of Mexico, the University of Oxford, Regeneron, AstraZeneca, and Abbvie. These funding sources had no role in the design, conduct, or analysis of the study or the decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The MCPS study was approved by the Mexican Ministry of Health, the Mexican National Council for Science and Technology, and the University of Oxford, and the UKB study has approval from the North-West Multi-centre Research Ethics Committee (11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary statistics for GWAS, ExWAS, gene burden association analysis, baseline phenotype association analysis, and mortality analysis are provided in the Supplementary Tables. Individual-level UK Biobank data may be requested via applicable to the UK Biobank. Individual-level MCPS data may be requested via Data and Sample Access Policy available on the Oxford-hosted webpage (http://www.ctsu.ox.ac.uk/research/mcps).