Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis
The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10<sup>-185</sup>). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10<sup>-19</sup>). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.
Authors
- Keren Carss (ORCID: https://orcid.org/0000-0003-4939-156X)
- Pablo Antonio Kuri-Morales (ORCID: https://orcid.org/0000-0002-0704-9507)
- George S. Vassiliou (ORCID: https://orcid.org/0000-0003-4337-8022)
- Fengyuan Hu (ORCID: https://orcid.org/0000-0002-1756-7551)
- Jonathan Emberson (ORCID: https://orcid.org/0000-0001-7792-9422)
- Jason Torres (ORCID: https://orcid.org/0000-0002-7537-7035)
- Abhishek Nag (ORCID: https://orcid.org/0000-0002-4638-2433)
- Katherine R. Smith (ORCID: https://orcid.org/0000-0002-0329-5938)
- Oliver S. Burren (ORCID: https://orcid.org/0000-0002-3388-5760)
- Douglas P. Loesch (ORCID: https://orcid.org/0000-0001-5716-4557)
- Andrew R. Harper (ORCID: https://orcid.org/0000-0001-5327-0328)
- Ryan S. Dhindsa (ORCID: https://orcid.org/0000-0002-8965-0813)
- Jesús Alegre-Díaz (ORCID: https://orcid.org/0000-0001-9390-3871)
- Margarete A. Fabre (ORCID: https://orcid.org/0000-0001-7794-610X)
- Jaime Berúmen (ORCID: https://orcid.org/0000-0001-6707-3317)
- Quanli Wang (ORCID: https://orcid.org/0000-0001-7717-4058)
- Sebastian Wasilewski
- Rory Collins (ORCID: https://orcid.org/0000-0001-8288-8602)
- Haeyam Taiy
- Sean Wen
- Roberto Tapia‐Conyer (ORCID: https://orcid.org/0000-0003-3814-2904)
- Slavé Petrovski (ORCID: https://orcid.org/0000-0002-1527-961X)
- Sri V. V. Deevi (ORCID: https://orcid.org/0000-0002-0405-4335)
- Ioanna Tachmazidou (ORCID: https://orcid.org/0000-0002-1953-2117)
- Jonathan Mitchell (ORCID: https://orcid.org/0000-0003-3792-4058)
Institutions
- AstraZeneca (United Kingdom) (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- University of Oxford (GB)
- AstraZeneca (Singapore) (SG)
- AstraZeneca (United States) (US)
- Universidad Nacional Autónoma de México (MX)
- Tecnológico de Monterrey (MX)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-02-13
- DOI
- https://doi.org/10.1038/s41588-025-02085-6
- Citations
- 9
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 15.93
Funders
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- Biogen
- Alnylam Pharmaceuticals
- Regeneron Pharmaceuticals
- Wellcome Trust
- Cancer Research UK
- British Heart Foundation
- Medical Research Council
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute