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<p>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], <i>P</i> = 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], <i>P</i> = 7.35 × 10<sup>−19</sup>). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the <i>TCL1B</i> locus with opposing effects on <i>DNMT3A</i>-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at <i>PARP11/CCND2</i>, <i>MEIS1</i> and <i>MYCN</i>. 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.</p>

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Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月13日

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  • Sean Wen,
  • Pablo Kuri-Morales,
  • Fengyuan Hu,
  • Abhishek Nag,
  • Ioanna Tachmazidou,
  • Sri V. V. Deevi,
  • Haeyam Taiy,
  • Katherine R. Smith,
  • Douglas P. Loesch,
  • Oliver S. Burren,
  • Ryan S. Dhindsa,
  • Sebastian Wasilewski,
  • Jesus Alegre-Díaz,
  • Jaime Berumen,
  • Jonathan Emberson,
  • Jason M. Torres,
  • Rory Collins,
  • Keren Carss,
  • Quanli Wang,
  • Slavé Petrovski,
  • Roberto Tapia-Conyer,
  • Margarete A. Fabre,
  • Andrew R. Harper,
  • George S. Vassiliou,
  • Jonathan Mitchell

摘要

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 × 10−185). 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 × 10−19). 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.