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<p>The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (<i>n</i> = 7612) and African/African American (<i>n</i> = 20,250), deriving ancestry-specific allele frequencies. We show that 78.5% and 85.1% of variants in these groups, respectively, exhibit at least a twofold difference in ancestry-specific frequencies. Moreover, 81.49% of variants with LAI information would be assigned a higher gnomAD-wide maximum frequency after incorporating LAI, potentially altering clinical interpretations. This LAI-informed release reveals clinically relevant frequency differences that are masked in aggregate estimates and may support reclassifying some variants from Uncertain Significance to Benign or Likely Benign.</p>

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Improved allele frequencies in gnomAD through local ancestry inference

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月6日

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  • Pragati Kore,
  • Michael W. Wilson,
  • Grace Tiao,
  • Katherine Chao,
  • Philip W. Darnowsky,
  • Nicholas A. Watts,
  • Jessica Honorato Mauer,
  • Samantha M. Baxter,
  • Heidi L. Rehm,
  • Mark J. Daly,
  • Konrad J. Karczewski,
  • Elizabeth G. Atkinson

摘要

The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (n = 7612) and African/African American (n = 20,250), deriving ancestry-specific allele frequencies. We show that 78.5% and 85.1% of variants in these groups, respectively, exhibit at least a twofold difference in ancestry-specific frequencies. Moreover, 81.49% of variants with LAI information would be assigned a higher gnomAD-wide maximum frequency after incorporating LAI, potentially altering clinical interpretations. This LAI-informed release reveals clinically relevant frequency differences that are masked in aggregate estimates and may support reclassifying some variants from Uncertain Significance to Benign or Likely Benign.