Kore Pragati, Wilson Michael W, Tiao Grace, Chao Katherine, Darnowsky Philip W, Watts Nick, Mauer Jessica Honorato, Baxter Samantha M, Rehm Heidi L, Daly Mark J, Karczewski Konrad J, Atkinson Elizabeth G
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
bioRxiv. 2025 Jun 9:2024.10.30.620961. doi: 10.1101/2024.10.30.620961.
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 = 7,612) 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.
基因组聚合数据库（gnomAD）是等位基因频率数据的基础资源，广泛应用于基因组研究和临床解读。然而，传统估计依赖个体水平的遗传血统分组，这可能会掩盖近期混合人群中的变异。为了提高分辨率，我们对两个混合群体中的2700多万个变异应用了局部血统推断（LAI）：美国混合群体（n = 7612）和非洲/非裔美国人群体（n = 20250），得出特定血统的等位基因频率。我们发现，这些群体中分别有78.5%和85.1%的变异在特定血统频率上表现出至少两倍的差异。此外，在纳入LAI后，81.49%具有LAI信息的变异将被赋予更高的gnomAD全范围最大频率，这可能会改变临床解读。这种基于LAI的发布揭示了在总体估计中被掩盖的临床相关频率差异，并可能支持将一些变异从不明确意义重新分类为良性或可能良性。
