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bioRxiv · 10.1101/2024.10.30.620961

Improved Allele Frequencies in gnomAD through Local Ancestry Inference

Atkinson, E. G.·Kore, P.·Wilson, M.·Tiao, G.·Chao, K. R.·Darnowsky, P.·Watts, N.·Honorato-Mauer, J.·Baxter, S. M.·Genome Aggregation Database Consortium,·Rehm, H.·Daly, M.·Karczewski, K. J.
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Abstract

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.

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Atkinson, E. G., Kore, P., Wilson, M., Tiao, G., Chao, K. R., Darnowsky, P., Watts, N., Honorato-Mauer, J., Baxter, S. M., Genome Aggregation Database Consortium,, Rehm, H., Daly, M., Karczewski, K. J.. 2024-10-31. Improved Allele Frequencies in gnomAD through Local Ancestry Inference. https://doi.org/10.1101/2024.10.30.620961

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