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bioRxiv · 10.1101/2025.11.06.686913

Genotype-level quality control substantially reduces error rates in population-scale whole-genome sequencing

Chundru, V. K.·Wright, H. I. W.·Frayling, T. M.·Wood, A. R.·Weedon, M. N.·Wright, C. F.·Beaumont, R. N.·Hawkes, G.
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Abstract

Population-scale whole-genome sequencing data will contain many individual-level genotype errors, even after allele-level quality control (QC). We establish the need for genotype-level QC using UK Biobank (N=490,726) and All of Us v8 (N=414,830), where we remove up to 100 million ([~]9%) additional low-quality variants. We demonstrate reduced false positive rate in downstream genetic association studies, highlight the power of parent-offspring trios for QC, and illustrate the need for sex-specific X-chromosome filtering. We provide a QCed All of Us v8 dataset in plink-pgen format, and an efficient pipeline for QC and conversion from VCF to plink-pgen for UK Biobank.

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Chundru, V. K., Wright, H. I. W., Frayling, T. M., Wood, A. R., Weedon, M. N., Wright, C. F., Beaumont, R. N., Hawkes, G.. 2025-11-07. Genotype-level quality control substantially reduces error rates in population-scale whole-genome sequencing. https://doi.org/10.1101/2025.11.06.686913

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