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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.

2025-11-07 genetics
10.1101/2025.11.06.686913 bioRxiv
Show 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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