Sex-aware Hardy-Weinberg equilibrium testing improves quality control in genome-wide association studies

Researchers led by Elika Garg, Jaffa Romain, Lei Sun, and Andrew D. Paterson, publishing in PLOS Genetics, have revisited the routine Hardy-Weinberg equilibrium (HWE) quality-control step applied to variants in genome-wide association studies (GWAS). Using high-coverage whole-genome sequencing data aligned to the telomere-to-telomere reference assembly (T2Tv2) from the 1000 Genomes Project, the team demonstrates that standard HWE testing — typically applied to a single apparently homogeneous population without stratifying by sex — can miss or misclassify deviations at numerous autosomal single-nucleotide polymorphisms (SNPs).

Two sources of distortion are identified. First, sex-based selection operates at a subset of autosomal loci in actively recruited cohorts, violating the assumptions of standard HWE tests. Second, sequences from the sex chromosomes can align erroneously to autosomal positions, generating apparent HWE departures that are artefactual rather than biologically meaningful. Both phenomena point toward the need for sex-stratified HWE testing as a routine component of GWAS quality control.

The study is directly relevant to researchers designing or re-analysing large association studies, particularly those seeking to ensure that variant filtering does not inadvertently exclude genuine signals or retain technical artefacts. It also has implications for statistical geneticists developing best-practice pipelines, and for educators teaching quality-control methodology in population genetics.