Assessing Hardy-Weinberg equilibrium in T2T-aligned 1000 genomes project

Quality control of markers in genome-wide association studies often includes testing for Hardy-Weinberg equilibrium (HWE). However, this is usually implemented in a homogeneous population without stratifying by sex. Previous work indicates sex-based selection at numerous autosomal loci in cohorts with active recruitment. Sex chromosome sequences can also interfere with autosomal SNPs. These motivate a re-examination of HWE in sex-aware analyses. Using the telomere-to-telomere (T2Tv2)-aligned high-coverage whole genome sequencing data from 2,490 individuals in the 1000 Genomes Project, we examined genome-wide sex-specific deviations from HWE across five super-populations. Our analyses were restricted to bi-allelic SNPs with non-missing genotypes and minor allele frequency (MAF) ≥5% in both sexes of the five super-populations. We applied an allele-based framework to quantify both the magnitude and direction of Hardy–Weinberg disequilibrium (HWD), followed by a second-order omnibus meta-analysis that combined HWD results across populations and sexes. At a genome-wide significance threshold of p