Assessing Hardy-Weinberg Equilibrium in T2T-aligned 1000 Genomes Project

Abstract 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. We examined genome-wide sex-specific HWE deviations across populations in the telomere-to-telomere (T2Tv2)-aligned high-coverage whole genome sequence of the 1000 Genomes Project data of 2,490 individuals. Our analysis was restricted to bi-allelic SNPs with non-missing genotypes and MAF>=5% in both sexes of the five super-populations. We employed a robust allele-based approach for HWE testing, which enabled the quantification of directional deviations from HWE. A second-order omnibus meta-analysis combining results from the five super-populations and both sexes revealed that 0.9% autosomal SNPs exhibited a significant deviation from HWE at p