Approximate and exact tests of Hardy-Weinberg equilibrium using uncertain genotypes.

Testing for Hardy-Weinberg equilibrium (HWE) is commonly used as a quality control filter in genome-wide scans for markers with experimentally determined genotypes. In contrast, for markers with imputed genotypes, there are post-imputation metrics of quality that can be used as screens but there are no formal tests of deviation from HWE. Similarly, there are no formal tests of deviation from HWE for probabilistic genotypes that are generated by sequencing projects. Here, I describe generalizations of the approximate χ(2) and exact tests of HWE for use with uncertain genotypes. The tests fully account for the probabilities of all possible genotypes at a marker for each individual. By computer simulation, the approximate and exact tests are shown to maintain valid control of the type I error rate. Calculations of the loss of power as the uncertainty in genotypes increases are illustrated. The tests are compatible with chip-based genotypes for single-nucleotide polymorphisms and copy number polymorphisms, imputed genotypes, and probabilistic assignments of genotype from variable-coverage sequence data.