Departure from Hardy Weinberg Equilibrium and Genotyping Error

Area of Science:

• Population Genetics
• Genomic Data Analysis

Background:

• Hardy-Weinberg Equilibrium (HWE) is a cornerstone principle in population genetics.
• Deviations from HWE can arise from various factors including selection, inbreeding, population substructure, copy number variation, or genotyping errors.

Purpose of the Study:

• To investigate specific characteristics differentiating Hardy-Weinberg Equilibrium departure (d-HWE) caused by genotyping errors versus natural genetic variations.
• To differentiate between d-HWE with loss of heterozygosity (LoH d-HWE) and d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE).

Main Methods:

• Utilized genotype data from the Exome Aggregation Consortium (ExAC) database, excluding variants with low genotyping success rates (<80%) or minor allele frequency (MAF) <1%.
• Analyzed HWE-departure significance at p < 10E-05, classifying deviations into LoH d-HWE and GoH d-HWE.
• Evaluated associations between HWE-departure and factors including missing genotypes, variant type (SNP vs. indel), MAF, MAF standard deviation across populations (MAF-SD), and copy number variation.

Main Results:

• Observed HWE-departure in 134 out of 3,204 variants (41 LoH d-HWE, 93 GoH d-HWE).
• LoH d-HWE was associated with deletion polymorphisms and higher MAF-SD, while GoH d-HWE correlated with low genotyping rates, insertion/deletion variants, and high MAF.
• In a high-quality subset (>98% genotyping rate), LoH d-HWE persisted, but GoH d-HWE was not detected, supporting its link to genotyping quality.

Conclusions:

• Gain of heterozygosity departures from HWE are indicative of potential genotyping errors.
• Loss of heterozygosity departures from HWE suggest underlying natural genetic phenomena like population substructure or common deletion polymorphisms.
• Distinguishing between these two types of HWE departure aids in accurate interpretation of genetic variation data.