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A heterozygote-homozygote test of Hardy-Weinberg equilibrium.

ABSTRACT: The century-old Hardy-Weinberg law remains fundamental to population genetics. Typically Hardy-Weinberg equilibrium is tested in unrelated individuals using a chi(2) goodness-of-fit test that compares expected and observed numbers of heterozygotes and homozygotes. In this report, we propose a likelihood ratio test for Hardy-Weinberg equilibrium that accommodates a mixture of pedigree and random sample data. The underlying statistical model depends on a parameter gamma determining the ratio of heterozygous genotypes to homozygous genotypes among pedigree founders. As our heterozygous-homozygous test accommodates markers with dominant and recessive alleles, it can handle the phase ambiguities encountered in combining several linked single nucleotide polymorphisms into a single supermarker. No prior haplotyping is necessary. Our experience on real and simulated data suggests that the heterozygous-homozygous test has good type-one error and power.

SUBMITTER: Zhou JJ

PROVIDER: S-EPMC2986695 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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A heterozygote-homozygote test of Hardy-Weinberg equilibrium.

Zhou Jin J JJ Lange Kenneth K Papp Jeanette C JC Sinsheimer Janet S JS

European journal of human genetics : EJHG 20090415 11

The century-old Hardy-Weinberg law remains fundamental to population genetics. Typically Hardy-Weinberg equilibrium is tested in unrelated individuals using a chi(2) goodness-of-fit test that compares expected and observed numbers of heterozygotes and homozygotes. In this report, we propose a likelihood ratio test for Hardy-Weinberg equilibrium that accommodates a mixture of pedigree and random sample data. The underlying statistical model depends on a parameter gamma determining the ratio of he ...[more]

PMID: 19367317

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Project description:Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at p < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure. Results: The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (p < 0.001) and in variants with higher MAF-SD (p = 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at p < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. Conclusions: We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.

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A heterozygote-homozygote test of Hardy-Weinberg equilibrium.

Publications

A heterozygote-homozygote test of Hardy-Weinberg equilibrium.

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