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A comparison of tests for Hardy-Weinberg Equilibrium in national genetic household surveys.

ABSTRACT: BACKGROUND: This study is motivated by National Household Surveys that collect genetic data, in which complex samples (e.g. stratified multistage cluster sample), partially from the same family, are selected. In addition to the differential selection probabilities of selecting households and persons within the sampled households, there are two levels of correlations of the collected genetic data in National Genetic Household Surveys (NGHS). The first level of correlation is induced by the hierarchical geographic clustered sampling of households and the second level of correlation is induced by biological inheritances from individuals sampled in the same household. RESULTS: To test for Hardy-Weinberg Equilibrium (HWE) in NGHS, two test statistics, the CCS method [1] and the QS method [2], appear to be the only existing methods that take account of both correlations. In this paper, I evaluate both methods in terms of the test size and power under a variety of complex designs with different weighting schemes and varying magnitudes of the two correlation effects. Both methods are applied to a real data example from the Hispanic Health and Nutrition Examination Survey with simulated genotype data. CONCLUSIONS: The QS method maintains the nominal size well and consistently achieves higher power than the CCS method in testing HWE under a variety of sample designs, and therefore is recommended for testing HWE of genetic survey data with complex designs.

SUBMITTER: Li Y

PROVIDER: S-EPMC3606615 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A comparison of tests for Hardy-Weinberg Equilibrium in national genetic household surveys.

Li Yan Y

BMC genetics 20130301

<h4>Background</h4>This study is motivated by National Household Surveys that collect genetic data, in which complex samples (e.g. stratified multistage cluster sample), partially from the same family, are selected. In addition to the differential selection probabilities of selecting households and persons within the sampled households, there are two levels of correlations of the collected genetic data in National Genetic Household Surveys (NGHS). The first level of correlation is induced by the ...[more]

PMID: 23448225

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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 comparison of tests for Hardy-Weinberg Equilibrium in national genetic household surveys.

Publications

A comparison of tests for Hardy-Weinberg Equilibrium in national genetic household surveys.

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