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A composite likelihood approach in testing for Hardy Weinberg Equilibrium using family-based genetic survey data.

ABSTRACT: In population-based household surveys, for example, the National Health and Nutrition Examination Survey, households are often sampled by stratified multistage cluster sampling, and multiple individuals related by blood are often sampled within households. Therefore, genetic data collected from these population-based household surveys, called National Genetic Household Surveys, can be correlated because of two levels of correlation. One level of correlation is caused by the multistage geographical cluster sampling and the other is caused by biological inheritance among participants within the same sampled family. In this paper, we develop an efficient Hardy Weinberg Equilibrium (HWE) test utilizing pairwise composite likelihood methods that incorporate the sample weighting effect induced by the differential selection probabilities in complex sample designs, as well as the two-level clustering (correlation) effects described above. Monte Carlo simulation studies show that the proposed HWE test maintains the nominal levels, and is more powerful than existing methods (Li et al. 2011) under various (non)informative sample designs that depend on genotypes (explicitly or implicitly), family relationships or both, especially when within-household sampling depends on the genotypes. The developed tests are further evaluated using simulated genetic data based on the Hispanic Health and Nutrition Survey. Copyright © 2016 John Wiley & Sons, Ltd.

SUBMITTER: Wang L

PROVIDER: S-EPMC7210008 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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A composite likelihood approach in testing for Hardy Weinberg Equilibrium using family-based genetic survey data.

Wang Lingxiao L Graubard Barry I BI Li Yan Y

Statistics in medicine 20160801 27

In population-based household surveys, for example, the National Health and Nutrition Examination Survey, households are often sampled by stratified multistage cluster sampling, and multiple individuals related by blood are often sampled within households. Therefore, genetic data collected from these population-based household surveys, called National Genetic Household Surveys, can be correlated because of two levels of correlation. One level of correlation is caused by the multistage geographic ...[more]

PMID: 27481259

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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.

Dataset Information

A composite likelihood approach in testing for Hardy Weinberg Equilibrium using family-based genetic survey data.

Publications

A composite likelihood approach in testing for Hardy Weinberg Equilibrium using family-based genetic survey data.

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