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Bayesian model selection for the study of Hardy-Weinberg proportions and homogeneity of gender allele frequencies.

ABSTRACT: Standard statistical tests for Hardy-Weinberg equilibrium assume the equality of allele frequencies in the sexes, whereas tests for the equality of allele frequencies in the sexes assume Hardy-Weinberg equilibrium. This produces a circularity in the testing of genetic variants, which has recently been resolved with new frequentist likelihood and exact procedures. In this paper, we tackle the same problem by posing it as a Bayesian model comparison problem. We formulate an exhaustive set of ten alternative scenarios for biallelic genetic variants. Using Dirichlet and Beta priors for genotype and allele frequencies, we derive marginal likelihoods for all scenarios, and select the most likely scenario using the posterior probabilities that each of these scenarios is the one in place. Different from the usual frequentist testing approach, the Bayesian approach allows one to compare any number of models, and not just two at a time, and the models compared do not have to be nested. We illustrate our Bayesian approach with genetic data from the 1,000 genomes project and through a simulation study.

SUBMITTER: Puig X

PROVIDER: S-EPMC6972714 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Bayesian model selection for the study of Hardy-Weinberg proportions and homogeneity of gender allele frequencies.

Puig Xavier X Ginebra Josep J Graffelman Jan J

Heredity 20190529 5

Standard statistical tests for Hardy-Weinberg equilibrium assume the equality of allele frequencies in the sexes, whereas tests for the equality of allele frequencies in the sexes assume Hardy-Weinberg equilibrium. This produces a circularity in the testing of genetic variants, which has recently been resolved with new frequentist likelihood and exact procedures. In this paper, we tackle the same problem by posing it as a Bayesian model comparison problem. We formulate an exhaustive set of ten a ...[more]

PMID: 31142813

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Project description:In case-control genetic association studies, cases are subjects with the disease and controls are subjects without the disease. At the time of case-control data collection, information about secondary phenotypes is also collected. In addition to studies of primary diseases, there has been some interest in studying genetic variants associated with secondary phenotypes. In genetic association studies, the deviation from Hardy-Weinberg proportion (HWP) of each genetic marker is assessed as an initial quality check to identify questionable genotypes. Generally, HWP tests are performed based on the controls for the primary disease or secondary phenotype. However, when the disease or phenotype of interest is common, the controls do not represent the general population. Therefore, using only controls for testing HWP can result in a highly inflated type I error rate for the disease- and/or phenotype-associated variants. Recently, two approaches, the likelihood ratio test (LRT) approach and the mixture HWP (mHWP) exact test were proposed for testing HWP in samples from case-control studies. Here, we show that these two approaches result in inflated type I error rates and could lead to the removal from further analysis of potential causal genetic variants associated with the primary disease and/or secondary phenotype when the study of primary disease is frequency-matched on the secondary phenotype. Therefore, we proposed alternative approaches, which extend the LRT and mHWP approaches, for assessing HWP that account for frequency matching. The goal was to maintain more (possible causative) single-nucleotide polymorphisms in the sample for further analysis. Our simulation results showed that both extended approaches could control type I error probabilities. We also applied the proposed approaches to test HWP for SNPs from a genome-wide association study of lung cancer that was frequency-matched on smoking status and found that the proposed approaches can keep more genetic variants for association studies.

Dataset Information

Bayesian model selection for the study of Hardy-Weinberg proportions and homogeneity of gender allele frequencies.

Publications

Bayesian model selection for the study of Hardy-Weinberg proportions and homogeneity of gender allele frequencies.

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