Investigating Hardy–Weinberg equilibrium in case–control or cohort studies or meta-analysis

Abstract

Purpose: Yu et al. [2009 Breast Cancer Res Treat 117:675-677] recently stated that testing for deviation from Hardy-Weinberg equilibrium (HWE) is necessary to identify systematic genotyping errors in case-control studies. They criticized a meta-analytic study for the deviation from HWE in the case group of one study. The aim of this paper is two-fold. First, 2 we derive recommendations on how to test for deviations from HWE in different study designs. Second, we develop a meta-analytic framework for assessing compatibility with HWE or measuring deviation from HWE. Methods:We sketch possible reasons behind deviation from HWE and provide guidelines for proper investigation of HWE deviations in different study designs. We argue that the standard HWE χ 2 lack of fit test is logically flawed and provide a logically unflawed approach for measuring deviation from HWE using confidence intervals. Our method is applicable to the meta-analysis of both case-control or cohort association studies. We illustrate our approach using the meta-analysis criticized by Yu et al. Results:In case-control studies, deviation from HWE should only be investigated in controls.In population-based cohort studies, deviation from HWE should be investigated using the entire sample. A simple meta-analytic framework based on confidence intervals is available for investigating deviation from HWE and establishing compatibility with HWE.Heterogeneity between studies can be assessed. Conclusions:We advocate the use of a confidence interval-based approach to assess HWE.The latter should only be investigated in control populations. In multicentre studies or metaanalysis, deviation from HWE should be analyzed using a meta-analytic approach.

Letter regarding Wang et al. entitled “Effects of murine double minute 2 polymorphisms on the risk and survival of osteosarcoma: a systemic review and meta-analysis”

“…A significant difference between the observed and expected genotype frequencies under Hardy-Weinberg equilibrium (HWE) may indicate genotyping error [2]. Departure from HWE can be caused by factors such as inbreeding caused by consanguinity, assortative mating, i.e., nonrandom mating, selection, or migration [3]. Although exceptions to the conditions of HWE may explain deviation, it is critical that investigators recognize the need to perform a test of HWE and then evaluate the reasons for any observed deviation.…”

Letter by Fu et al. regarding the article, “Polymorphisms in the vitamin D receptor gene and the lung cancer risk”

“…A significant difference between the observed and expected genotype frequencies under Hardy-Weinberg equilibrium (HWE) may indicate genotyping error [2]. Departure from HWE can be caused by factors such as inbreeding caused by consanguinity, assortative mating, i.e., non-random mating, selection, or migration [3]. Although exceptions to the conditions of HWE may explain deviation, it is critical that investigators recognize the need to perform a test of HWE and then evaluate the reason(s) for any observed deviation.…”

Association between functionalIRF7variant and systemic lupus erythematosus may need more critical examination: Comment on the article by Fu et al

“…When the proportion of affected subjects in a population is small, the degree of deviation from Hardy-Weinberg equilibrium is expected to be stronger in cases than in controls. As an indicator of genotyping quality, compatibility with Hardy-Weinberg equilibrium should be assessed in control groups (4). Additionally, the authors indicated that the genotype distribution in African American subjects was not within Hardy-Weinberg equilibrium.…”

“…Most studies of SLE genetics, including 6 recently published genome-wide association studies (GWAS) (3)(4)(5)(6)(7)(8), are focused on the identification of disease-associated variants. Although no analyses with adjustment for environmental risk factors were performed, these GWAS have been shown to provide useful insights into disease pathogenesis and potential new targets for treatment without the results being distorted.…”