The Merits of Testing Hardy-Weinberg Equilibrium in the Analysis of Unmatched Case-Control Data: A Cautionary Note

Testing for departures from the assumption of Hardy-Weinberg equilibrium (HWE) has been widely recommended as a preliminary step in the analysis of genetic case-control studies. Some authors suggest using a two-stage procedure in which gene/disease associations are ultimately evaluated using either the Pearson chi-square procedure or the Cochran-Armitage test for trend. Other authors go further and encourage investigators to discard data that are in violation of HWE, essentially using the test as a tool for identifying genotyping errors. In this paper we show that 1) testing for HWE should not be used as a tool to identify genotyping errors; and 2) it is not necessary, and possibly even harmful, to test the HWE assumption before testing for association between alleles and disease. Instead one should inherently account for deviations from HWE with an adjusted chi-square test statistic, a procedure which in the present context is identical to the trend test. Examples from previous reports are used to illustrate the methodology.