Evaluating HWE and Association in Genome Wide Association Studies: A Unified Procedure

Abstract

In genome wide association studies (GWASs) based on a case-control design, single nucleotide polymorphisms (SNPs) are typically evaluated for an association test and a Hardy-Weinberg equilibrium (HWE) goodness-of-fit test. SNPs are then excluded from analysis based on a HWE cutoff to avoid false positives. In order to avoid cutoffs based on arbitrary threshold values, we propose a conditional genotype--based test that conditions the Pearson $χ^2$-statistic in the 3x2 contingency table on the $χ^2$-statistic for HWE in the control group, and develop the relevant asymptotic distribution theory. We show by simulations that our test in most scenarios is more powerful than two competing retrospective procedures. Another important advantage of the proposed method is a better ranking of SNPs in GWASs as HWE is accounted for in computing p-values of SNP association. We demonstrate this effect on a data set in an alopecia study. In conclusion, our test makes separate HWE testing superfluous by providing a unified framework and strictly improves on the standard procedure in terms of power and interpretability, thereby making replication more cost effective and improving subsequent fine mapping.\par