Leveraging Hardy-Weinberg disequilibrium for association testing in case-control studies

In a case-control association study, deviation from Hardy-Weinberg equilibrium (HWE) or Hardy-Weinberg dis-equilibrium (HWD) in the control group is usually considered as evidence for potential genotyping error, and the corresponding SNP is then removed from the study. On the other hand, assuming HWE holds in the study population, a truly associated SNP is expected to be out of HWE in the case group. Efforts have been made in combining association tests with tests of HWE in the cases to increase the power of detecting disease susceptibility loci (Song and Elston (2006), Wang and Shete (2010)). However, these existing methods are ad-hoc and sensitive to model assumptions. Utilizing the recent robust allele-based (RA) regression model for conducting allelic association tests (Zhang and Sun (2020)), here we propose a joint RA test that naturally integrates association evidence from the traditional association test and a test that evaluates the difference in HWD between the case and control groups. The proposed test is robust to genotyping error, as well as to potential HWD in the population attributed to factors that are unrelated to phenotype-genotype association. We provide the asymptotic distribution of the proposed test statistic so that it is easy to implement, and we demonstrate the accuracy and efficiency of the test through extensive simulation studies and an application.