LEVERAGING HARDY-WEINBERG DISEQUILIBRIUM FOR ASSOCIATION TESTING IN CASE-CONTROL STUDIES

Modern genome-wide association studies (GWAS) remove single nu-cleotide polymorphisms (SNPs) that are in Hardy-Weinberg disequilibrium (HWD), despite limited rigor for this practice. In a case-control GWAS, al-though HWD in the control sample is an evidence for genotyping error, a truly associated SNP may be in HWD in the case and/or control populations. We, therefore, develop a new case-control association test that: (i) leverages HWD attributed to true association to increase power, (ii) is robust to HWD caused by genotyping error, and (iii) is easy-to-implement at the genome-wide level. The proposed robust allele-based joint test incorporates the difference in HWD between the case and control samples into the traditional association measure to gain power. We provide the asymptotic distribution of the pro-posed test statistic under the null hypothesis. We evaluate its type 1 error control at the genome-wide significance level of 5 x 10-8 in the presence of HWD attributed to factors unrelated to phenotype-genotype association, such as genotyping error. Finally, we demonstrate that the power of the proposed allele-based joint test is higher than the standard association test for a variety of genetic models, through derivations of the noncentrality parameters of the tests, as well as simulation and application studies.