title: HYST: a hybrid set-based test for genome-wide association studies, with application to protein-protein interaction-based association analysis.
abstract: The extended Simes' test (known as GATES) and scaled chi-square test were proposed to combine a set of dependent genome-wide association signals at multiple single-nucleotide polymorphisms (SNPs) for assessing the overall significance of association at the gene or pathway levels. The two tests use different strategies to combine association p values and can outperform each other when the number of and linkage disequilibrium between SNPs vary. In this paper, we introduce a hybrid set-based test (HYST) combining the two tests for genome-wide association studies (GWASs). We describe how HYST can be used to evaluate statistical significance for association at the protein-protein interaction (PPI) level in order to increase power for detecting disease-susceptibility genes of moderate effect size. Computer simulations demonstrated that HYST had a reasonable type 1 error rate and was generally more powerful than its parents and other alternative tests to detect a PPI pair where both genes are associated with the disease of interest. We applied the method to three complex disease GWAS data sets in the public domain; the method detected a number of highly connected significant PPI pairs involving multiple confirmed disease-susceptibility genes not found in the SNP- and gene-based association analyses. These results indicate that HYST can be effectively used to examine a collection of predefined SNP sets based on prior biological knowledge for revealing additional disease-predisposing genes of modest effects in GWASs.
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Miao-Xin
authors.initials: MX
authors.lastname: Li
authors.forename: Johnny S H
authors.initials: JS
authors.lastname: Kwan
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D060148:HapMap Project; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps