Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 91, Issue 3, Pages 478-488Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2012.08.004
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Funding
- Hong Kong Research Grants Council [HKU 774707M, 777511M]
- Theme-Based Research Scheme [T12-705/11]
- European Community Seventh Framework Programme Grant on European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI)
- University of Hong Kong [HKU 201109176063]
- Strategic Research Theme on Genomics
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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.
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