A gene-based method for detecting gene–gene co-association in a case–control association study

Association study (especially the genome-wide association study) now has a key function in identification and characterization of disease-predisposing genetic variant(s), which customarily involve multiple single nucleotide polymorphisms (SNPs) in a candidate region or across the genome. Case–control association design remains the most popular and a challenging issue in the statistical analysis is the optimal use of all information contained in these SNPs. Previous approaches often treated gene–gene interaction as deviation from additive genetic effects or replaced it with SNP–SNP interaction. However, these approaches are limited for their failure of consideration of gene–gene interaction or gene–gene co-association at gene level. Although the co-association of the SNPs within a candidate gene can be detected by principal component analysis-based logistic regression model, the detection of co-association between genes in genome remains uncertain. Here, we proposed a canonical correlation-based U statistic (CCU) for detecting gene-based gene–gene co-association in the case–control design. We explored its type I error rates and power through simulation and analyzed two real data sets. By treating gene as a functional unit in analysis, we found that CCU was a strong alternative to previous approaches. We discussed the performance of CCU as a gene-based gene–gene co-association statistic and the prospect of further improvement.