Pathway Analysis by Adaptive Combination of P-Values

It is increasingly recognized that pathway analyses-a joint test of association between the outcome and a group of single nucleotide polymorphisms (SNPs) within a biological pathway-could potentially complement single-SNP analysis and provide additional insights for the genetic architecture of complex diseases. Building upon existing P-value combining methods, we propose a class of highly flexible pathway analysis approaches based on an adaptive rank truncated product statistic that can effectively combine evidence of associations over different SNPs and genes within a pathway. The statistical significance of the pathway-level test statistics is evaluated using a highly efficient permutation algorithm that remains computationally feasible irrespective of the size of the pathway and complexity of the underlying test statistics for summarizing SNP- and gene-level associations. We demonstrate through simulation studies that a gene-based analysis that treats the underlying genes, as opposed to the underlying SNPs, as the basic units for hypothesis testing, is a very robust and powerful approach to pathway-based association testing. We also illustrate the advantage of the proposed methods using a study of the association between the nicotinic receptor pathway and cigarette smoking behaviors. Genet. Epidemiol. 33:700-709, 2009. Published 2009 Wiley-Liss, Inc.(dagger)