Impaired performance of FDR-based strategies in whole-genome association studies when SNPs are excluded prior to the analysis

With recent advances in genomewide microarray technologies, whole-genome association (WGA) studies have aimed at identifying susceptibility genes for complex human diseases using hundreds of thousands of single nucleotide polymorphisms (SNPs) genotyped at the same time. In this context and to take into account multiple testing, false discovery rate (FDR)-based strategies are now used frequently. However, a critical aspect of these strAtegies is that they are applied to a collection or a family of hypotheses and, thus, critically depend on these precise hypotheses. We investigated how modifying the family of hypotheses to be tested affected the performance of FDR-based procedures in WGA studies. We showed that FDR-based procedures performed more poorly when excluding SNPs with high prior probability of being associated. Results of simulation studies mimicking WGA studies according to three scenarios are reported, and show the extent to which SNPs elimination (family contraction) prior to the analysis impairs the performance of FDR-based procedures. To illustrate this situation, we used the data from a recent WGA study on type-1 diabetes (Clayton et al. 2005] Nat. Genet. 37:1243-1246) and report the results obtained when excluding or not SNPs located inside the human leukocyte antigen region. Based on our findings, excluding markers with high prior probability of being associated cannot be recommended for the analysis of WGA data with FDR-based strategies.