Pathway analysis can be complex in regions like the MHC that have extensive disequilibrium between genes (Stenzel et al., 2004). When we repeated the ALIGATOR analysis after excluding genes in the MHC region, there was no evidence for over-representation of smaller p-values (p ~ 0.48) indicating that the marginal enrichment was due to bias. We repeated the pathway analysis using InRich, which may be more robust than ALIGATOR in regions of high linkage disequilibrium. InRich evaluates regions defined by linkage disequilibrium. We tested the full candidate gene data set, using the same significance thresholds as in ALIGATOR, and found no evidence for enrichment of significant findings in the candidate genes (Table 2). Therefore, the pathway analyses are consistent with the null hypothesis as all p-values were non-significant or marginal and would not survive correction for multiple testing and as removal of the MHC region and analysis with a program that corrects for linkage disequilibrium indicates the results are a false positive resulting from extensive linkage disequilibrium in the MHC region.
