hg18 RefSeq genes (Pruitt et al., 2005). We determined the significance threshold (generally 0.002–0.004) that designated the top 5% of all genes as “significant” (Holmans et al., 2009). The key statistical comparison is akin to a 2×2 table of whether a gene is in the top 5% by whether a gene is a member of a pathway. Assessing significance is complex due to violation of independence assumptions. ALIGATOR uses a SNP-based permutation algorithm to create a reference distribution for a pathway. InRich controls linkage disequilibrium between genes by comparing a gene set of interest to linkage disequilibrium independent regions. Using the same significance thresholds as in ALIGATOR, we identified linkage disequilibrium independent significant regions from the ISC dataset using the clump function within PLINK (r2=0.5 over 1Mb). We then used InRich to determine if the candidate gene set showed enrichment for these regions.
