Gene sets used for pathway analyses of our GWAS data came from four sources (28): Gene Ontology (29), the Kyoto Encyclopedia of Genes and Genomes (ftp://ftp.genome.jp/pub/kegg/genes/organisms/hsa/hsa_pathway.list), the Mouse Genome Informatics database (30), and PANTHER (Protein Analysis Through Evolutionary Relationships [31]). Gene sets were required to contain between three and 1,000 genes to be included in the analysis, giving a total of 12,371 gene sets. Analysis was carried out using ALIGATOR (28), which converts a list of significant and nominally significant SNPs into a list of significant genes and tests this list for enrichment for genes within the gene sets, allowing for variable numbers of SNPs per gene. ALIGATOR generates p values for enrichment for each gene set and corrects these for testing multiple nonindependent gene sets. It also tests whether the number of significantly enriched gene sets is higher than expected given the observed set of SNP p values in the GWAS. Gene sets required at least two signals to be tested to remove the possibility of a small gene set being deemed significantly enriched based on one signal. An
