For the final analytical approach, the focus was shifted from the general, genetic architecture of AD to the detection of specific polygenic mechanisms giving rise to the disorder, as permuted gene enrichment analyses were conducted on the bins of potential risk alleles applied in the scoring calculations described above. For each population-specific bin, representing one of twenty GWAS P-value thresholds defined by increments of 0.05, alleles exhibiting contrasting directions of effect between the discovery and target samples (accounting for ∼50% of the markers) were assumed to be predominantly due to chance and removed from analysis to help control statistical noise. The remaining SNPs were then assigned to genes based on the UCSC hg18 gene coordinates, with the boundaries extended +/− 20 kb to include regions that may have cis-regulatory functions. The resulting gene lists were tested for enrichment for genes belonging to various biological ontologies (n = 507) and receptor signaling pathways (n = 227), as defined in the ResNet Mammalian v. 7.0 database curated by Ariadne Genomics (Bethesda, MD). Unlike the “GO” vocabulary from the Gene Ontology Consortium, the
