We next evaluated whether the total group of genes mapping within rare genic CNV intervals in cases pointed to the involvement of particular biological pathways or processes. As described above, to maximize the sensitivity of this analysis, we considered all predicted high confidence rare exonic CNVs in cases derived from full array probe sets. We relied on three programs, MetaCore (MC), PANTHER (PA), and Ingenuity Pathway Analysis (IPA). A list of all 2,646 genes identified in TS cases was used as input for each algorithm. The five pathways showing greatest significance (smallest p-values), relative to all known genes in the genome, included pathways involving ubiquitin (MC, p=9.6 × 10-5), GABA receptor signaling (MC, p=1.9 × 10-4), sphingolipid metabolism (IPA, p=3.1 × 10-4), histamine receptor signaling (MC, p=5.8 × 10-4, H1R), and alpha-2 adrenergic receptor function (MC, p=7.7 × 10-4). Overlapping results among differing algorithms occurred for GABA (IPA, p=6.0 × 10-3; MC, p=1.9 × 10-4) and histamine (MC, p=5.8×10-4, H1R; PA, p=0.016A, H2R; p=0.058, H1R) signaling pathways only (Table 1; Figure S5 in Supplement 1).
