Table 2. Clusters of significant pathways in combined IGAP GWAS and replication data (Sidak-corrected p-value <0.05).
| Cluster | Pathway number | #genes | #sig | p-value | p-value no GWS | Description |
|---|---|---|---|---|---|---|
| 1 | GO: 2455 | 32 | 5 | 3.27E-12 | 5.72E-01 | humoral immune response mediated by circulating immunoglobulin |
| 1 | GO:50776 | 421 | 29 | 3.24E-09 | 1.57E-04 | regulation of immune response |
| 1 | GO: 2684 | 421 | 31 | 3.95E-09 | 2.11E-04 | positive regulation of immune system process |
| 1 | GO:50778 | 271 | 21 | 1.55E-07 | 6.65E-04 | positive regulation of immune response |
| 1 | KEGG 4664 | 78 | 13 | 5.76E-04 | 2.18E-02 | Fc epsilon RI signaling pathway |
| 2 | GO:60627 | 140 | 20 | 1.31E-11 | 2.00E-01 | regulation of vesicle-mediated transport |
| 2 | GO:30100 | 88 | 14 | 6.76E-10 | 1.06E-01 | regulation of endocytosis |
| 2 | GO:45806 | 19 | 6 | 3.91E-07 | 1.77E-02 | negative regulation of endocytosis |
| 2 | GO:48261 | 6 | 3 | 3.89E-06 | 9.82E-01 | negative regulation of receptor-mediated endocytosis |
| 2 | GO:48259 | 30 | 6 | 6.19E-05 | 1.00E+00 | regulation of receptor-mediated endocytosis |
| 3 | GO:30301 | 41 | 8 | 2.96E-09 | 2.51E-01 | cholesterol transport |
| 3 | GO:43691 | 16 | 5 | 3.90E-09 | 2.78E-01 | reverse cholesterol transport |
| 3 | GO:15918 | 42 | 8 | 3.91E-09 | 3.15E-01 | sterol transport |
| 3 | GO:34366 | 8 | 2 | 6.40E-07 | N/A | spherical high-density lipoprotein particle |
| 4 | KEGG 4640 | 81 | 11 | 1.05E-08 | 4.91E-01 | Hematopoietic cell lineage |
| 5 | GO:32434 | 40 | 5 | 1.34E-06 | 1.00E+00 | regulation of proteasomal ubiquitin-dependent protein catabolic process positive regulation of ubiquitin-protein ligase activity involved in mitotic cell |
| 5 | GO:51437 | 70 | 9 | 2.60E-03 | 2.60E-03 | cycle |
| 5 | GO:51439 | 76 | 9 | 3.82E-03 | 3.82E-03 | regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle |
| 5 | REACT 440 | 108 | 11 | 3.89E-03 | 3.89E-03 | REACTOME_CELL_CYCLE_CHECKPOINTS |
| 5 | GO:51443 | 77 | 9 | 9.62E-03 | 9.62E-03 | positive regulation of ubiquitin-protein ligase activity |
| 6 | REACT 539 | 261 | 25 | 2.95E-05 | 6.93E-02 | REACTOME_HEMOSTASIS |
| 7 | GO:30131 | 31 | 7 | 1.20E-03 | 9.13E-01 | clathrin adaptor complex |
| 7 | GO:30119 | 32 | 7 | 1.53E-03 | 9.54E-01 | AP-type membrane coat adaptor complex |
| 7 | GO:44433 | 301 | 31 | 1.01E-02 | 1.00E+00 | cytoplasmic vesicle part |
| 7 | GO:30122 | 9 | 4 | 1.29E-02 | 1.00E+00 | AP-2 adaptor complex |
| 7 | GO:30118 | 39 | 7 | 1.35E-02 | 1.00E+00 | clathrin coat |
| 8 | GO: 6457 | 200 | 12 | 1.60E-03 | 1.00E+00 | protein folding |
To obtain the most strongly enriched pathways in the entire dataset (IGAP GWAS and replication), the p-values from the ALIGATOR analysis (counting the top 5% of genes as significant) were combined with those from the replication study using Fisher's method. The resulting p-values from the combined samples were corrected for multiple testing of 9,816 pathways using Sidak's formula. For each pair of gene sets, an overlap measure K was defined as the number of genes common to both sets divided by the number of genes in the smaller dataset. A gene set was assigned to a cluster if the average K between it and the gene sets already in the cluster was greater than 0.4. If it was not possible to assign a gene set to an existing cluster, a new cluster was started. This procedure was carried out recursively, in descending order of enrichment significance. Clusters containing a significant pathway are listed here, and where more than 5 pathways are significant only the five most significant pathways in each cluster are shown. A complete list of pathways significant at p<0.01 in the ALIGATOR analysis of the IGAP GWAS data is given in Supplementary Table 4. “No GWS” refers to analyses in which genes containing a SNP genome-wide significant (p<5×10-8) in the IGAP GWASdataset (and thus expected to be strongly significant in the replication dataset) are removed from the analysis of the replication data.