Table 3.
Gene Set Overrepresentation Analysis of Pyrethroid-Associated CpG Sites, GO Biological Processes
| ONTOLOGY | TERM | N | DE | P.DE | FDR |
|---|---|---|---|---|---|
| BMIQ Normalized Methylation | |||||
| CC | membrane | 1853 | 1313.3 | 8.0E−08 | 7.0E−04 |
| CC | nucleoplasm | 3123 | 2164.8 | 1.4E−06 | 7.9E−03 |
| CC | cytosol | 4871 | 3288.1 | 1.3E−05 | 3.9E−02 |
| MF | protein binding | 9664 | 6483.3 | 2.0E−12 | 3.6E−08 |
| MF | ATP binding | 1451 | 1041.5 | 4.0E−06 | 1.8E−02 |
| MF | transcription factor binding | 264 | 213.5 | 5.3E–06 | 1.9E–02 |
| Illumina Normalized Methylation | |||||
| BP | negative regulation of transcription by RNA polymerase II | 707 | 655.5 | 9.2E–12 | 1.8E–08 |
| BP | positive regulation of transcription, DNA-templated | 535 | 497.0 | 4.8E–10 | 6.5E–07 |
| BP | positive regulation of transcription by RNA polymerase II | 975 | 872.0 | 7.2E–8 | 6.3E–05 |
| BP | protein ubiquitination | 419 | 384.0 | 1.3E–07 | 1.1E–04 |
| BP | cellular response to DNA damage stimulus | 224 | 212.5 | 3.2E−07 | 2.1E−04 |
| BP | viral process | 366 | 337.0 | 3.7E–07 | 2.4E–04 |
| BP | proteasome-mediated ubiquitin-dependent protein catabolic process | 133 | 129.5 | 1.5E–06 | 9.0E–04 |
| BP | cell division | 344 | 316.0 | 1.8E–06 | 9.3E–04 |
| BP | mRNA splicing, via spliceosome | 224 | 210.0 | 1.8E-06 | 9.3E-04 |
| BP | neural tube closure | 76 | 76.0 | 4.1E–06 | 2.0E–03 |
| BP | in utero embryonic development | 168 | 160.0 | 1.1E–05 | 4.6E–03 |
| BP | protein polyubiquitination | 206 | 192.5 | 1.8E–05 | 7.1E–03 |
| BP | mitotic cell cycle | 90 | 88.0 | 1.9E–05 | 7.5E–03 |
| BP | protein deubiquitination | 236 | 218.5 | 3.3E–05 | 1.2E–02 |
| BP | DNA repair | 194 | 179.5 | 6.8E–05 | 2.2E–02 |
| BP | translational initiation | 130 | 122.5 | 1.0E–04 | 3.0E–02 |
| BP | embryonic digit morphogenesis | 56 | 56.0 | 1.4E–04 | 3.8E–02 |
| BP | cilium assembly | 152 | 142.0 | 1.4E–04 | 3.8E-02 |
| BP | RNA splicing | 143 | 134.5 | 1.5E–04 | 4.2E–02 |
| BP | Golgi organization | 65 | 64.0 | 1.6E–04 | 4.2E–02 |
| CC | nucleoplasm | 3123 | 2860.8 | 2.2E–47 | 1.9E–43 |
| CC | cytosol | 4871 | 4293.7 | 1.6E–31 | 9.3E–28 |
| CC | membrane | 1853 | 1692.8 | 4.8E–26 | 2.1E–22 |
| CC | nucleus | 4561 | 3946.8 | 6.1E–19 | 1.8E–15 |
| CC | mitochondrion | 1106 | 996.0 | 4.9E–14 | 1.2E–10 |
| CC | centrosome | 447 | 424.5 | 5.4E–14 | 1.2E–10 |
| CC | nuclear speck | 386 | 363.5 | 1.6E–10 | 2.6E–07 |
| CC | Golgi apparatus | 820 | 741.0 | 3.7E–10 | 5.4E–07 |
| CC | protein-containing complex | 592 | 535.0 | 6.2E–08 | 5.8E–05 |
| CC | mitochondrial matrix | 349 | 321.0 | 1.7E–07 | 1.3E–04 |
| CC | cytoplasm | 3433 | 2918.7 | 7.1E–07 | 4.5E–04 |
| CC | perinuclear region of cytoplasm | 684 | 611.2 | 1.5E–06 | 9.0E–04 |
| CC | microtubule | 254 | 238.0 | 1.7E–06 | 9.3E–04 |
| CC | glutamatergic synapse | 346 | 321.5 | 1.8E–06 | 9.3E–04 |
| CC | focal adhesion | 397 | 365.5 | 2.5E–06 | 1.2E–03 |
| CC | late endosome | 120 | 116.5 | 4.8E–06 | 2.2E–03 |
| CC | lysosomal membrane | 285 | 263.0 | 5.2E–06 | 2.3E–03 |
| CC | nuclear body | 277 | 256.5 | 6.9E–06 | 3.0E–03 |
| CC | endoplasmic reticulum | 850 | 743.6 | 8.3E–06 | 3.6E–03 |
| CC | nuclear chromatin | 167 | 159.0 | 1.2E–05 | 4.8E–03 |
| CC | Golgi membrane | 585 | 522.0 | 2.0E–05 | 7.7E–03 |
| CC | intracellular membrane-bounded organelle | 579 | 514.0 | 5.1E–05 | 1.8E–02 |
| CC | dendrite | 331 | 303.0 | 5.9E–05 | 2.0E–02 |
| CC | spindle | 114 | 109.0 | 9.7E–05 | 3.0E–02 |
| CC | nuclear membrane | 234 | 215.5 | 1.1E–04 | 3.3E–02 |
| CC | microtubule cytoskeleton | 122 | 116.0 | 1.4E–04 | 3.8E–02 |
| CC | lamellipodium | 175 | 164.0 | 1.4E–04 | 3.8E–02 |
| CC | cilium | 187 | 172.0 | 1.6E–04 | 4.3E-02 |
| MF | protein binding | 9664 | 8427.8 | 1.0E–58 | 1.8E–54 |
| MF | RNA binding | 1334 | 1229.6 | 3.4E–24 | 1.2E–20 |
| MF | ATP binding | 1451 | 1295.2 | 3.0E–11 | 5.3E–08 |
| MF | cadherin binding | 280 | 267.2 | 1.5E–09 | 1.8E–06 |
| MF | protein kinase binding | 401 | 375.5 | 3.5E–09 | 4.1E–06 |
| MF | DNA-binding transcription factor activity | 480 | 444.0 | 8.6E–09 | 9.4E–06 |
| MF | enzyme binding | 345 | 323.5 | 1.3E–08 | 1.4E–05 |
| MF | transcription factor binding | 264 | 251.5 | 6.3E-08 | 5.8E-05 |
| MF | identical protein binding | 1041 | 919.1 | 2.2E–07 | 1.7E–04 |
| MF | protein C-terminus binding | 186 | 179.0 | 2.4E–07 | 1.7E–04 |
| MF | RNA polymerase II proximal promoter sequence-specific DNA binding | 379 | 352.5 | 2.4E–07 | 1.7E–04 |
| MF | DNA-binding transcription repressor activity, RNA polymerase II-specific | 224 | 212.0 | 2.2E–06 | 1.1E–03 |
| MF | histone deacetylase binding | 102 | 99.0 | 2.1E-05 | 7.7E-03 |
| MF | protein domain specific binding | 255 | 235.0 | 3.4E–05 | 1.2E–02 |
| MF | double-stranded DNA binding | 72 | 71.0 | 4.2E–05 | 1.5E–02 |
| MF | DNA-binding transcription activator activity, RNA polymerase II-specific | 390 | 354.0 | 6.5E–05 | 2.2E–02 |
| MF | transcription corepressor activity | 205 | 191.5 | 8.4E–05 | 2.7E–02 |
| MF | DNA-binding transcription factor activity, RNA polymerase II-specific | 1537 | 1330.5 | 9.0E–05 | 2.8E–02 |
| MF | ubiquitin-protein transferase activity | 224 | 206.0 | 1.7E–04 | 4.5E–02 |
These overrepresentation pathways were derived from the gometh function in the missMethyl R package, after accounting for prior probabilities. The input list includes the CpG sites that were associated with pyrethroids at raw p<0.05 (N=32,695 CpG sites for BMIQ normalized models and N=69,180 for Illumina normalized models). These estimates were from the EWAS beta regression model that controlled for age, sex, education, cell count, and an ancestral marker for Hispanic ancestry. Ontology codes are BP=biological process, CC=cellular component, MF= molecular function. N is number of genes in the GO term, DE is the number of genes that are differentially methylated, P.DE is the p-value for over-representation of the GO term, and FDR is the False discovery rate q value.