Table 3.
Association of canonical pathways and PD risk through rare variation
| Gene set | Functional subcategory | MAF < 3 | MAF < 1 | ||
|---|---|---|---|---|---|
| Num SNP | SKAT-O P | Num SNP | SKAT-O P | ||
| Activation of AMPK downstream of NMDARS (REACTOME) | Missense | 84 | 0.633 | 73 | 0.680 |
| Loss of function | 31 | 0.015 | 28 | 0.892 | |
| CADD > 12% | 2 | 0.491 | 2 | 0.491 | |
| Adaptive immune system (REACTOME) | Missense | 3369 | 0.061 | 3128 | 9.38E−02 |
| Loss of function | 1724 | 0.003 | 1589 | 6.79E−03 | |
| CADD > 12% | 93 | 0.332 | 86 | 1 | |
| Alpha synuclein pathway (PID) | Missense | 130 | 0.654 | 121 | 0.653 |
| Loss of function | 82 | 0.023 | 77 | 1.32E−02 | |
| CADD > 12% | 3 | 0.006 | 3 | 5.95E−03 | |
| Alzheimers disease (KEGG) | Missense | 594 | 2.15E−10 | 563 | 1.02E−06 |
| Loss of function | 375 | 0.739 | 343 | 0.326 | |
| CADD > 12% | 13 | 0.075 | 13 | 0.075 | |
| Amyloid fiber formation (REACTOME) | Missense | 308 | 0.026 | 289 | 0.204 |
| Loss of function | 120 | 0.086 | 112 | 4.86E−02 | |
| CADD > 12% | 6 | 1 | 4 | 1 | |
| Apoptotic cleavage of cellular proteins (REACTOME) | Missense | 356 | 0.073 | 332 | 0.686 |
| Loss of function | 122 | 0.791 | 115 | 0.796 | |
| CADD > 12% | 5 | 0.616 | 5 | 0.616 | |
| Apoptotic execution phase (REACTOME) | Missense | 397 | 0.111 | 372 | 0.631 |
| Loss of function | 128 | 0.475 | 120 | 0.572 | |
| CADD > 12% | 7 | 0.794 | 7 | 0.794 | |
| Asparagine N linked glycosylation (REACTOME) | Missense | 2956 | 0.021 | 2728 | 6.14E−04 |
| Loss of function | 1226 | 0.233 | 1123 | 0.448 | |
| CADD > 12% | 69 | 0.544 | 68 | 0.427 | |
| Caspase mediated cleavage of cytoskeletal proteins (REACTOME) | Missense | 159 | 0.313 | 151 | 0.516 |
| Loss of function | 33 | 0.737 | 29 | 0.534 | |
| CADD > 12% | 1 | 0.691 | NA | NA | |
| Chromatin organization (REACTOME) | Missense | 1213 | 0.284 | 1134 | 0.622 |
| Loss of function | 680 | 0.813 | 628 | 0.777 | |
| CADD > 12% | 24 | 0.794 | 23 | 0.594 | |
| Class B 2 secretin family receptors (REACTOME) | Missense | 327 | 0.452 | 298 | 0.080 |
| Loss of function | 109 | 0.297 | 97 | 0.157 | |
| CADD > 12% | 15 | 0.525 | 13 | 0.592 | |
| Clathrin mediated endocytosis (REACTOME) | Missense | 668 | 0.196 | 632 | 0.240 |
| Loss of function | 410 | 0.256 | 363 | 0.892 | |
| CADD > 12% | 15 | 0.295 | 15 | 0.295 | |
| Copi dependent GOLGI to ER retrograde traffic (REACTOME) | Missense | 576 | 0.474 | 525 | 0.237 |
| Loss of function | 234 | 0.369 | 202 | 0.896 | |
| CADD > 12% | 8 | 0.081 | 8 | 0.081 | |
| COPI mediated anterograde transport (REACTOME) | Missense | 595 | 0.711 | 547 | 0.568 |
| Loss of function | 232 | 0.671 | 216 | 1 | |
| CADD > 12% | 13 | 1 | 13 | 1 | |
| COPII mediated vesicle transport (REACTOME) | Missense | 327 | 0.742 | 300 | 3.13E−01 |
| Loss of function | 149 | 0.729 | 140 | 0.417 | |
| CADD > 12% | 5 | 0.644 | 5 | 0.644 | |
| ER to Golgi anterograde transport (REACTOME) | Missense | 900 | 0.307 | 826 | 3.42E−02 |
| Loss of function | 378 | 0.426 | 356 | 0.808 | |
| CADD > 12% | 16 | 1 | 16 | 1 | |
| Glutamate binding activation of AMPA receptors and synaptic plasticity (REACTOME) | Missense | 83 | 0.222 | 75 | 0.399 |
| Loss of function | 87 | 0.493 | 80 | 0.224 | |
| CADD > 12% | 5 | 0.236 | 5 | 0.236 | |
| GOLGI associated vesicle biogenesis (REACTOME) | Missense | 277 | 0.224 | 260 | 0.428 |
| Loss of function | 118 | 0.315 | 110 | 0.771 | |
| CADD > 12% | 8 | 1 | 8 | 1 | |
| GPCR ligand binding (REACTOME) | Missense | 1769 | 2.12E−06 | 1632 | 2.16E−10 |
| Loss of function | 438 | 0.185 | 395 | 0.445 | |
| CADD > 12% | 49 | 0.540 | 45 | 0.605 | |
| Innate immune system (REACTOME) | Missense | 7162 | 0.009 | 6663 | 2.56E−03 |
| Loss of function | 2965 | 0.122 | 2714 | 0.212 | |
| CADD > 12% | 178 | 0.819 | 169 | 0.521 | |
| Intra GOLGI and retrograde GOLGI to ER traffic (REACTOME) | Missense | 1052 | 0.241 | 969 | 0.065 |
| Loss of function | 441 | 0.853 | 389 | 0.405 | |
| CADD > 12% | 20 | 0.857 | 18 | 0.873 | |
| Intra GOLGI traffic (REACTOME) | Missense | 213 | 0.284 | 199 | 0.077 |
| Loss of function | 76 | 1 | 69 | 0.870 | |
| CADD > 12% | 5 | 0.801 | 5 | 0.801 | |
| Lkb1 pathway (PID) | Missense | 233 | 0.114 | 224 | 0.440 |
| Loss of function | 148 | 0.576 | 140 | 0.928 | |
| CADD > 12% | 6 | 0.270 | 4 | 1 | |
| Long-term depression (KEGG) | Missense | 334 | 0.073 | 309 | 0.444 |
| Loss of function | 195 | 0.164 | 166 | 0.818 | |
| CADD > 12% | 8 | 0.003 | 7 | 8.86E−03 | |
| Lysosome (KEGG) | Missense | 673 | 0.034 | 628 | 0.528 |
| Loss of function | 356 | 0.400 | 332 | 0.390 | |
| CADD > 12% | 29 | 0.272 | 28 | 0.837 | |
| Mapk signaling pathway (KEGG) | Missense | 1156 | 0.091 | 1088 | 0.332 |
| Loss of function | 669 | 0.691 | 616 | 1 | |
| CADD > 12% | 28 | 0.066 | 25 | 0.111 | |
| Metabolism of lipids (REACTOME) | Missense | 3975 | 0.287 | 3701 | 0.204 |
| Loss of function | 1881 | 0.713 | 1703 | 0.874 | |
| CADD > 12% | 149 | 0.782 | 138 | 0.640 | |
| Metabolism of vitamins and cofactors (REACTOME) | Missense | 1252 | 0.210 | 1161 | 0.105 |
| Loss of function | 593 | 0.765 | 527 | 0.872 | |
| CADD > 12% | 45 | 0.151 | 40 | 0.196 | |
| Metabolism of water soluble vitamins and cofactors (REACTOME) | Missense | 740 | 0.487 | 688 | 0.187 |
| Loss of function | 405 | 0.367 | 366 | 0.396 | |
| CADD > 12% | 29 | 0.287 | 26 | 0.114 | |
| Neuroactive ligand receptor interaction (KEGG) | Missense | 1270 | 1.33E−09 | 1172 | 2.15E−10 |
| Loss of function | 378 | 0.489 | 344 | 0.594 | |
| CADD > 12% | 37 | 0.260 | 33 | 0.814 | |
| Neuronal system (REACTOME) | Missense | 1848 | 0.374 | 1704 | 0.606 |
| Loss of function | 872 | 0.222 | 787 | 0.858 | |
| CADD > 12% | 47 | 0.011 | 40 | 9.62E−03 | |
| Neurotransmitter receptors and postsynaptic signal transmission (REACTOME) | Missense | 753 | 0.931 | 696 | 0.870 |
| Loss of function | 396 | 0.115 | 364 | 1 | |
| CADD > 12% | 16 | 0.006 | 15 | 7.76E−03 | |
| Neutrophil degranulation (REACTOME) | Missense | 2715 | 0.353 | 2525 | 0.111 |
| Loss of function | 1207 | 0.766 | 1088 | 0.942 | |
| CADD > 12% | 98 | 0.572 | 91 | 0.613 | |
| P38 gamma delta pathway (PID) | Missense | 62 | 0.386 | 56 | 0.391 |
| Loss of function | 40 | 0.813 | 36 | 0.680 | |
| CADD > 12% | 2 | 0.664 | 2 | 0.664 | |
| Parkinsons disease (KEGG) | Missense | 301 | 2.15E−10 | 276 | 2.72E−09 |
| Loss of function | 185 | 0.024 | 175 | 9.14E−03 | |
| CADD > 12% | 11 | 0.289 | 11 | 0.289 | |
| Post-translational protein modification (REACTOME) | Missense | 9055 | 0.011 | 8385 | 1.54E−03 |
| Loss of function | 3643 | 0.675 | 3315 | 0.638 | |
| CADD > 12% | 213 | 0.471 | 199 | 0.467 | |
| PTK6 promotes HIF1A stabilization (REACTOME) | Missense | 42 | 0.047 | 39 | 5.87E−03 |
| Loss of function | 16 | 0.309 | 14 | 0.256 | |
| CADD > 12% | 2 | 0.170 | 2 | 0.170 | |
| Retrograde transport at the trans GOLGI network (REACTOME) | Missense | 241 | 0.044 | 230 | 1.70E−02 |
| Loss of function | 94 | 0.902 | 80 | 0.854 | |
| CADD > 12% | 3 | 0.499 | 2 | 0.792 | |
| Signaling by GPCR (REACTOME) | Missense | 5789 | 0.002 | 5312 | 1.39E−05 |
| Loss of function | 1623 | 0.388 | 1464 | 0.688 | |
| CADD > 12% | 138 | 0.445 | 128 | 0.306 | |
| Snare interactions in vesicular transport (KEGG) | Missense | 108 | 0.316 | 101 | 0.087 |
| Loss of function | 40 | 0.531 | 35 | 0.590 | |
| CADD > 12% | 3 | 0.034 | 2 | 0.072 | |
| Trafficking of GLUR2 containing AMPA receptors (REACTOME) | Missense | 48 | 1 | 45 | 1 |
| Loss of function | 49 | 0.095 | 43 | 0.920 | |
| CADD > 12% | NA | NA | |||
| Trans GOLGI network vesicle budding (REACTOME) | Missense | 330 | 0.118 | 313 | 0.229 |
| Loss of function | 160 | 0.197 | 148 | 0.728 | |
| CADD > 12% | 11 | 1 | 11 | 1 | |
| Transmission across chemical synapses (REACTOME) | Missense | 1117 | 0.441 | 1028 | 0.731 |
| Loss of function | 572 | 0.134 | 518 | 0.771 | |
| CADD > 12% | 23 | 9.99E−04 | 21 | 7.88E−03 | |
| Transport to the GOLGI and subsequent modification (REACTOME) | Missense | 1018 | 0.180 | 933 | 2.75E−02 |
| Loss of function | 435 | 0.505 | 404 | 0.865 | |
| CADD > 12% | 19 | 0.672 | 19 | 0.672 | |
| Vasopressin-regulated water reabsorption (KEGG) | Missense | 196 | 0.318 | 185 | 0.199 |
| Loss of function | 84 | 0.650 | 78 | 0.439 | |
| CADD > 12% | 2 | 0.239 | 2 | 0.239 | |
| Vesicle-mediated transport (REACTOME) | Missense | 3655 | 1 | 3395 | 0.484 |
| Loss of function | 1757 | 1 | 1584 | 0.165 | |
| CADD > 12% | 87 | 0.818 | 80 | 1 | |
MAF minor allele frequency, SKAT SNP-set Sequence Kernel Association Test, P P-value, CADD combined annotation dependent depletion, NA non applicable