Single Cell Transcriptomics of Human PINK1 Ipsc Differentiation Dynamics Reveal a Core Network of Parkinson’S Disease

Supplementary Information for

Single cell transcriptomics of human PINK1 iPSC differentiation dynamics reveal a core network of Parkinson’s disease

Gabriela Novak, Dimitrios Kyriakis, Kamil Grzyb, Michela Bernini, Steven Finkbeiner, and Alexander Skupin

Day -1 Plate iPSCs at 1.5 to double confluent density in MTeSR with ROCK inhibitor, remove ROCK inhibitor afer ±8 hours Day 0 SRM, LDN193189 (100nM), SB431542 (10 μM) Day 1-2 SRM, LDN193189 (100nM), SB431542 (10 μM), SHH (100ng/ml, Purmorphamine (2 μM), FgF-8b (100ng/ml) Day 3-4 SRM, LDN193189 (100nM), SB431542 (10μM), SHH (100ng/ml), Purmorphamine (2μM), FgF-8b (100ng/ml), CHIR (3μM) Day 5-6 75% SRM/25% N2 with LDN193189 (100nM), SHH (100ng/ml), Purmorphamine (2 μM), FgF-8b (100ng/ml), CHIR (3 μM) Day 7-8 50% SRM/50% N2 with LDN193189 (100nM), SHH (100ng/ml), CHIR (3 μM) Day 9-10 25% SRM/75% N2 with LDN193189 (100nM), SHH (100ng/ml), CHIR (3 μM) Day 11-12 NB/B27, CHIR (3 μM), BDNF (20ng/ml), AA (0.2mM), GDNF (20ng/ml), cAMP (1mM), TGFB3 (1ng/ml), DAPT (10 μM) Day 13-20 NB/B27 with with BDNF (20ng/ml), AA (0.2mM), GDNF (20ng/ml), cAMP (1mM), TGFB3 (1ng/ml), DAPT (10 μM) Day 21 Dissociate using Accutase and passage 1:1 onto poly-L-ornithine/fibronectin/laminin-coated dishes. Day 25 Passage again using Accutase, onto to poly-L-ornithine/fibronectin/laminin-coated dishes at about 3x10e6 cells/6-well well Day 26+ NB/B27 with BDNF (20ng/ml), AA (0.2mM), GDNF (20ng/ml), cAMP (1mM), TGFB3 (1ng/ml), DAPT (10 μM) SRM media contains 410 mL of Knockout DMEM (Invitrogen; cat. no. 10829-018), 75 mL Knockout Serum Replacement (Invitrogen, cat. no. 10828-028), 5 mL L-glutamine (200 mM, Invitrogen, cat. no. 25030-081), 5 mL MEM NEAA (Invitrogen, cat. no. 11140-050), and 0.5 mL of 1000x 2-mercaptoethanol (Invitrogen, cat. no. 21985-023). N2 media contains 470 mL of Neurobasal media, 5 mL L-glutamine (200 mM, Invitrogen, cat. no. 25030-081), N2 supplement (17502048), B27 supplement (12587010), 1% penicillin/streptomycin NB/B27 media contains 470 mL of Neurobasal media (Life Technologies Europe, 21103049), B27 supplement, 1% penicillin/streptomycin

Supplementary Table 1. Timing of the differentiation protocol and differentiation factor concentrations used.

TH DDC SLC6A3 SLC18a2 PAX6 Other (AADC) (DAT) (VMAT) A8-10 Midbrain dopaminergic + + + + - ALDH1A1 neurons A11 periventricular nucleus + + - + - (PVN) (DA to the spinal cord) A12 arcuate nucleus + + + + - Dlx1 (endocrine) (prolactin regulation) ALDH1A3 A13 medial zona incerta + + - + +* Dlx1, (gonadotropin release) somatostatin A14 preoptic periventricular + + - + +* nucleus (regul. Ant.pituitary) A15 preoptic & endopeduncular + - - +? + area (estradiol release) A16 periglomerular cells in the + + + - + ALDH1A1 olfactory bulb A17 interplexiform cells in the + + + NKR retina

Supplementary Table 2. DA neuron heterogeneity: mDA and non-mDA markers. 1–9 When studying PD, it is important to ascertain that the DA neurons are in fact mDA neurons. In an in vitro differentiation system, simple marker combinations that normally distinguish mDA neurons, such as positional and anatomical information, are missing. We relied instead on molecular markers culled from the literature to monitor our differentiation protocols. (* A13 and A14PAVH express Pax6 transiently during development. PAX6 is expressed early in development, whereas the remaining markers are expressed later and are markers of mature DA neurons. “?” indicates that the literature regarding the expression is not unanimous.)

Gene qRT-PCR primer forward qRT-PCR primer reverse OTX2 GAGGTGGCACTGAAAATCAAC TCTTCTTTTTGGCAGGTCTCA EN1 CGTGGTCAAAACTGACTCGC CGCTTGTCCTCCTTCTCGTT LMX1A GCTCAGAGCAGTTCAGAGGG CAAGCAGGAGTTTGCCCAAC FOXA2 ATTTTAAACTGCCATGCACTCG ATGTTGCTCACGGAGGAGTAG TH GGAAATTGAGAAGCTGTCCACG GAATCTCAGGCTCCTCAGACAG ALDH1A1 GAGAGTGGGAAGAAAGAAGGGG TTCATGATTTGCTGCACTGGTC GIRK2/KCNJ6 AGCTGCCCAAAGAGGAACTG ACAGGTGTGAACCGGTAACC GAPDH AAGAAGGTGGTGAAGCAGGC GTCAAAGGTGGAGGAGTGGG

Supplementary Table 3. Primers used for qPCR expression analysis.

Max p- Max p- Max p- Gene val. Avg Gene val. Avg Gene val. Avg SNHG5 2,84E-40 1,2233 DNAJC15 2,13E-05 -0,2908 YPEL1 2,24E-03 0,1418 PGK1 8,78E-31 0,5781 TTC3 2,27E-05 -0,2084 DPH3 2,27E-03 0,1660 CALM2P2 1,65E-22 -0,4551 MYL9 2,32E-05 0,1653 ZNF593 2,38E-03 0,1409 MTRNR2L1 3,71E-21 -0,7731 IPO7 3,20E-05 0,1495 SNHG8 2,44E-03 0,2942 MYL6 1,24E-19 0,3070 PTGR1 3,38E-05 -0,2377 RNF26 2,65E-03 0,1134 S100A6 2,09E-17 -0,4393 C14ORF119 3,53E-05 0,2194 SLC7A8 2,66E-03 -0,2006 ZNF280D 2,49E-17 -0,4377 RP11.288E14.2 4,65E-05 -0,1661 THUMPD3 2,66E-03 0,2241 TYW3 1,73E-14 0,4748 NSA2 4,67E-05 -0,2075 NUP62 2,75E-03 0,1122 TCEAL5 6,78E-14 -0,3745 SRA1 5,11E-05 0,2118 RTCB 2,78E-03 0,1859 MT.ND5 3,70E-13 -0,2243 ZNF75A 6,89E-05 -0,1561 EIF3A 2,83E-03 0,1690 RP11.641D5.1 4,00E-13 -0,4508 GTF2I 7,03E-05 -0,2326 CD164 2,83E-03 0,2346 HMGN1P38 3,95E-12 -0,3460 FAM208A 7,79E-05 -0,1284 IPO9 2,84E-03 0,1533 CRYZ 1,36E-11 0,2732 RP11.676M6.1 9,09E-05 -0,1732 FAM126A 2,86E-03 0,2571 MORF4L1P1 1,39E-11 -0,4552 HLA.B 1,25E-04 0,1239 IQCB1 2,93E-03 0,1169 TCF25 5,14E-11 -0,2072 SMARCB1 1,47E-04 -0,1477 HNRNPCP1 2,93E-03 -0,1692 CRKL 1,44E-10 0,2138 SEPT2 1,52E-04 -0,1305 HSD17B4 2,97E-03 -0,1338 CYFIP1 1,47E-10 0,3021 HIC2 1,57E-04 0,1798 CCNB1IP1 3,00E-03 0,1361 PTMAP5 2,02E-10 -0,4196 EIF5P1 1,70E-04 -0,2675 SHROOM3 3,03E-03 0,1114 RP11.692N5.2 3,69E-10 -0,5485 SNAP29 2,12E-04 0,2991 RP13.258O15.1 3,39E-03 -0,2489 HSPA8 4,07E-10 0,4696 ACTN1 2,14E-04 0,2552 PSMD7 3,85E-03 0,1997 C6ORF48 5,37E-10 0,3012 RRP7A 2,19E-04 0,1897 TMEM38B 3,98E-03 -0,1816 RP11.475C16.1 8,30E-10 -0,3438 EIF1AY 3,64E-04 0,2735 SRSF9 4,05E-03 -0,1431 NLRP2 1,91E-09 -0,4704 RP11.488C13.1 3,83E-04 -0,4249 MYO10 4,23E-03 0,1666 CCDC144NL.AS1 2,27E-09 0,5870 AZI2 4,11E-04 -0,1967 AK6 4,24E-03 0,1088 ZNF37A 3,66E-09 0,2595 THAP9.AS1 4,34E-04 -0,1848 LANCL1 4,28E-03 0,1186 MALAT1 8,50E-09 -0,2594 CTSB 5,60E-04 0,1873 RRAGD 4,30E-03 0,1525 HNRNPC 1,95E-08 -0,2880 HNRNPCP2 5,82E-04 -0,2255 PFKP 4,80E-03 0,2555 CD59 1,96E-08 0,2756 CNTNAP2 6,80E-04 0,2072 NONO 4,82E-03 -0,1609 MINOS1P3 2,08E-08 -0,3666 SH3YL1 7,01E-04 -0,1055 STK33 4,87E-03 -0,1139 NIPA2 2,62E-08 0,2650 IWS1 7,26E-04 0,1393 PDAP1 4,93E-03 -0,1437 THAP7 2,82E-08 0,1644 WBSCR22 7,45E-04 0,1442 KMT2A 5,37E-03 0,1419 TUBGCP5 3,34E-08 0,2310 CSNK1G3 7,96E-04 0,1590 CHCHD2 5,40E-03 -0,1740 ZNF880 5,11E-08 0,2523 TRA2A 8,89E-04 -0,1567 EGLN3 5,56E-03 0,2413 RP4.765C7.2 5,86E-08 -0,4253 ATG101 9,22E-04 0,1437 RP4.796I17.5 5,89E-03 -0,2372 CBX3P9 1,01E-07 -0,3360 GOPC 9,27E-04 -0,2850 IFI27L1 6,12E-03 0,1175 EFCAB2 1,23E-07 -0,2189 RAB4A 9,50E-04 -0,1061 TCTN3 6,14E-03 0,1193 ADGRG7 2,23E-07 -0,2592 PSMB5 1,02E-03 0,2740 TCEAL7 6,36E-03 0,1544 COMT 2,24E-07 0,2857 PCBP1 1,10E-03 0,2692 SLC25A4 6,39E-03 0,3074 AC009245.3 2,69E-07 -0,3344 RP11.64B16.2 1,15E-03 -0,1741 CMTM8 6,62E-03 -0,1925 PGD 6,71E-07 0,2393 BTN2A2 1,35E-03 0,1140 FZD7 7,11E-03 0,1098 PALLD 1,89E-06 0,2538 RFWD3 1,37E-03 0,1330 ZNF83 7,35E-03 -0,1129 GPC3 2,07E-06 0,3866 NDUFB11 1,46E-03 -0,2012 LINC00909 7,53E-03 -0,1021 SMARCA4 2,97E-06 0,2588 EIF3B 1,52E-03 0,1427 C21ORF91 7,57E-03 0,1393 NME4 4,13E-06 -0,2830 CBX1 1,56E-03 -0,2092 CEP350 7,93E-03 0,1442 PKP2 4,26E-06 0,1924 AK4 1,80E-03 0,1560 SLK 8,24E-03 0,1787 MLF1 4,69E-06 -0,3043 MRPL15 1,83E-03 0,1734 CSTB 8,38E-03 0,2675 C19ORF53 5,42E-06 0,3207 EEF1A1 1,88E-03 -0,2174 SC5D 8,78E-03 0,1420 MED15 1,26E-05 0,2428 PSMG3 1,90E-03 -0,1677 CAT 9,46E-03 -0,1288 OSBPL8 1,56E-05 0,2914 WDR34 2,01E-03 0,1276 NAA20 9,72E-03 0,1481 SMARCE1P6 1,86E-05 -0,1960 RBM12 2,10E-03 0,1040 MRPL17 9,86E-03 0,1464 WDR11 9,94E-03 0,1321

Supplementary Table 4. The 151 DEGs of Group B.

Gene Max p-val. Avg Gene Max p-val. Avg Gene Max p-val. Avg MTRNR2L1 3,71E-21 -7,73E-01 SMARCB1 1,47E-04 -1,48E-01 TCEAL7 6,36E-03 1,54E-01 RP11.692N5.2 3,69E-10 -5,49E-01 PDAP1 4,93E-03 -1,44E-01 AK4 1,80E-03 1,56E-01 NLRP2 1,91E-09 -4,70E-01 SRSF9 4,05E-03 -1,43E-01 CSNK1G3 7,96E-04 1,59E-01 MORF4L1P1 1,39E-11 -4,55E-01 HSD17B4 2,97E-03 -1,34E-01 THAP7 2,82E-08 1,64E-01 CALM2P2 1,65E-22 -4,55E-01 SEPT2 1,52E-04 -1,30E-01 MYL9 2,32E-05 1,65E-01 RP11.641D5.1 4,00E-13 -4,51E-01 CAT 9,46E-03 -1,29E-01 DPH3 2,27E-03 1,66E-01 S100A6 2,09E-17 -4,39E-01 FAM208A 7,79E-05 -1,28E-01 MYO10 4,23E-03 1,67E-01 ZNF280D 2,49E-17 -4,38E-01 STK33 4,87E-03 -1,14E-01 EIF3A 2,83E-03 1,69E-01 RP4.765C7.2 5,86E-08 -4,25E-01 ZNF83 7,35E-03 -1,13E-01 MRPL15 1,83E-03 1,73E-01 RP11.488C13.1 3,83E-04 -4,25E-01 GOLGA8B 3,36E-03 -1,11E-01 SLK 8,24E-03 1,79E-01 PTMAP5 2,02E-10 -4,20E-01 MGMT 8,83E-03 -1,11E-01 HIC2 1,57E-04 1,80E-01 TCEAL5 6,78E-14 -3,75E-01 RNPC3 5,86E-03 -1,08E-01 RTCB 2,78E-03 1,86E-01 MINOS1P3 2,08E-08 -3,67E-01 RAB4A 9,50E-04 -1,06E-01 CTSB 5,60E-04 1,87E-01 PLCB4 6,73E-03 -3,61E-01 SH3YL1 7,01E-04 -1,06E-01 RRP7A 2,19E-04 1,90E-01 HMGN1P38 3,95E-12 -3,46E-01 FBXO9 1,03E-03 -1,03E-01 PKP2 4,26E-06 1,92E-01 RP11.475C16.1 8,30E-10 -3,44E-01 LINC00909 7,53E-03 -1,02E-01 PSMD7 3,85E-03 2,00E-01 CBX3P9 1,01E-07 -3,36E-01 RBM12 2,10E-03 1,04E-01 CNTNAP2 6,80E-04 2,07E-01 AC009245.3 2,69E-07 -3,34E-01 SPRED1 8,51E-05 1,05E-01 SRA1 5,11E-05 2,12E-01 MLF1 4,69E-06 -3,04E-01 ABRACL 3,57E-03 1,05E-01 CRKL 1,44E-10 2,14E-01 DNAJC15 2,13E-05 -2,91E-01 CNN3 2,49E-04 1,07E-01 C14ORF119 3,53E-05 2,19E-01 HNRNPC 1,95E-08 -2,88E-01 AK6 4,24E-03 1,09E-01 THUMPD3 2,66E-03 2,24E-01 GOPC 9,27E-04 -2,85E-01 FZD7 7,11E-03 1,10E-01 TAGLN 3,67E-03 2,31E-01 NME4 4,13E-06 -2,83E-01 CUL3 1,58E-06 1,10E-01 TUBGCP5 3,34E-08 2,31E-01 EIF5P1 1,70E-04 -2,68E-01 SHROOM3 3,03E-03 1,11E-01 CD164 2,83E-03 2,35E-01 RALGPS2 5,42E-04 -2,64E-01 NUP62 2,75E-03 1,12E-01 PGD 6,71E-07 2,39E-01 MALAT1 8,50E-09 -2,59E-01 RNF26 2,65E-03 1,13E-01 EGLN3 5,56E-03 2,41E-01 ADGRG7 2,23E-07 -2,59E-01 BTN2A2 1,35E-03 1,14E-01 MED15 1,26E-05 2,43E-01 RP13.258O15.1 3,39E-03 -2,49E-01 IQCB1 2,93E-03 1,17E-01 ZNF880 5,11E-08 2,52E-01 PTGR1 3,38E-05 -2,38E-01 IFI27L1 6,12E-03 1,17E-01 PALLD 1,89E-06 2,54E-01 RP4.796I17.5 5,89E-03 -2,37E-01 LANCL1 4,28E-03 1,19E-01 ACTN1 2,14E-04 2,55E-01 GTF2I 7,03E-05 -2,33E-01 PTPRZ1 2,10E-03 1,19E-01 PFKP 4,80E-03 2,56E-01 FOS 2,71E-03 -2,31E-01 TCTN3 6,14E-03 1,19E-01 FAM126A 2,86E-03 2,57E-01 HNRNPCP2 5,82E-04 -2,26E-01 EXOC5 3,74E-05 1,21E-01 SMARCA4 2,97E-06 2,59E-01 MT-ND5 3,70E-13 -2,24E-01 HLA.B 1,25E-04 1,24E-01 ZNF37A 3,66E-09 2,59E-01 EFCAB2 1,23E-07 -2,19E-01 WDR34 2,01E-03 1,28E-01 NIPA2 2,62E-08 2,65E-01 EEF1A1 1,88E-03 -2,17E-01 CYCS 5,25E-04 1,31E-01 CSTB 8,38E-03 2,68E-01 PHYH 6,13E-05 -2,17E-01 WDR11 9,94E-03 1,32E-01 PCBP1 1,10E-03 2,69E-01 CBX1 1,56E-03 -2,09E-01 RFWD3 1,37E-03 1,33E-01 CRYZ 1,36E-11 2,73E-01 TTC3 2,27E-05 -2,08E-01 CCNB1IP1 3,00E-03 1,36E-01 EIF1AY 3,64E-04 2,73E-01 NSA2 4,67E-05 -2,08E-01 IWS1 7,26E-04 1,39E-01 PSMB5 1,02E-03 2,74E-01 TCF25 5,14E-11 -2,07E-01 C21ORF91 7,57E-03 1,39E-01 CD59 1,96E-08 2,76E-01 NDUFB11 1,46E-03 -2,01E-01 ZNF593 2,38E-03 1,41E-01 COMT 2,24E-07 2,86E-01 SLC7A8 2,66E-03 -2,01E-01 GNB1 3,01E-03 1,41E-01 OSBPL8 1,56E-05 2,91E-01 RSRP1 2,91E-06 -1,98E-01 YPEL1 2,24E-03 1,42E-01 SNHG8 2,44E-03 2,94E-01 AZI2 4,11E-04 -1,97E-01 KMT2A 5,37E-03 1,42E-01 SNAP29 2,12E-04 2,99E-01 SMARCE1P6 1,86E-05 -1,96E-01 SC5D 8,78E-03 1,42E-01 C6ORF48 5,37E-10 3,01E-01 CMTM8 6,62E-03 -1,93E-01 EIF3B 1,52E-03 1,43E-01 CYFIP1 1,47E-10 3,02E-01 THAP9.AS1 4,34E-04 -1,85E-01 FRA10AC1 2,39E-04 1,43E-01 MYL6 1,24E-19 3,07E-01 TMEM38B 3,98E-03 -1,82E-01 IPO5 6,49E-03 1,43E-01 SLC25A4 6,39E-03 3,07E-01 RP11.64B16.2 1,15E-03 -1,74E-01 ATG101 9,22E-04 1,44E-01 C19ORF53 5,42E-06 3,21E-01 CHCHD2 5,40E-03 -1,74E-01 CEP350 7,93E-03 1,44E-01 GPC3 2,07E-06 3,87E-01 RP11.676M6.1 9,09E-05 -1,73E-01 WBSCR22 7,45E-04 1,44E-01 HSPA8 4,07E-10 4,70E-01 HNRNPCP1 2,93E-03 -1,69E-01 MRPL17 9,86E-03 1,46E-01 TYW3 1,73E-14 4,75E-01 PSMG3 1,90E-03 -1,68E-01 NAA20 9,72E-03 1,48E-01 PGK1 8,78E-31 5,78E-01 RP11.288E14.2 4,65E-05 -1,66E-01 IPO7 3,20E-05 1,50E-01 CCDC144NL.AS1 2,27E-09 5,87E-01 NONO 4,82E-03 -1,61E-01 CENPW 2,16E-03 1,50E-01 SNHG5 2,84E-40 1,22E+00 TRA2A 8,89E-04 -1,57E-01 RRAGD 4,30E-03 1,52E-01 ZNF75A 6,89E-05 -1,56E-01 IPO9 2,84E-03 1,53E-01

Supplementary Table 5. The 172 DEGs of Group C.

gene max_pval Avg gene max_pval Avg gene max_pval Avg gene max_pval Avg gene max_pval Avg MTRNR2L1 3,71E-21 -6,33E-01 PTMAP5 2,02E-10 -1,85E-01 RP11.676M6.1 9,09E-05 -1,16E-01 CCT8 6,49E-03 1,40E-01 FAM126A 2,86E-03 2,33E-01 S100A6 8,08E-18 -5,19E-01 ARGLU1 2,98E-04 -1,84E-01 CHD2 1,63E-03 -1,13E-01 TCTN3 5,20E-03 1,40E-01 TUBGCP5 3,34E-08 2,33E-01 ZNF280D 2,49E-17 -5,01E-01 IRX3 5,15E-05 -1,73E-01 SFSWAP 1,89E-03 -1,11E-01 IQCB1 6,27E-04 1,41E-01 PGD 6,71E-07 2,35E-01 PLCB4 6,73E-03 -4,84E-01 AZI2 4,11E-04 -1,72E-01 TTC6 4,37E-03 -1,11E-01 PHB 3,06E-03 1,43E-01 SMARCA4 2,97E-06 2,37E-01 VWA5A 9,85E-06 -4,45E-01 GOLGA8B 3,36E-03 -1,71E-01 RP11.64B16.2 1,15E-03 -1,07E-01 UQCRFS1 2,72E-03 1,44E-01 CTSB 2,31E-06 2,38E-01 TCEAL5 6,78E-14 -4,07E-01 RSRC2 4,62E-10 -1,67E-01 HNRNPCP2 5,82E-04 -1,06E-01 LANCL1 1,78E-03 1,45E-01 NIPA2 2,62E-08 2,41E-01 RP11.692N5.2 3,69E-10 -4,07E-01 MAGI2.AS3 5,03E-04 -1,67E-01 SOD1 1,95E-04 -1,05E-01 CAMK2D 7,48E-04 1,46E-01 MED15 1,26E-05 2,41E-01 GOPC 5,87E-20 -3,75E-01 CSRP1 2,14E-06 -1,65E-01 RP4.796I17.5 5,89E-03 -1,03E-01 POU6F2 1,73E-03 1,54E-01 CD164 2,83E-03 2,43E-01 NLRP2 1,91E-09 -3,62E-01 ZNF75A 8,42E-07 -1,63E-01 TBRG1 9,37E-03 -1,03E-01 ABLIM1 1,31E-03 1,54E-01 PEG10 3,82E-04 2,47E-01 RALGPS2 5,42E-04 -3,55E-01 ARMC2 4,94E-04 -1,62E-01 SMARCB1 1,47E-04 -1,02E-01 SC5D 8,78E-03 1,56E-01 ZNF880 5,11E-08 2,56E-01 MLF1 1,34E-17 -3,52E-01 FNBP1L 1,26E-03 -1,59E-01 TRMT1L 1,29E-03 -1,00E-01 GHITM 2,46E-05 1,56E-01 LMAN1 7,77E-08 2,57E-01 CALM2P2 1,65E-22 -3,43E-01 CAT 8,06E-03 -1,57E-01 SNX9 9,90E-03 1,01E-01 LSM3 6,57E-03 1,56E-01 ZNF37A 3,66E-09 2,60E-01 BBS2 2,76E-15 -3,38E-01 NSA2 4,67E-05 -1,56E-01 DAB1 4,30E-05 1,02E-01 WDR11 9,94E-03 1,57E-01 ACTN1 3,91E-10 2,64E-01 MORF4L1P1 1,39E-11 -3,29E-01 MGMT 8,83E-03 -1,56E-01 FTH1 3,41E-04 1,03E-01 RPN2 3,88E-03 1,59E-01 CYCS 5,25E-04 2,66E-01 FOS 6,99E-13 -3,23E-01 SMARCE1P6 1,86E-05 -1,56E-01 NAA20 9,72E-03 1,04E-01 SRA1 5,11E-05 1,59E-01 OSBPL8 1,55E-08 2,68E-01 RSRP1 5,42E-13 -3,08E-01 MT.CYB 1,51E-08 -1,55E-01 CEP350 7,93E-03 1,06E-01 GOLT1B 6,52E-04 1,59E-01 MYL12A 1,52E-12 2,70E-01 PHYH 6,13E-05 -3,04E-01 MT.CO3 1,28E-08 -1,55E-01 CTC.444N24.7 9,77E-03 1,10E-01 C21ORF91 4,03E-03 1,60E-01 GABPB1.AS1 2,90E-04 2,89E-01 NAP1L5 4,87E-12 -2,82E-01 KIF27 6,39E-03 -1,55E-01 FZD7 7,11E-03 1,10E-01 IARS 4,71E-03 1,60E-01 HSPA1A 3,35E-03 2,92E-01 MT.ND5 1,36E-17 -2,82E-01 CECR1 1,54E-07 -1,53E-01 AK6 4,24E-03 1,10E-01 RRP7A 2,19E-04 1,60E-01 C6ORF48 4,00E-20 2,93E-01 ZNF528.AS1 2,88E-13 -2,77E-01 SLC7A8 2,66E-03 -1,52E-01 NUDT21 1,83E-03 1,10E-01 CNN3 2,49E-04 1,61E-01 PCBP1 1,10E-03 2,97E-01 RP4.765C7.2 5,86E-08 -2,77E-01 LUC7L3 4,10E-04 -1,52E-01 FGFR1 4,69E-03 1,12E-01 CHAC1 8,92E-10 1,64E-01 CD59 1,96E-08 2,99E-01 MALAT1 8,50E-09 -2,67E-01 PSMA4 1,86E-03 -1,52E-01 IFI27L1 6,12E-03 1,12E-01 RRAGD 4,30E-03 1,65E-01 C19ORF53 5,42E-06 3,00E-01 CROT 6,31E-05 -2,67E-01 RP11.288E14.2 4,65E-05 -1,51E-01 CCNB1IP1 3,00E-03 1,13E-01 XPOT 1,54E-03 1,66E-01 SNHG8 5,67E-09 3,01E-01 ADGRG7 2,23E-07 -2,65E-01 ANKRD36 2,43E-03 -1,49E-01 UBE2D2 1,20E-03 1,13E-01 CCT4 5,01E-07 1,66E-01 CSTB 1,31E-03 3,04E-01 CALR 1,08E-08 -2,64E-01 TTC12 4,30E-05 -1,48E-01 ABCA5 5,45E-04 1,13E-01 THUMPD3 2,66E-03 1,67E-01 PALLD 4,80E-08 3,06E-01 PTGR1 1,97E-08 -2,57E-01 AKAP8L 8,47E-03 -1,48E-01 TET3 2,94E-03 1,15E-01 SPRED1 8,51E-05 1,69E-01 MYL6 1,24E-19 3,07E-01 CMTM8 3,02E-08 -2,56E-01 ZCCHC11 3,46E-05 -1,48E-01 HLA.B 1,25E-04 1,15E-01 YPEL1 2,24E-03 1,71E-01 CRYZ 1,31E-11 3,10E-01 ZNF528 8,01E-10 -2,55E-01 RNPC3 5,86E-03 -1,46E-01 WBSCR22 7,45E-04 1,15E-01 NDUFB6 1,30E-03 1,73E-01 SNAP29 2,12E-04 3,12E-01 TTC3 4,16E-08 -2,53E-01 SEPT02 1,52E-04 -1,45E-01 SREK1IP1 4,88E-03 1,16E-01 CSRP2 4,69E-03 1,75E-01 CYFIP1 1,47E-10 3,13E-01 AC009245.3 2,69E-07 -2,52E-01 FBXO9 1,03E-03 -1,43E-01 CSNK1G3 7,96E-04 1,17E-01 CUL3 1,58E-06 1,75E-01 EGLN3 5,56E-03 3,20E-01 NCALD 1,74E-06 -2,50E-01 NDUFB11 1,46E-03 -1,42E-01 GXYLT1 4,33E-03 1,17E-01 PTPRZ1 2,10E-03 1,77E-01 RANBP1 1,73E-16 3,42E-01 DNAJC15 2,13E-05 -2,50E-01 FGD4 7,85E-03 -1,42E-01 ATG101 2,79E-04 1,18E-01 TCEAL7 5,01E-11 1,77E-01 TAGLN 3,67E-03 3,47E-01 SHH 2,05E-04 -2,46E-01 NKD1 3,76E-03 -1,40E-01 NR1D2 7,71E-05 1,18E-01 PSMB5 1,02E-03 1,77E-01 COMT 1,25E-11 3,55E-01 MINOS1P3 2,08E-08 -2,42E-01 MRPS21 3,39E-03 -1,39E-01 EIF3A 2,83E-03 1,20E-01 EMP2 1,06E-08 1,81E-01 SLC25A4 1,61E-13 3,66E-01 EFCAB2 1,23E-07 -2,39E-01 DAAM1 9,04E-03 -1,39E-01 RAB9A 6,09E-03 1,20E-01 ABRACL 3,57E-03 1,85E-01 TYW3 1,73E-14 3,92E-01 RP11.488C13.1 3,83E-04 -2,37E-01 CCNL1 5,81E-05 -1,37E-01 RPA3 4,76E-03 1,22E-01 PSMD7 3,85E-03 1,85E-01 EPHA4 1,45E-06 4,02E-01 RP11.475C16.1 8,30E-10 -2,34E-01 STK33 4,87E-03 -1,37E-01 SHROOM3 3,03E-03 1,22E-01 TIMELESS 2,26E-05 1,86E-01 RP11.122G18.7 1,54E-05 4,14E-01 NME4 4,13E-06 -2,30E-01 NKX6.1 3,63E-04 -1,36E-01 USP49 3,50E-03 1,22E-01 ANXA5 2,16E-09 1,90E-01 HSPA8 4,07E-10 4,44E-01 GPATCH8 6,37E-03 -2,24E-01 TRA2A 8,89E-04 -1,35E-01 MRPL17 9,86E-03 1,24E-01 HNRNPA3 5,41E-06 1,90E-01 PCSK1 3,39E-05 4,45E-01 TMEM132C 8,05E-07 -2,19E-01 MAP3K12 3,47E-04 -1,35E-01 EIF3B 1,52E-03 1,25E-01 RP11.298C3.2 2,98E-06 1,91E-01 LGI1 2,79E-09 5,00E-01 TSPYL5 2,51E-11 -2,16E-01 FAM208A 7,79E-05 -1,34E-01 MRPL15 1,83E-03 1,26E-01 HSPA1B 1,21E-04 1,91E-01 PGK1 8,78E-31 5,12E-01 TCF25 5,59E-13 -2,16E-01 NSMCE1 1,87E-05 -1,33E-01 RTCB 5,00E-04 1,26E-01 C14ORF119 3,53E-05 1,92E-01 GPC3 2,49E-17 5,13E-01 RP11.641D5.1 4,00E-13 -2,14E-01 ZNF83 1,99E-04 -1,33E-01 MYO10 4,23E-03 1,26E-01 PKP2 4,26E-06 1,92E-01 CCDC144NL.AS1 2,27E-09 7,13E-01 EEF1A1 1,88E-03 -2,12E-01 NONO 4,82E-03 -1,33E-01 RBM12 1,06E-03 1,29E-01 IPO5 6,10E-05 1,93E-01 SNHG5 2,84E-40 1,04E+00 TMEM38B 3,98E-03 -2,10E-01 NAALAD2 1,08E-03 -1,31E-01 CNTNAP2 6,80E-04 1,29E-01 IPO7 3,09E-07 1,95E-01 DLK1 8,21E-25 1,17E+00 PRTG 2,00E-11 -2,08E-01 C6ORF118 9,31E-04 -1,30E-01 IPO9 2,84E-03 1,31E-01 NME1 2,74E-04 1,97E-01 PDIA6 4,07E-06 -2,08E-01 CHCHD2 5,40E-03 -1,29E-01 MCL1 4,96E-03 1,32E-01 EXOC5 3,08E-09 1,98E-01 THAP9.AS1 4,34E-04 -2,07E-01 RP11.76E16.2 8,54E-04 -1,29E-01 NUP62 2,75E-03 1,32E-01 SLK 8,24E-03 1,98E-01 KIAA1211 8,03E-03 -2,07E-01 PSMD5.AS1 5,92E-03 -1,29E-01 SUGT1 4,58E-03 1,33E-01 GNB1 2,04E-03 2,08E-01 RBM39 1,82E-03 -2,06E-01 PPP1R21 3,23E-03 -1,26E-01 WDR34 2,01E-03 1,33E-01 FRA10AC1 2,39E-04 2,09E-01 Genes identified only at four HNRNPC 1,95E-08 -2,05E-01 PHTF1 6,29E-03 -1,26E-01 ZNF593 2,38E-03 1,34E-01 MYL9 2,32E-05 2,10E-01 timepoints iPSCs, D6, D15, D21 CBX3P9 1,01E-07 -2,04E-01 SH3YL1 7,01E-04 -1,25E-01 BTN2A2 1,35E-03 1,34E-01 PLIN2 2,15E-11 2,11E-01 RP13.258O15.1 3,39E-03 -2,49E-01 GTF2I 7,03E-05 -2,03E-01 SPATA7 1,74E-03 -1,25E-01 ANKRD11 1,98E-03 1,35E-01 ENAH 5,29E-09 2,13E-01 HNRNPCP1 2,93E-03 -1,69E-01 CLHC1 1,97E-03 -2,02E-01 FAM184A 2,20E-03 -1,24E-01 ELOVL5 1,14E-03 1,37E-01 HIC2 2,23E-06 2,13E-01 SRSF9 4,05E-03 -1,43E-01 HMGN1P38 3,95E-12 -1,98E-01 RAB4A 9,50E-04 -1,22E-01 NDUFA12 1,14E-04 1,37E-01 PFKP 4,80E-03 2,13E-01 HSD17B4 2,97E-03 -1,34E-01 ZSCAN30 2,36E-03 -1,95E-01 LINC00909 1,52E-03 -1,20E-01 THAP7 2,82E-08 1,37E-01 BRCA2 9,99E-07 2,15E-01 RNF26 2,65E-03 1,13E-01 EIF5P1 1,70E-04 -1,94E-01 VPS39 5,83E-03 -1,19E-01 RFWD3 1,13E-05 1,39E-01 EIF1AY 3,64E-04 2,16E-01 KMT2A 5,37E-03 1,42E-01 LRIG3 6,90E-06 -1,90E-01 PDAP1 4,93E-03 -1,18E-01 GNAS 2,74E-03 1,39E-01 CENPW 5,06E-10 2,18E-01 CBX1 1,56E-03 -1,86E-01 ANKRD26 8,88E-04 -1,18E-01 PSMC3IP 8,07E-03 1,39E-01 DPH3 1,47E-04 2,18E-01 PSMG3 1,90E-03 -1,86E-01 RRAGB 9,27E-04 -1,16E-01 AK4 1,80E-03 1,39E-01 CRKL 1,44E-10 2,24E-01

Supplementary Table 6. The 285 DEGs of group D. In black: genes of group D only. In blue: genes of group D that are also part of group C. In green: genes of group C that were not found in Group D. Hence, even though group D consists of 285 genes, the total number of genes used in the network analysis was 291.

Source Target Source Target Source Target Source Target Source Target Source Target Source Target Source Target Source Target ABCA5 C19ORF53 EIF3A MALAT1 HSPA1A IARS MYL12A MYL9 PCSK1 PEG10 RALGPS2 SLK SHH ZCCHC11 TTC3 TUBGCP5 TTC6 RPA3 AK4 CHCHD2 EIF3A FAM126A HSPA1A IPO7 MYL12A MYO10 PCSK1 PSMA4 RALGPS2 AK6 SHH AK6 TTC3 TYW3 TTC6 FGD4 AK4 CUL3 EIF3A FGD4 HSPA1A IPO9 MYL12A NCALD PCSK1 PTPRZ1 RANBP1 RBM39 SHROOM3 SLC7A8 TTC3 UQCRFS1 TTC6 NAP1L5 ANKRD11 ANKRD26 EIF3A TCEAL7 HSPA1B KMT2A MYL12A NDUFA12 PCSK1 SMARCA4 RANBP1 RNPC3 SHROOM3 SLK TTC3 USP49 TTC6 ZNF528 ANKRD26 YPEL1 EIF3B MALAT1 HSPA8 IARS MYL12A AK6 PCSK1 MTRNR2L1 RANBP1 RPN2 SLC25A4 SLK TTC3 VWA5A YPEL1 RPA3 ANXA5 ATG101 EIF3B TCEAL7 HSPA8 IPO5 MYL6 MYL9 PDAP1 PDIA6 RANBP1 RRAGD SLC25A4 SMARCA4 TTC3 ZCCHC11 YPEL1 FGD4 ANXA5 FNBP1L ELOVL5 GPC3 HSPA8 KIF27 MYL6 MYO10 PDAP1 PEG10 RANBP1 RRP7A SLC25A4 SPRED1 TTC3 FGD4 YPEL1 FNBP1L ANXA5 AK6 ELOVL5 HNRNPA3 HSPA8 LSM3 MYL6 NCALD PDIA6 PEG10 RANBP1 RSRC2 SLC25A4 SRA1 TTC3 ZNF528 YPEL1 NAP1L5 ARGLU1 AZI2 ELOVL5 HSPA8 IARS IPO5 MYL6 NME1 PDIA6 PGD RANBP1 RTCB SLC25A4 SUGT1 TTC3 AK6 YPEL1 MTRNR2L1 ARGLU1 CAMK2D EMP2 AK6 IARS LGI1 MYL9 MYO10 PDIA6 PGK1 RANBP1 SLC7A8 SLC7A8 SLK TUBGCP5 TYW3 YPEL1 CENPW ARGLU1 CCNL1 ENAH MALAT1 IARS MTRNR2L1 MYL9 NAALAD2 PDIA6 PHTF1 RANBP1 SLK SLC7A8 SOD1 TUBGCP5 USP49 YPEL1 ZNF528 ATG101 C19ORF53 ENAH EPHA4 IPO5 IPO7 MYL9 NCALD PDIA6 PKP2 RANBP1 SMARCA4 SLK SMARCA4 TUBGCP5 VWA5A YPEL1 TCEAL7 ATG101 ZNF528 ENAH EXOC5 IPO5 KIF27 MYL9 NDUFA12 PDIA6 PLIN2 RANBP1 TIMELESS SLK SOD1 TYW3 UQCRFS1 RPA3 ADGRG7 AZI2 CAMK2D ENAH FAM126A IPO5 LGI1 MYL9 NONO PDIA6 PSMA4 RANBP1 AK6 SLK SPATA7 TYW3 VWA5A RPA3 NLRP2 BRCA2 CSRP2 ENAH GPC3 IPO5 LSM3 MYL9 OSBPL8 PDIA6 RALGPS2 RBM12 SH3YL1 SLK TTC3 TYW3 WBSCR22 RPA3 PSMG3 C19ORF53 CALR MALAT1 EPHA4 IPO7 IPO9 MYL9 PALLD PDIA6 GXYLT1 RBM12 SMARCB1 SLK ZNF280D TYW3 TTC6 RPA3 FGD4 C19ORF53 CCT4 MALAT1 EXOC5 IPO7 KIF27 MYO10 NAALAD2 PEG10 PGD RBM12 ZCCHC11 SLK TCEAL7 TYW3 RPA3 RPA3 EIF1AY C21ORF91 CALR MALAT1 FAM126A IPO7 KMT2A MYO10 NCALD PEG10 PHB RBM12 YPEL1 SMARCA4 SPRED1 TYW3 CENPW RPA3 CENPW CALR CAMK2D MALAT1 HNRNPC IPO7 LGI1 MYO10 NDUFA12 PEG10 PHTF1 RBM12 RPA3 SMARCA4 SRA1 UBE2D2 UQCRFS1 RPA3 AK6 CALR CCNB1IP1 MALAT1 HSPA8 IPO7 LMAN1 MYO10 OSBPL8 PEG10 RALGPS2 RBM12 FGD4 SMARCA4 SUGT1 UBE2D2 VWA5A ADGRG7 NLRP2 CAMK2D CCNL1 MALAT1 KIF27 IPO7 LSM3 MYO10 ZCCHC11 PEG10 YPEL1 RBM12 FNBP1L SMARCB1 XPOT UBE2D2 WBSCR22 ADGRG7 FGD4 CAMK2D ZCCHC11 MALAT1 MYO10 IPO7 CENPW MYO10 AK6 PFKP PGD RBM39 RRAGD SMARCB1 FGD4 UQCRFS1 USP49 ADGRG7 NAP1L5 CAMK2D TTC6 EPHA4 EXOC5 IPO9 LSM3 NAALAD2 NCALD PGD PGK1 RBM39 RSRC2 SOD1 SPRED1 UQCRFS1 VWA5A ADGRG7 ZNF528 CBX1 ZCCHC11 EPHA4 FAM126A IQCB1 NDUFB11 NAALAD2 NDUFB6 PGD PHB RBM39 RSRP1 SOD1 SRA1 UQCRFS1 WBSCR22 TBRG1 ZNF75A CCNB1IP1 CCT4 EPHA4 GPC3 IRX3 KIF27 NAALAD2 NKD1 PGD PHTF1 RBM39 VWA5A SOD1 SUGT1 USP49 VWA5A NLRP2 PSMG3 CCNB1IP1 CSNK1G3 EPHA4 PLIN2 IRX3 LGI1 NAALAD2 NME1 PGD MTRNR2L1 RBM39 ZCCHC11 SOD1 TAGLN USP49 WBSCR22 NLRP2 FGD4 CCNB1IP1 FAM126A EPHA4 MTRNR2L1 IRX3 LMAN1 NAALAD2 ZCCHC11 PGK1 PHB RFWD3 SPRED1 SOD1 WBSCR22 USP49 WDR11 NLRP2 FNBP1L CCNL1 CCT8 EXOC5 FAM126A KIF27 LGI1 NCALD NDUFA12 PGK1 PHTF1 RFWD3 SUGT1 SOD1 ZNF528 USP49 ZCCHC11 NLRP2 NAP1L5 CCNL1 CEP350 EXOC5 FAM208A KIF27 LMAN1 NCALD NDUFB6 PGK1 PKP2 RFWD3 TAGLN SPATA7 SPRED1 USP49 C6ORF118 NLRP2 TCEAL7 CCNL1 CHD2 EXOC5 FGFR1 KIF27 LRIG3 NCALD NKD1 PGK1 PLIN2 RFWD3 TCEAL5 SPATA7 SRA1 USP49 RPA3 PSMG3 FGD4 CCNL1 PLIN2 EXOC5 FZD7 KIF27 LSM3 NCALD NME1 PGK1 TCEAL7 RFWD3 TTC3 SPATA7 SUGT1 USP49 FGD4 PSMG3 EIF1AY CCT4 CCT8 FAM126A FAM208A KIF27 RBM12 NCALD PCSK1 PHB PHTF1 RFWD3 TUBGCP5 SPATA7 TAGLN USP49 MTRNR2L1 PSMG3 MTRNR2L1 CCT4 MTRNR2L1 FAM126A FGFR1 KMT2A LGI1 NCALD PDIA6 PHB PHYH RNPC3 SPATA7 SPATA7 TCEAL5 VPS39 YPEL1 PSMG3 CENPW CCT4 TCEAL7 FAM208A FGFR1 KMT2A LMAN1 NCALD RALGPS2 PHB PKP2 RNPC3 TAGLN SPATA7 TCF25 VWA5A WBSCR22 PSMG3 ZNF528 CCT8 CD164 FAM208A FOS KMT2A PCSK1 NCALD VWA5A PHB PLCB4 RNPC3 TCF25 SPATA7 TRA2A VWA5A WDR11 FGD4 RNF26 CCT8 CNTNAP2 FAM208A GPATCH8 KMT2A FNBP1L NCALD ZNF593 PHB PSMA4 RNPC3 TMEM38B SPATA7 TTC3 VWA5A ZCCHC11 FGD4 FNBP1L CD164 CEP350 FAM208A GPC3 LANCL1 LUC7L3 NDUFA12 NDUFB6 PHB PSMB5 RPN2 RRAGB SPRED1 SRA1 WBSCR22 WDR11 FGD4 NAP1L5 CD164 CNTNAP2 FAM208A HSPA8 LANCL1 MCL1 NDUFA12 NIPA2 PHTF1 PHYH RPN2 RRAGD SPRED1 SUGT1 WBSCR22 ZCCHC11 FGD4 CENPW CD59 THAP7 FAM208A KIF27 LANCL1 MYO10 NDUFA12 NME1 PHTF1 PLCB4 RPN2 RRP7A SPRED1 TAGLN WBSCR22 ZNF593 EIF1AY MTRNR2L1 CECR1 NKX6.1 FAM208A CMTM8 LGI1 LMAN1 NDUFA12 FGD4 PHYH PKP2 RPN2 RSRC2 SPRED1 TRA2A WBSCR22 C6ORF118 EIF1AY CENPW CEP350 CHD2 FAM208A MTRNR2L1 LGI1 MYO10 NDUFB11 NSA2 PHYH PLCB4 RPN2 RSRP1 SPRED1 TTC3 WBSCR22 RPA3 FNBP1L NAP1L5 CHD2 CNN3 FBXO9 LUC7L3 LGI1 NCALD NDUFB6 NIPA2 PHYH TSPYL5 RPN2 RTCB SPRED1 TUBGCP5 WBSCR22 ADGRG7 FNBP1L MTRNR2L1 CHD2 CNTNAP2 FBXO9 MT.CO3 LMAN1 LRIG3 NDUFB6 NME1 PHYH AK6 RPN2 SLC25A4 SRA1 SUGT1 WBSCR22 NLRP2 FNBP1L CENPW CHD2 CROT FGFR1 FTH1 LMAN1 LSM3 NIPA2 NKD1 PKP2 PLCB4 RPN2 SLC7A8 SRA1 TCEAL7 WBSCR22 FNBP1L FNBP1L ZNF528 CNN3 CNTNAP2 FGFR1 FZD7 LMAN1 LUC7L3 NIPA2 NME1 PKP2 PLIN2 RPN2 ZNF528 SRSF9 RPA3 WBSCR22 AK6 FNBP1L AK6 CNN3 CROT FGFR1 GHITM LMAN1 MRPL15 NIPA2 NUDT21 PKP2 PSMA4 RPN2 TCEAL7 SRSF9 NLRP2 WBSCR22 WDR34 FNBP1L TCEAL7 CNN3 MALAT1 FOS FTH1 LMAN1 MT.ND5 NIPA2 PCBP1 PKP2 PSMB5 RRAGB RSRC2 SRSF9 PSMG3 WDR11 ZCCHC11 NAP1L5 CENPW CNN3 RTCB FOS FZD7 LMAN1 MYO10 NKD1 NME1 PLCB4 PLIN2 RRAGB RSRP1 SRSF9 FNBP1L XPOT YPEL1 NAP1L5 ZNF528 CNTNAP2 CSTB FOS GHITM LMAN1 NUDT21 NKD1 NONO PLCB4 PSMA4 RRAGD RSRC2 SRSF9 MTRNR2L1 XPOT FNBP1L ZNF75A MTRNR2L1 COMT HIC2 FOS NCALD LMAN1 ZNF37A NKD1 OSBPL8 PLCB4 PSMB5 RRAGD SHROOM3 SUGT1 TAGLN XPOT MTRNR2L1 ZNF75A ZNF528 COMT NSA2 FOS AK6 LMAN1 TTC6 NKD1 PDAP1 PLCB4 RALGPS2 RRP7A RSRP1 SUGT1 TCEAL5 XPOT CENPW MTRNR2L1 CENPW CRKL EIF3B FRA10AC1 MYL6 LMAN1 CENPW NKD1 PDIA6 PLCB4 MTRNR2L1 RRP7A RTCB SUGT1 THUMPD3 XPOT AK6 MTRNR2L1 ZNF528 CROT CSTB FRA10AC1 MYO10 LRIG3 LSM3 NKD1 PHYH PLCB4 AK6 RRP7A SLC7A8 SUGT1 TRA2A ZCCHC11 ZNF83 MTRNR2L1 AK6 CROT CTSB FTH1 FZD7 LRIG3 MCL1 NKX6.1 PALLD PLCB4 TCEAL7 RRP7A SOD1 SUGT1 TSPYL5 ZCCHC11 ZSCAN30 MTRNR2L1 TCEAL7 CROT CUL3 FTH1 YPEL1 LRIG3 MRPS21 NKX6.1 SHH PLIN2 PSMB5 RSRC2 RSRP1 SUGT1 TTC3 ZCCHC11 C6ORF118 CENPW ZNF528 CROT ZNF528 FZD7 GHITM LRIG3 MYO10 NKX6.1 SHROOM3 PLIN2 PTPRZ1 RSRC2 RTCB SUGT1 TYW3 ZCCHC11 BBS2 CENPW AK6 CRYZ CYCS FZD7 GPC3 LRIG3 MTRNR2L1 NKX6.1 SLK PLIN2 RALGPS2 RSRC2 S100A6 SUGT1 AK6 ZCCHC11 ZNF280D CENPW WDR34 CSNK1G3 CUL3 FZD7 GTF2I LSM3 LUC7L3 NME1 NME4 PLIN2 RANBP1 RSRC2 SLC7A8 TAGLN THAP7 ZCCHC11 TTC6 ZNF528 AK6 CSNK1G3 DPH3 FZD7 HNRNPC LSM3 MRPL15 NME1 NONO PLIN2 RBM39 RSRC2 SOD1 TAGLN THUMPD3 ZCCHC11 FGD4 ZNF528 TCEAL7 CSRP2 CSTB FZD7 HSPA8 LSM3 MRPS21 NME1 NUDT21 PLIN2 RPN2 RSRP1 S100A6 TAGLN TRA2A ZCCHC11 AK6 AK6 TCEAL7 CSRP2 CYCS GHITM GTF2I LSM3 MYO10 NME1 OSBPL8 PLIN2 RRAGD RSRP1 SHH TAGLN TTC3 ZNF593 BBS2 CSRP2 TCTN3 GHITM HNRNPC LSM3 OSBPL8 NME1 PALLD PLIN2 RSRP1 RSRP1 SHROOM3 TAGLN TUBGCP5 ZNF593 CLHC1 CSTB CTSB GHITM HSPA8 LSM3 YPEL1 NME1 PCSK1 PLIN2 RTCB RSRP1 SLK TAGLN AK6 ZNF593 CMTM8 CSTB CYCS GHITM AK6 LSM3 AK6 NME1 AK6 PLIN2 SHH RSRP1 TCEAL7 TCEAL5 TCF25 ZNF593 ZNF280D CTSB CYCS GNAS NSA2 LUC7L3 MRPL15 NME4 NONO PLIN2 SLC25A4 RSRP1 GXYLT1 TCEAL5 TMEM38B ZNF593 TTC6 CTSB MALAT1 GNB1 NR1D2 LUC7L3 MRPS21 NME4 NUDT21 PLIN2 SLK RTCB SC5D TCEAL5 TRA2A ZNF593 RPA3 CTSB AK6 GOPC KIF27 LUC7L3 MT.CO3 NME4 ZNF528 PLIN2 SOD1 RTCB SFSWAP TCEAL5 NLRP2 ZNF83 ZSCAN30 CYCS DAAM1 GOPC KMT2A LUC7L3 MT.ND5 NONO NR1D2 PLIN2 SPRED1 RTCB SLC25A4 TCF25 TRA2A ZNF83 YPEL1 CYCS DLK1 GOPC LRIG3 LUC7L3 MYO10 NONO NUDT21 PLIN2 FGD4 RTCB SLC7A8 TCF25 TSPYL5 ZNF880 CENPW CYCS EGLN3 GOPC LSM3 MAP3K12 MRPS21 NONO OSBPL8 POU6F2 RFWD3 RTCB SOD1 TCF25 TTC3 ZSCAN30 C6ORF118 CYCS EIF3A GOPC LUC7L3 MAP3K12 MT.CO3 NONO PALLD POU6F2 SPATA7 RTCB SUGT1 TCF25 TYW3 ZSCAN30 BBS2 CYCS XPOT GOPC NCALD MAP3K12 MT.ND5 NR1D2 OSBPL8 POU6F2 TAGLN RTCB FNBP1L TCF25 ZNF528 ZSCAN30 CMTM8 CYFIP1 DPH3 GOPC PDIA6 MCL1 MYL12A NSA2 NUDT21 POU6F2 TMEM38B S100A6 SLK TCTN3 FGD4 C6ORF118 BBS2 CYFIP1 EIF3B GPATCH8 HNRNPA3 MCL1 MYL6 NSA2 NUP62 PSMA4 PSMB5 S100A6 SOD1 TCTN3 FNBP1L C6ORF118 TTC6 CYFIP1 EMP2 GPATCH8 HSPA1A MCL1 PLIN2 NSA2 OSBPL8 PSMA4 PTPRZ1 S100A6 SPATA7 TCTN3 MTRNR2L1 C6ORF118 YPEL1 CYFIP1 ENAH GPATCH8 HSPA8 MED15 SRSF9 NSA2 PCBP1 PSMA4 S100A6 S100A6 SPRED1 THAP7 THUMPD3 C6ORF118 ZNF528 CYFIP1 MALAT1 GPATCH8 IPO5 MLF1 MYL9 NUDT21 NUP62 PSMB5 PSMD7 S100A6 SRA1 THAP7 TRA2A BBS2 CLHC1 DAAM1 EGLN3 GPATCH8 KIF27 MLF1 MYO10 NUDT21 OSBPL8 PSMB5 PTPRZ1 S100A6 SUGT1 THUMPD3 TRA2A BBS2 CMTM8 DAAM1 MALAT1 GPATCH8 KMT2A MLF1 NAALAD2 NUDT21 PALLD PSMB5 RALGPS2 S100A6 TAGLN THUMPD3 TSPYL5 BBS2 ZNF280D DLK1 EEF1A1 GPC3 GTF2I MRPL15 MRPL17 NUDT21 PCBP1 PSMB5 RANBP1 S100A6 TCEAL5 THUMPD3 TTC3 BBS2 TTC6 DLK1 EGLN3 GPC3 HNRNPC MRPL17 MRPS21 NUP62 OSBPL8 PSMC3IP PTPRZ1 S100A6 TTC3 THUMPD3 TUBGCP5 CLHC1 CMTM8 DLK1 EIF3A GPC3 HSPA8 MRPL17 MT.CO3 NUP62 PCBP1 PSMC3IP RALGPS2 S100A6 AK6 THUMPD3 TYW3 CLHC1 ZNF280D DLK1 FZD7 GPC3 IPO5 MRPL17 MYO10 NUP62 PCSK1 PSMC3IP RANBP1 SC5D SFSWAP THUMPD3 UBE2D2 CLHC1 TTC6 DLK1 C6ORF118 GPC3 KIF27 MRPL17 TCEAL7 OSBPL8 PALLD PSMD7 PTPRZ1 SC5D SLC25A4 THUMPD3 RPA3 CLHC1 FGD4 DNAJC15 EPHA4 GPC3 LGI1 MRPS21 MT.CO3 OSBPL8 PCBP1 PSMD7 RALGPS2 SC5D SMARCA4 THUMPD3 ZNF528 CMTM8 ZNF280D DNAJC15 FGFR1 GPC3 NCALD MRPS21 MT.CYB OSBPL8 RBM12 PSMD7 RPN2 SC5D SOD1 TIMELESS TUBGCP5 CMTM8 TTC6 DPH3 EEF1A1 GTF2I HNRNPC MRPS21 AK6 OSBPL8 TTC3 PTPRZ1 RALGPS2 SC5D SRA1 TIMELESS TYW3 CMTM8 FGD4 DPH3 EIF3A GTF2I HSPA8 MT.CO3 MT.CYB PALLD PCBP1 PTPRZ1 RANBP1 SFSWAP SHH TIMELESS UBE2D2 CMTM8 ZNF528 EEF1A1 EGLN3 HIC2 NUP62 MT.CO3 MYO10 PALLD PCSK1 PTPRZ1 RBM39 SFSWAP SLC25A4 TIMELESS UQCRFS1 STK33 YPEL1 EEF1A1 EIF3A HLA.B PKP2 MT.CO3 FNBP1L PALLD PDAP1 PTPRZ1 AK6 SFSWAP SLC7A8 TIMELESS VWA5A STK33 FNBP1L EEF1A1 AK6 HNRNPA3 HSPA8 MT.CO3 AK6 PALLD PDIA6 RAB4A SRSF9 SFSWAP SLK TIMELESS WBSCR22 STK33 NAP1L5 EFCAB2 FAM184A HNRNPA3 IARS MT.CYB MT.ND5 PALLD PKP2 RAB4A ZNF280D SFSWAP SOD1 TIMELESS AK6 STK33 ZNF75A EFCAB2 MYO10 HNRNPA3 IPO7 MT.CYB MYL12A PALLD PLIN2 RAB4A TTC6 SFSWAP SRA1 TMEM38B TRA2A STK33 CENPW EGLN3 EIF3A HNRNPC HSD17B4 MT.ND5 MYL12A PALLD RALGPS2 RAB4A RPA3 SH3YL1 YPEL1 TRA2A TSPYL5 STK33 ZNF528 EGLN3 EIF3B HNRNPC HSPA8 MT.ND5 MYO10 PCBP1 PCSK1 RAB4A NLRP2 SH3YL1 CHAC1 TRA2A TTC12 ZNF280D TTC6 EGLN3 EMP2 HNRNPC RTCB MT.ND5 NCALD PCBP1 PDAP1 RAB4A NAP1L5 SHH SHROOM3 TRA2A TTC3 ZNF280D ADGRG7 EGLN3 MTRNR2L1 HSD17B4 HSPA8 MT.ND5 NONO PCBP1 PDIA6 RALGPS2 RANBP1 SHH SLC7A8 TRA2A RPA3 ZNF280D FGD4 EGLN3 AK6 HSD17B4 MTRNR2L1 MT.ND5 OSBPL8 PCBP1 PEG10 RALGPS2 RBM39 SHH SLK TRA2A ZNF528 ZNF37A YPEL1 EIF3A EIF3B HSD17B4 GXYLT1 MT.ND5 PALLD PCSK1 PDAP1 RALGPS2 RSRP1 SHH SOD1 TSPYL5 TTC12 ZNF37A PSMG3 EIF3A ENAH HSPA1A HSPA1B MYL12A MYL6 PCSK1 PDIA6 RALGPS2 S100A6 SHH SPRED1 TSPYL5 TTC3 TTC6 YPEL1

Supplementary Table 7. Correlation-based interactions.

Gene Group Ncmp/Acmp Vmt/exoc. Stress/Ccp RNA met. Protein met. Nuclear/mito/secretory Ubbiquitination PD Gene Group Ncmp/Acmp Vmt/exoc. Stress/Ccp RNA met. Protein met. Nuclear/mito/secretory Ubbiquitination PD ACTN1 A Vmt/exoc. Secv PD THUMPD3 B Acmp RNAp Nu BBS2 A Vmt Pl TMEM38B B Nu CALR A Ncmp/Acmp Vmt Stress Ps/Pl Nu/secv PD TRA2A B Acmp RNAp Nu Ubi PD CD59 A Vmt/exoc. Secv PD TTC3 B Ncmp/Acmp Ccp Nu PD CECR1 A Acmp Vmt/exoc. Ccp Secv/lys PD TUBGCP5 B PD CMTM8 A Pl Nu PD WBSCR22 B Acmp RNAm Nu Ubi COMT A Acmp Stress/Ccp PD WDR11 B Nu CRYZ A Ccp PD WDR34 B Pl CYFIP1 A Vmt/exoc. Secv PD YPEL1 B Nu DLK1 A PD ZNF593 B Acmp Pl Nu PD EFCAB2 A PD ZNF75A B Acmp Nu PD ENAH A PD ZNF83 B Acmp Nu PD EXOC5 A Vmt Pl PD CHCHD2 B-PD Acmp Stress Pl Nu/mito PD FOS A Acmp Stress Nu Ubi PD ABRACL C PD GOPC A Vmt Pl Lys PD CNN3 C PD GPC3 A Ncmp/Acmp Ptpm Lys PD CUL3 C Ncmp/Acmp Vmt Stress/Ccp Ps Nu Ubi PD GPR128 A PD CYCS C Acmp Stress Nu/mito PD GPR128 A PD FRA10AC1 C Nu HNRNPC A Acmp RNAm Nu Ubi PD GNB1 C Stress PD HSPA8 A Acmp Vmt/exoc. Stress/Ccp RNAm Ps/Pl Nu/secv/lys Ubi PD IPO5 C Pt/Pl Nu PD LGI1 A PD MGMT C Acmp Stress Nu LMAN1 A Vmt Pl PD PHYH C Ccp Pl MALAT1 A PD PLCB4 C Nu PD MALAT1 A PD PTPRZ1 C Ncmp/Acmp PD MLF1 A Acmp PD RALGPS2 C PD MTRNR2L1 A PD RNPC3 C Acmp RNAm Nu MYL12A A PD SPRED1 C Ncmp/Acmp Stress Nu PD MYL6 A PD TAGLN C PD NAP1L5 A Nu ABCA5 D Lys PD NIPA2 A PD ABLIM1 D Ubi PD NLRP2 A PD AKAP8L D Acmp RNAp Nu PD OSBPL8 A Ncmp/Acmp Pl Nu PD ANKRD11 D Nu PALLD A Nu PD ANKRD26 D PD PGK1 A Acmp Stress/Ccp PD ANKRD36 D PD PTGR1 A PD ANXA5 D Vmt/exoc. Ubi PD RANBP1 A Ncmp/Acmp Ccp Pl Nu Ubi PD ARGLU1 D Acmp Nu S100A6 A Nu PD ARMC2 D PD SLC25A4 A Pl Mito PD BRCA2 D Acmp Stress Pl Nu/secv Ubi PD TCEAL5 A Acmp Nu CAMK2D D Ncmp/Acmp Stress Nu PD TSPYL5 A Nu PD CCNL1 D Acmp RNAp Nu Ubi PD TYW3 A Acmp RNAm CCT4 D Ps/Pl Nu PD ZNF280D A Acmp Nu Ubi PD CCT8 D Vmt/exoc. Ps/Pl Nu/secv/lys Ubi PD ZNF37A A Acmp Nu CHAC1 D Ncmp/Acmp Stress/Ccp PD ZNF528 A Acmp Nu CHD2 D Acmp Stress Nu CLHC1 D PD AK4 B Ncmp/Acmp PD CROT D Acmp Ccp Pl AK6 B Acmp Stress Ps Nu CSRP1 D Nu Ubi ATG101 B Ccp PD CSRP2 D Nu Ubi PD C19ORF53 B Nu DAAM1 D PD C21ORF91 B PD DAB1 D PD CAT B Ncmp/Acmp Vmt/exoc. Stress/Ccp Pl Secv/mito/lys PD ELOVL5 D Acmp PD CBX1 B Nu Ubi PD EMP2 D Vmt Pl Nu CBX3P9 B PD EPHA4 D Ncmp/Acmp Stress Ps Mito PD CCNB1IP1 B Acmp Nu Ubi PD FAM184A D PD CD164 B Lys FGD4 D PD CENPW B Nu FGFR1 D Acmp Nu Ubi PD CEP350 B Nu PD FNBP1L D Vmt Ccp CNTNAP2 B Pl PD FTH1 D Vmt/exoc. Secv/lys PD CRKL B Ncmp/Acmp Stress Nu PD GHITM D Mito PD CSNK1G3 B Ncmp/Acmp Vmt Nu PD GNAS D Acmp Pl Nu PD CSTB B Vmt/exoc. Nu/secv PD GOLT1B D Vmt Pl PD CTSB B Ncmp/Acmp Vmt/exoc. Ccp Nu/secv/lys PD GPATCH8 D Ubi PD DNAJC15 B Pl Mito PD GXYLT1 D Ncmp/Acmp PD DPH3 B Ncmp/Acmp Nu PD HNRNPA3 D Acmp RNAm Nu Ubi EEF1A1 B Acmp Vmt/exoc. Stress Nu/secv/lys Ubi PD HSPA1A D Acmp Vmt/exoc. Stress/Ccp RNAm Ps/Pf Nu/secv PD EGLN3 B Ncmp/Acmp Stress Nu PD HSPA1B D Acmp Vmt/exoc. Stress/Ccp Ps/Pf Nu/secv PD EIF1AY B PD IARS D Acmp PD EIF3A B Ncmp/Acmp Nu PD IRX3 D Acmp Nu EIF3B B Ncmp/Acmp PD LSM3 D Acmp Ccp RNAm Nu PD FAM126A B Pl PD LUC7L3 D Acmp RNAp Nu Ubi PD FAM208A B Acmp Nu Ubi MAP3K12 D Ncmp/Acmp Stress PD FBXO9 B Ncmp/Acmp Ccp Ptpm PD MCL1 D Stress Pt/Pl Nu/mito Ubi PD FZD7 B Stress Ubi MRPS21 D Ncmp/Acmp Mito GTF2I B Acmp Nu Ubi MT-CO3 D Mito HIC2 B Acmp Nu MT-CYB D Acmp Mito HLA-B B Vmt/exoc. Ubi PD MT-ND5 D Acmp Mito PD HSD17B4 B Acmp Ccp Pl PD NAALAD2 D Ncmp/Acmp Ccp PD IPO7 B Pt/Pl Nu PD NCALD D Vmt PD IPO9 B Pt/Pl Nu PD NDUFA12 D Acmp Mito PD IQCB1 B Nu PD NDUFB6 D Acmp Nu/mito PD KMT2A B Acmp Nu Ubi NKX6-1 D Acmp Nu PD LANCL1 B PD NME1 D Acmp Vmt Nu/mito Ubi PD MED15 B Acmp Nu Ubi NR1D2 D Acmp Nu Ubi MRPL15 B Ncmp/Acmp Mito PD NSMCE1 D Acmp Stress Nu Ubi MRPL17 B Ncmp/Acmp Mito NUDT21 D Acmp RNAm Nu PD MYL9 B PD PCSK1 D Ncmp/Acmp Secv PD MYO10 B Vmt Nu PD PDIA6 D Ncmp/Acmp Vmt Stress Ptpm PD NDUFB11 B Mito PD PEG10 D Nu PD NME4 B Acmp mito PD PHB D Acmp Ps Nu/mito NONO B Acmp Stress RNAp Nu Ubi PD PHTF1 D Acmp Nu NSA2 B Acmp RNAp Nu Ubi PLIN2 D Nu NUP62 B Acmp Stress RNAm Pl Nu POU6F2 D Acmp Nu PCBP1 B Acmp RNAm Nu Ubi PD PSMA4 D Ncmp/Acmp Stress/Ccp RNAm Ptpm Nu PD PDAP1 B Vmt/exoc. Secv Ubi PD PSMC3IP D Acmp Nu PD PFKP B Acmp Ccp PD RAB9A D Vmt Pl Lys PD PGD B Acmp PD RBM39 D Acmp RNAp Nu Ubi PD PKP2 B Pl Nu RPA3 D Acmp Stress Nu Ubi PD PSMB5 B Ncmp/Acmp Stress/Ccp RNAm Ptpm Nu PD RPN2 D Ncmp/Acmp Ubi PD PSMD7 B Ncmp/Acmp Vmt/exoc. Stress/Ccp RNAm Ptpm Nu/secv Ubi PD RRAGB D Stress Pl Nu/lys Ubi PD PSMG3 B PD RSRC2 D Ubi PD RAB4A B Pt/Pl Secv PD SFSWAP D Acmp RNAp Nu PD RBM12 B Nu SHH D Ncmp/Acmp Vmt Pl PD RFWD3 B Acmp Stress Nu PD SNX9 D Vmt Pl Ubi PD RNF26 B Ncmp/Acmp Pl PD SOD1 D Ncmp/Acmp Vmt/exoc. Stress Nu/secv/lys/mito Ubi PD RRAGD B Stress Pl Nu/lys PD SPATA7 D Pl Nu RRP7A B Acmp RNAm Nu SREK1IP1 D Acmp RNAp RTCB B Acmp RNAm Nu Ubi PD SUGT1 D Ps Nu Ubi SHROOM3 B Pl TBRG1 D Acmp Ps/Pl Nu Ubi SLC7A8 B Ncmp/Acmp PD TET3 D PD SLK B Ncmp/Acmp Stress PD TIMELESS D Acmp Stress Nu SMARCA4 B Acmp Nu Ubi DA TRMT1L D Acmp RNAp Ubi PD SMARCB1 B Acmp Stress Nu Ubi TTC12 D PD SNAP29 B Vmt/exoc. Ccp Pl Nu/secv/lys PD UBE2D2 D Ncmp/Acmp Stress/Ccp Pl Nu PD SRA1 B Acmp Nu PD UQCRFS1 D Mito PD SRSF9 B Acmp RNAm Pl Nu Ubi PD USP49 D Acmp Ccp RNAp Nu PD STK33 B Ncmp/Acmp VPS39 D Vmt Pl Lys PD TCEAL7 B Acmp Nu VWA5A D Nu PD TCF25 B Acmp Nu XPOT D RNAm Pl Nu TCTN3 B Nu PD ZCCHC11 D Acmp RNAm Nu PD THAP7 B Acmp Nu ZSCAN30 D Acmp Nu Ubi

Supplementary Table 8. Pathway and PD associations. Pathway association for each DEG was obtained from String, except for association with PD. PD association was obtained through a manual search and references are listed in Supp. Table 10.

Supplementary Table 8: Abbreviations

Acmp aromatic compound metabolic process (par of Ncmp) ccp cellular catabolic process exoc exocytosis lys lysosome mito mitochondrial Ncmp nitrogen compound metabolic process Nu nucleus Pf protein folding Pl protein localization Pn-m Metabolism of proteins Ps protein stability Pt protein transporter Ptpm post-translational protein modification RNAm Metabolism of RNA RNAp RNA processing secv secretory vesicle stress cellular response to stress Ubi Ubl conjugation Vmt vesicle-mediated transport

PARK1&4 SNCA PARK2 PARKIN PARK3 unknown / not found PARK5 UCHL1 PARK6 PINK1 PARK7 DJ-1 PARK8 LRRK2 PARK9 ATP13A2 PARK10 USP24 PARK11 GRB10 PARK12 unknown / risk factor locus PARK13 HTRA2 PARK14 PLA2G6 PARK15 FBXO7 PARK16 unknown / risk factor locus PARK17 VPS35 PARK18 EIF4G1 PARK19 DNAJC6 PARK20 SYNJ1 PARK21 DNAJC13 PARK22 CHCHD2 PARK23 VPS13C

Supplementary Table 9. Parkinson’s disease-associated genes (PARK genes 10–16). CHCHD2 is not only a PARK gene, but also a DEG in our network (highlighted in blue).

Gene G Excluded PD Gene G Excluded PD Gene G Excluded PD AC009245.3 A Pseudogene BTN2A2 B PSMB5 B PD17 ACTN1 A PD18 C14ORF119 B PSMD7 B PD19,20 GPR128 (ADGRG7) A PD21 C19ORF53 B PSMG3 B PD22 BBS2 A C21ORF91 B PD23 PTMAP5 B Pseudogene C6ORF48 A Locus CAT B PD24 RAB4A B PD25 CALM2P2 A Pseudogene CBX1 B PD23 RBM12 B CALR A PD26 CBX3P9 B Proc. pseud. PD23 RFWD3 B PD19,20 CCDC144NL.AS1 A RNA Gene CCNB1IP1 B PD19,20 RNF26 B PD19,20 CD59 A PD27 CD164 B RP11.288E14.2 B Pseudogene CECR1 (ADA2) A PD28 CENPW B RP11.475C16.1 B Pseudogene CMTM8 A PD23 CEP350 B PD29 RP11.488C13.1 B Pseudogene COMT A PD30 CHCHD2 B PD31 RP11.641D5.1 B Pseudogene CRYZ A PD23 CNTNAP2 B PD32 RP11.64B16.2 B Antisense CYFIP1 A PD33 CRKL B PD18 RP11.676M6.1 B Pseudogene DLK1 A PD34 CSNK1G3 B PD23 RP13.258O15.1 B Pseudogene EFCAB2 A PD35 CSTB B PD36 RP4.796I17.5 B Proc. pseud. ENAH A PD37 CTSB B PD38 RRAGD B PD39 EXOC5 A PD40 DNAJC15 B PD41 RRP7A B FOS A PD42 DPH3 B PD43 RTCB B PD44 GOPC A PD23 EEF1A1 B PD45 SC5D B GPC3 A PD46 EGLN3 B PD47 SEPT02 B HNRNPC A PD48 EIF1AY B PD49 SH3YL1 B HSPA8 A PD50 EIF3A B PD23 SHROOM3 B LGI1 A PD51 EIF3B B PD52 SLC7A8 B PD53 LMAN1 A PD54 EIF5P1 B Pseudogene SLK B PD35 MALAT1 A PD55 FAM126A B PD56,57 SMARCA4 B (BRG1) PD 58,59 MINOS1P3 A Pseudogene FAM208A B SMARCB1 B MLF1 A PD60 FBXO9 B PD61 SMARCE1P6 B Pseudogene MORF4L1P1 A Pseudogene FZD7 B SNAP29 B PD62 MTRNR2L1 A PD48 GTF2I B SRA1 B PD63 MYL12A A PD48 HIC2 B SRSF9 B PD64 MYL6 A PD18 HLA-B B PD65 STK33 B NAP1L5 A HMGN1P38 B Pseudogene TCEAL7 B NIPA2 A PD66 HNRNPCP1 B Pseudogene TCF25 B NLRP2 A PD67 HNRNPCP2 B Pseudogene TCTN3 B PD68 OSBPL8 A PD18 HSD17B4 B PD18 THAP7 B PALLD A PD69 IFI27L1 B THAP9-AS1 B antis. RNA PGK1 A PD70,71 IPO7 B PD35 THUMPD3 B PTGR1 A PD72 IPO9 B PD18 TMEM38B B RANBP1 A PD73 IQCB1 B PD74 TRA2A B PD75 RP11.692N5.2 A Pseudogene KMT2A B TTC3 B PD31 RP4.765C7.2 A Pseudogene LANCL1 B PD76 TUBGCP5 B PD* RSRP1 A LINC00909 B RNA gene WBSCR22 B S100A6 A PD77 MED15 B WDR11 B SLC25A4 A PD48 MRPL15 B PD17 WDR34 B SNHG5 A RNA Gene PD 55,78 MRPL17 B YPEL1 B SNHG8 A RNA Gene MYL9 B PD18 ZNF593 B PD79 TCEAL5 A MYO10 B PD80 ZNF75A B PD81 TSPYL5 A PD82 NAA20 B ZNF83 B PD83 TYW3 A NDUFB11 B PD17,79 ABRACL C PD84 ZNF280D A PD23 NME4 B PD85 CNN3 C PD86 ZNF37A A NONO B PD87 CUL3 C PD19,20 ZNF528 A NSA2 B CYCS C PD88 ZNF528.AS1 A RNA Gene NUP62 B FRA10AC1 C ZNF880 A PCBP1 B PD89 GNB1 C PD18 AK4 B PD85 PDAP1 B PD18 GOLGA8B C AK6 B PFKP B PD90 IPO5 C PD23 ATG101 B PD91 PGD B PD92 MGMT C AZI2 B PKP2 B PHYH C

Gene G Excluded PD Gene G Excluded PD PLCB4 C PD23 MT-CYB D 93 94 PTPRZ1 C PD MT-ND5 D PD RALGPS2 C PD95, + NAALAD2 D PD23 RNPC3 C NCALD D PD96 SPRED1 C PD97 NDUFA12 D PD98 TAGLN C PD23 NDUFB6 D PD99 ABCA5 D PD100 NKD1 D ABLIM1 D PD101, + NKX6-1 D PD102 AKAP8L D PD103 NME1 D PD85 ANKRD11 D NR1D2 D ANKRD26 D PD23 NSMCE1 D ANKRD36 D PD104 NUDT21 D PD105,106 ANXA5 D PD77 PCSK1 D PD49107 ARGLU1 D PDIA6 D PD19,20 ARMC2 D PD66 PEG10 D PD108 109 BRCA2 D PD PHB D C6ORF118 D PHTF1 D CAMK2D D PD110 PLIN2 D CCNL1 D PD111 POU6F2 D CCT4 D PD112 PPP1R21 D CCT8 D PD113 PRTG D CHAC1 D PD114 PSMA4 D PD19,20 CHD2 D PSMC3IP D PD17 CLHC1 D PD115,* PSMD5.AS1 D Pseudogene CROT D RAB9A D PD35 CSRP1 D RBM39 D PD116 CSRP2 D PD117 RP11.122G18.7 D lncRNA CTC.444N24.7 D RNA gene RP11.298C3.2 D Pseudogene DAAM1 D PD 23 RP11.76E16.2 D Pseudogene 118 119 DAB1 D PD RPA3 D PD ELOVL5 D PD120 RPN2 D PD121 EMP2 D RRAGB D PD122 EPHA4 D PD123 RSRC2 D PD23 FAM184A D PD124 SFSWAP D PD23 FGD4 D PD23 SHH D PD125 FGFR1 D PD126 SNX9 D PD127 FNBP1L D SOD1 D PD17 FTH1 D PD128 SPATA7 D GABPB1.AS1 D RNA gene SREK1IP1 D GHITM D PD129 SUGT1 D GNAS D PD83 TBRG1 D GOLT1B D PD107 TET3 D PD130 GPATCH8 D PD131 TIMELESS D 132 GXYLT1 D PD TMEM132C D HNRNPA3 D TRMT1L D PD101 + HSPA1A D PD49 TTC12 D PD133 HSPA1B D PD49 TTC6 D IARS D PD134 UBE2D2 D PD135 IRX3 D UQCRFS1 D PD 19,20,136 KIAA1211 D USP49 D PD137 KIF27 D VPS39 D PD138 LRIG3 D VWA5A D PD139 LSM3 D PD23 XPOT D LUC7L3 D PD140 ZCCHC11 D PD95+ MAGI2.AS3 D RNA gene ZSCAN30 D MAP3K12 D PD141 MCL1 D PD142 MRPS21 D MT-CO3 D

Supplementary Table 10. PD association. Manual literature search was used to identify the potential association with PD of the 291 genes identified in this study. “Excluded” category lists the reason these genes do not appear in the protein-protein interaction network. “G” = group the genes belong to. * www.genecards.org + via http://bioinfo.wilmer.jhu.edu/AAgMarker

Supplementary Figure 1. Fibroblast ND40066 cytogenetic analysis.

Supplementary Figure 2. iPSC ND40066 clone 8 aCGH analysis performed at P9.

Supplementary Figure 2 cont’d. iPSC ND40066 clone 8 aCGH analysis performed at P9.

Supplementary Figure 3. Staining for the non-midbrain DA marker PAX6. “indirect” indicates indirect differentiation of DA neurons using rosettes 9, while “direct” indicates mDA differentiation using our protocol 9,143.

Supplementary Figure 4. Quality control plots of control sample at Day 06. a. Cumulative Total number of counts. The red vertical lines represent the lower and upper bounds of the expected elbow. The blue dot represents the transitional point calculated using ecp r package. b. Histograms of the three criteria used for filtering out low-quality cells. c. Cell score before filtering. Red dots are the cells that filtered through the quality control. d. Overview of the three criteria after filtering step.

a. b.

c. Gene groups

Supplementary Figure 5. Network analysis. DEG interactions downloaded from String or GeneMANIA and visualized by Gephi a. Interactions based on GeneMANIA. b. Interactions based on String. c. Both sources of interactions combined. Genes of the various analyses (A-D) are colored as per illustration. Group A: top 56 genes (Table 2). Group B: additional genes, to a total of 151 genes (Suppl. Table 4). Group C: additional genes to a total of 172 genes (Supp. Table 5). Group D: additional genes to a total of 291 genes (Supp. Table 6). The Network Diameter was used to illustrate Betweenness Centrality, which indicates the relative connectedness of the nodes. Large nodes are a point of convergence and may represent genes and pathways central to PD pathology, in fact, they are already known to play an important role in PD disease (Table 3).

a. b. c.

d. e.

f. g.

Supplementary Figure 6. Functional pathways significantly represented in the network. Functional pathways as obtained from String database. a. Reaction to stress, cell catabolic processes. b. nitrogen and aromatic compound metabolism. c. Vesicle-mediated transport & exocytosis. d. RNA metabolism e. Protein metabolism. f. Localization. g. ubiquitination. (Supplement Table 8) a. b.

c. d.

Supplementary Figure 7. Parkinson-associated genes (PARK genes) integrated into the network. Only direct interactions between PARK genes and DEGs were included, PARK-PARK gene interactions were excluded, so that only PARK genes that directly interact with DEGs would be retained (Supplement Table 5). a. STRING-based interactions. PARK genes are in blue, DEGs in grey. DEGs that are part of the KEGG-PD pathway are highlighted in yellow b. The nearest neighbour of each PARK gene is colored in pink. The darker the color, the more PARK genes the DEG interacts with. HSPA8 is one of the most highly differentially expressed genes (Group A), forms a central node of the network, is known to play an important role in PD (Table 3 main text), and it connects to several of the PARK genes. c. GeneMANIA-based interactions. d. PARK nearest neighbors.

Supplementary Figure 8. The interaction of genes from Groups A-C with ubiquitination and mitochondrial genes. Only the direct contacts between ubiquitination or mitochondrial genes and the genes in groups A-C were used. The graph illustrates which ubiquitination and mitochondrial genes the DEGs interact with. DEGs are in blue, ubiquitination genes are in purple and mitochondrial genes are in green. The DEGs interact with a vast array of ubiquitination and mitochondrial genes, so their differential expression likely greatly impacts these networks.

Figure 9. At least 68% of the DEGs have some association with PD. For all 291 genes, a possible link to PD disease was determined. The interactions listed in Table 10 are not exhaustive, as only one or two references were included. Due to the time-consuming nature of literature search, some genes were very likely omitted. The association with PD varied from a mutation in the DEG that was associated with PD, to dysregulation of the gene in PD, to identification through GWAS, etc. These are all listed in Supplement Table 10. The major nodes play an important role in PD, see Table 3 for description and references.

Figure 10. Nearest neighbour of LGI1. LGI1 in light blue and its direct contacts in dark blue.

a. b. c.

Supplementary Figure 11. Network analysis performed on randomly selected genes using Gephi. a. 200 randomly selected genes, processed the same way as the DEGs. Central group consists of unconnected nodes. b. After unconnected nodes are filtered out, a few nodes with a connection to at least one other remain. c. Connectedness of nodes, as rendered by node size, after applying betweenness centrality applied.

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