Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome
Abstract
1. Introduction
2. Results
2.1. Protein–Protein Interaction Network of PCOS
2.2. PCOS–Disease Subnetwork
2.3. Pathway Enrichment Analysis
3. Discussion
4. Materials and Methods
4.1. Compilation of PCOS-Related Proteins and Their Associated Diseases
4.2. Construction of PCOS PPI Network
4.3. Construction of PCOS–Disease Subnetworks
4.4. Pathway Enrichment Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
DGA | Disease and gene annotation |
EWAS | Epigenome-wide association study |
FDR | False discovery rate |
GWAS | Genome-wide association study |
HGMD | Human Gene Mutation Database |
HIPPIE | Human Integrated Protein–protein Interaction Reference |
IVF | In vitro fertilization |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
MHC | Major histocompatibility complex |
OMIM | Online Mendelian Inheritance in Man |
PCOS | Polycystic ovarian syndrome |
PCOSrp | PCOS-related protein |
PPI | Protein–protein interaction |
Appendix A
Cluster | Score (Density × #Nodes) | #Nodes | Edges | PCOSrps |
---|---|---|---|---|
1 | 17.882 | 18 | 152 | RPL10, RPS10, RPS13, RPS14, RPS15A, RPS16, RPS18, RPS2, RPS20, RPS25, RPS26, RPS3A, RPS5, RPS6, RPS7, RPS8, RPS9, VCAM1 |
2 | 15.4 | 41 | 308 | ADRM1, CCDC74B, CDK19, CDK8, ESR1, MED12, MED14, MED15, MED17, MED19, MED20, MED21, MED30, MED4, MED6, MED7, MED9, PAAF1, POMP, PSMA1, PSMA2, PSMA3, PSMA4, PSMB1, PSMB3, PSMB4, PSMB5, PSMB8, PSMB9, PSMC1, PSMC2, PSMC3, PSMC4, PSMC6, PSMD10, PSMD11, PSMD12, PSMD2, PSMD3, PSMD7, UCHL5 |
3 | 8 | 9 | 32 | C1D, DIS3, EXOSC2, EXOSC3, EXOSC4, EXOSC6, EXOSC7, EXOSC8, EXOSC9 |
4 | 7.607 | 57 | 213 | ACTL6A, ARID1A, ARID1B, CCNA1, CCT2, CCT3, CCT6A, CCT7, CCT8, CDK2AP1, CDT1, CHD4, DPF3, EPC1, FZR1, GATAD2A, IGBP1, ING3, INO80B, INO80C, INO80D, INO80E, MBD3, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, MORF4L1, MORF4L2, MTA1, NFRKB, PLK1, POLR2A, POLR2B, POLR2D, POLR2E, POLR2G, POLR2J, PPP2CB, PPP4C, RBBP4, RUVBL1, RUVBL2, SLMAP, SMARCA2, SMARCC1, SMARCC2, SMARCD1, SSRP1, STK24, STRN3, STRN4, TCP1, YEATS4, YY1 |
5 | 6.333 | 7 | 19 | BRD4, CHTF18, DSCC1, RFC2, RFC3, RFC4, RFC5 |
6 | 6 | 7 | 18 | SUPT3H, SUPT7L, TADA1, TADA2B, TADA3, TAF12, USP22 |
7 | 6 | 7 | 18 | LSM2, LSM3, LSM4, LSM5, LSM6, LSM7, USP15 |
8 | 5.5 | 25 | 66 | BRCA1, CDK1, CDK5, CDKN1B, CKS1B, CREBBP, DDX17, DSN1, KNL1, NCOA1, NCOA2, NDC80, NSL1, NUF2, PPP1CA, PPP1CC, RPAP3, RUNX1, SKP2, SPC24, SPC25, URI1, UXT, VDR, ZWINT |
9 | 5 | 5 | 10 | RPL13, RPL21, RPL36, RPL7A, RPLP0 |
10 | 5 | 5 | 10 | NUP37, NUP43, NUP85, SEC13, SEH1L |
11 | 4.857 | 8 | 17 | CCDC93, COMMD1, COMMD10, COMMD2, COMMD4, COMMD6, ELOC, SOCS1 |
12 | 4.8 | 6 | 12 | ABI1, ABI2, CYFIP1, CYFIP2, WASF2, ZNF511 |
13 | 4.571 | 8 | 16 | MRPL1, MRPL12, MRPL42, MRPL44, MRPL50, MRPL51, MRPL55, MRPL58 |
14 | 4.5 | 5 | 9 | CTTNBP2NL, FGFR1OP2, PDCD10, PPP2R1A, STRIP1 |
15 | 4.259 | 55 | 115 | ARMC8, BARD1, BCL3, BCLAF1, BRCA2, BRCC3, CARM1, CDCA5, CLK2, CTNNB1, DDX5, FOS, GPS2, ILF2, LUC7L2, MAEA, MET, MRE11, NBN, NCOA3, NDRG1, NOP2, NOP56, NR3C1, NXF1, PDS5A, PDS5B, PGR, PPARGC1A, PRG2, RAD21, RAD50, RANBP2, RANBP9, RELA, RNPS1, RPL14, RPL15, RPL18, RPL18A, RPL23A, RPL24, RPL26, RPL37A, SMC1A, SMC3, SRPK2, SRRM1, SRRM2, SUMO3, TBL1X, TBL1XR1, TRA2A, TRIM28, WAPL |
16 | 4.027 | 76 | 151 | ACTR1B, ACTR3, ARPC2, ARPC3, ARPC4, ATF4, BHLHE40, BORCS6, CBLB, CEBPG, CFLAR, CSPP1, DCTN1, DCTN2, DCTN5, DCTN6, DNMT1, DNMT3B, EAF1, ERBB3, ETS1, EWSR1, EZR, FADD, FAS, FOSL1, GADD45A, GADD45G, GPR137B, HAUS1, HAUS2, HAUS4, HAUS5, HAUS6, HAUS7, HDAC1, HDAC2, IDI2, INSR, KDM1A, LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4, LMO4, LUC7L, MAF, MAP2K1, MAP2K2, MAPK3, NCAPD2, NCAPG, NCAPH, NCOR2, NPM1, PIK3R1, PRMT1, PTMA, PTPN11, RAF1, RRAGC, SMC2, SMC4, SOCS3, SSBP2, SSBP3, SSBP4, SUZ12, SYK, TAF1D, TDG, TOP2A, TRADD, UBE2I, ZEB2, ZHX1 |
17 | 4 | 4 | 6 | GSE1, HMG20A, HMG20B, RCOR3 |
18 | 4 | 4 | 6 | APBA1, CASK, KCNJ12, LIN7B |
19 | 4 | 4 | 6 | MRPS2, MRPS31, MRPS5, PTCD3 |
20 | 4 | 4 | 6 | IFT122, IFT43, TULP3, WDR35 |
21 | 4 | 4 | 6 | ARCN1, COPA, COPG1, COPZ1 |
22 | 4 | 4 | 6 | POLE, POLE2, POLE3, POLE4 |
23 | 3.882 | 35 | 66 | ANAPC1, ANAPC10, ANAPC16, ANAPC5, BUB1B, CBX1, CBX3, CDC23, CDC7, CHAF1A, CHAF1B, DBF4, EMSY, EXOC1, EXOC2, EXOC3, EXOC4, EXOC5, EXOC7, GATAD1, KDM5A, KPNA2, KPNB1, MDC1, MYC, NUP153, NUP62, PENK, PHF12, PPP2R5A, PPP2R5D, RBL1, SGO1, SIN3B, SMAD3 |
24 | 3.689 | 46 | 83 | ANAPC4, BUB3, CCDC8, CDC25A, CDC25B, CDC25C, CDC27, CDC37, CUL4A, CUL7, DCAF5, DDA1, FAAP100, FAAP20, FANCB, FANCG, FANCM, IRS1, IRS2, LATS1, LATS2, MAD2L1, MAP3K5, MAPK14, NEK2, NF2, NTRK1, OBSL1, PHLPP2, POLA1, POLA2, PRIM1, PRIM2, RAE1, RASSF8, RB1, SET, STK11, STK4, TTLL1, UBTF, USP12, USP46, WDR20, WDR48, YWHAH |
25 | 3.5 | 5 | 7 | SNAP23, STX6, STXBP5, VAMP2, VAMP3 |
26 | 3.5 | 5 | 7 | HLA-A, HLA-C, HLA-E, HLA-F, LILRB1 |
27 | 3.5 | 5 | 7 | CCND2, CCND3, CDK4, CDK6, CDKN2C |
28 | 3.357 | 29 | 47 | ATF7, BBIP1, BBS1, BBS2, BBS7, CDK2, CREB5, DNAJB1, E2F1, FOXO3, HNRNPD, HSPA1A, HSPA4, HUWE1, JUN, JUNB, MAPK9, MCL1, MDM2, MYH9, NFATC2, PPP1CB, PPP1R10, PTBP1, SMAD4, STUB1, TOX4, TRIM33, TTC8 |
29 | 3.333 | 4 | 5 | ASF1A, ASF1B, NASP, TONSL |
30 | 3.333 | 4 | 5 | DMD, DTNA, SNTA1, SNTB1 |
31 | 3.333 | 4 | 5 | HBA1, HBB, NDUFAF5, PGPEP1 |
32 | 3.333 | 4 | 5 | CDC42EP3, SEPT2, SEPT6, SEPT7 |
33 | 3.25 | 9 | 13 | AMFR, AP2A2, AP2M1, AP2S1, CFTR, DAB2, DERL2, SELENOS, SYVN1 |
34 | 3.067 | 91 | 138 | ACTB, ACTN1, AES, AKAP1, AKAP11, AKT1, APP, AR, ARHGEF7, ATF3, BAX, BCL2L2, BID, BLOC1S1, BLOC1S3, BLOC1S6, CASP8, CDKN1A, CEBPB, CSNK1D, DAG1, DBN1, DBNL, DDIT3, EEA1, ENO2, FGFR1, FN1, GABARAP, GIT1, GIT2, GRB10, HDAC3, HIF1A, HMGA1, HNRNPH1, ITGA5, JAK2, JUP, LGALS8, MAP1LC3A, MAPK8IP1, MAPRE1, MAPT, NCBP1, NR0B2, OPTN, PA2G4, PAK2, PARP1, PARP2, PKM, PMAIP1, PPARG, PRKACA, PRKAR2A, PRKAR2B, PRKDC, PRLR, PRPF31, PTPRK, RAB5A, RABEP1, RABGEF1, RB1CC1, RIPK1, RNF146, S100B, SHB, SIAH2, SIRT2, SNAP29, SNAPIN, SSX2IP, STX3, STX4, STX7, STXBP1, TERF1, TGFB1, TGFB1I1, TGFB2, TGFBR3, TPI1, TUBB3, UBD, VAMP7, VAV1, VCP, XPO1, YWHAE |
35 | 3.043 | 24 | 35 | ASH2L, CTNND1, CTTN, EGFR, GNAI1, GSTM2, GSTM3, GSTM4, HCFC2, HSP90AB1, IGF1R, KMT2B, KMT2C, MAPK8IP2, MTNR1B, NME1, PHB, RBBP5, RGS4, RRAD, TIAM1, TP53, TUBB, ZBTB33 |
36 | 3 | 3 | 3 | POP4, RBM4B, RPP25 |
37 | 3 | 3 | 3 | CCDC94, PLRG1, PRPF19 |
38 | 3 | 3 | 3 | CNOT3, CNOT7, TNRC6A |
39 | 3 | 9 | 12 | ACD, ALDH2, ANXA2, FGA, FGB, FGG, LDHA, PLAT, POT1 |
40 | 3 | 3 | 3 | FOXP1, FOXP2, FOXP4 |
41 | 3 | 3 | 3 | VPS26A, VPS29, VPS35 |
42 | 3 | 3 | 3 | CD81, CD9, TSPAN4 |
43 | 3 | 3 | 3 | TMED2, TMED3, TMED4 |
44 | 3 | 3 | 3 | CENPM, CENPO, CENPQ |
45 | 3 | 3 | 3 | THOC2, THOC3, THOC7 |
46 | 3 | 3 | 3 | EHMT2, H3F3A, KAT2B |
47 | 3 | 3 | 3 | DDX23, SNRNP40, SNRPD2 |
48 | 3 | 3 | 3 | FAF2, UFD1, VCPIP1 |
49 | 3 | 3 | 3 | CEP135, OFD1, PCM1 |
50 | 3 | 3 | 3 | GOLGA4, NOL11, UTP4 |
51 | 3 | 3 | 3 | CACNA1C, RYR2, SRI |
52 | 3 | 3 | 3 | EMC1, EMC2, EMC3 |
53 | 3 | 3 | 3 | FHIT, HSPD1, HSPE1 |
54 | 3 | 3 | 3 | SKA1, SKA2, SKA3 |
55 | 3 | 3 | 3 | AKR1C1, AKR1C2, AKR1C3 |
56 | 3 | 3 | 3 | BCKDHA, BCKDHB, PPM1K |
57 | 3 | 3 | 3 | MAB21L1, MEIS1, PBX1 |
58 | 3 | 3 | 3 | AP3D1, AP3M1, AP3S2 |
59 | 3 | 3 | 3 | MIS18A, MIS18BP1, OIP5 |
60 | 3 | 3 | 3 | C3, CFB, CFP |
61 | 3 | 3 | 3 | ANKRD55, IFT46, IFT74 |
62 | 3 | 3 | 3 | MTMR1, MTMR2, SBF1 |
63 | 3 | 3 | 3 | LMNA, PCBP1, YWHAZ |
64 | 3 | 3 | 3 | CUL3, KCTD10, KCTD13 |
65 | 3 | 3 | 3 | MAP3K7, STRADB, XIAP |
66 | 3 | 3 | 3 | SMC5, SMC6, STN1 |
67 | 3 | 3 | 3 | RAB3IP, TRAPPC10, TRAPPC2 |
68 | 3 | 3 | 3 | SCNN1A, SCNN1G, USP2 |
69 | 3 | 3 | 3 | FLNB, FLNC, OTUD1 |
70 | 3 | 3 | 3 | IFNAR2, IRF9, STAT2 |
71 | 3 | 3 | 3 | CALR, PDIA3, SLC2A1 |
72 | 2.868 | 77 | 109 | ACVR2A, AHCTF1, AP2B1, ATRX, BLNK, BMPR1A, BMPR2, CBX5, CRKL, DDX20, DDX3X, DOK1, EEF1E1, EIF2B1, EIF2B5, EIF4A2, EIF4G3, FKBP4, GDF5, GEMIN6, GPR183, HDAC5, HSP90AA1, IL1R1, IL1RAP, INPP5D, IRAK2, KARS, MRPL16, MRPL37, MRPL38, MRPL47, MRPL48, NEDD8, NIFK, NUP107, NUP205, NUP93, OSBPL10, OSBPL11, OSBPL9, OTUB1, P2RX4, PHB2, PLCG2, PRKD1, PTGER3, PTGES3, QKI, RARS, RBFOX1, RBFOX2, RBMX, RBPMS, RUNX3, SMAD1, SMAD5, SMURF2, SNRPB, SNRPF, SREK1, SRPK1, STAMBP, TAF1A, TAF1B, TAF1C, TBK1, TGFBR1, TOLLIP, UQCRB, UQCRC1, UQCRC2, UQCRQ, VAPA, VAPB, YTHDC1, ZBTB16 |
73 | 2.857 | 8 | 10 | ACTG1, GEMIN5, MLH1, MSH6, SNRPA1, SNRPD1, SNRPD3, SUMO2 |
74 | 2.8 | 6 | 7 | MYO5B, RAB11A, RAB11FIP2, RALBP1, REPS1, REPS2 |
75 | 2.667 | 4 | 4 | DNAAF2, H2AFY2, NUFIP1, SYN1 |
76 | 2.56 | 26 | 32 | ADRB2, ARRDC1, ATP6AP2, ATP6V0D1, ATP6V1D, BCL2, BNIP3, BNIP3L, CA8, CBX7, FAM175B, IGHG1, IGKC, ITPR1, L3MBTL2, MYO1C, NEK6, NEK7, NEK9, PHC3, PSME3, RING1, SNAPC1, SNAPC3, TMEM11, USP20 |
77 | 2.491 | 58 | 71 | ASAP1, ATXN3, CCNL2, CDK13, COG2, COG6, COL6A1, COL9A1, ERCC1, ERCC4, FAM122A, FRS2, FYN, GRB2, IQGAP1, KIT, LMNB1, LYN, MAG, MSH2, MSH3, MYL6, MYL6B, NRBF2, NTRK2, PCNA, PIK3C3, PIK3R4, PINK1, POU2F1, PPP3CA, PRKCB, PRKN, RCAN1, RP2, RRAS, SNX9, SPRY1, SPRY2, SQSTM1, SYNJ1, TMEM185A, TNK2, TNPO2, TOMM20, TOMM22, TOMM40, TUBA1A, TUBB4B, TXNRD1, UBA52, UBE4B, UBL7, USP32, VSIG2, XPA, XRCC5, YWHAB |
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PCOS–Disease Subnetwork | Density Score | Number of Nodes | Number of Interactions | PCOS-Associated Disease | Shared PCOSrps |
---|---|---|---|---|---|
1 | 17.882 | 18 | 152 | Migraine | RPS7, RPS10, RPS26 |
8 | 5.5 | 25 | 66 | Ovarian cancer | BRCA1, CDKN1B, PPP1CC, SKP2, URI1 |
26 | 3.5 | 5 | 7 | Schizophrenia | HLA-A, HLA-C, HLA-E, LILRB1 |
28 | 3.357 | 29 | 47 | Hypertension | BBS1, BBS2, JUN, MYH9, SMAD4 |
31 | 3.333 | 4 | 5 | Anemia | HBA1, HBBHBA1, HBB |
Polycythemia vera | |||||
34 | 3.067 | 91 | 138 | Schizophrenia | ACTB, AKT1, AR, BID, BLOC1S3, CSNK1D, DBN1, ENO2, FGFR1, FN1, GABARAP, GRB10, HDAC3, HMGA1, PAK2, PPARG, RB1CC1, S100B, SNAP29, TGFB1, TPI1, VAMP7, YWHAE |
Depressive disorder | AKT1, APP, AR, ATF3, CSNK1D, FGFR1, HIF1A, MAPT, OPTN, PRKACA, S100B, TGFB1, VCP | ||||
Obesity | AKAP1, AKT1, DDIT3, NR0B2, PARP1, PPARG, PRKAR2B, PRPF31 | ||||
35 | 3.043 | 24 | 35 | Acute kidney injury | EGFR, GSTM2, TP53 |
39 | 3 | 9 | 12 | Gastrointestinal hemorrhage | FGA, FGB, FGG |
Pulmonary embolism | FGA, PLAT | ||||
51 | 3 | 3 | 3 | Syncope | CACNA1C, RYR2 |
55 | 3 | 3 | 3 | Endometriosis | AKR1C1, AKR1C2, AKR1C3 |
Osteoarthritis | AKR1C1, AKR1C2 | ||||
56 | 3 | 3 | 3 | Hallucinations | BCKDHA, BCKDHB |
68 | 3 | 3 | 3 | Hyperkalemia | SCNN1A, SCNN1G |
Hypotension | SCNN1A, SCNN1G |
PCOS–Disease Subnetwork | PCOS-Associated Disease | Shared Pathway |
---|---|---|
1 | Migraine | Ribosome |
8 | Ovarian cancer | Long-term potentiation |
26 | Schizophrenia | Antigen processing and presentation |
28 | Hypertension | Mitophagy |
31 | Anemia and polycythemia vera | No enriched pathway |
34 | Schizophrenia, depressive disorder, and obesity | Longevity regulation pathway, necroptosis, apoptosis, regulation of actin cytoskeleton, autophagy, p53 signaling pathway, and SNARE interactions in vesicular transport |
35 | Acute kidney injury | Adherens junction, glutathione metabolism |
39 | Pulmonary embolism and gastrointestinal hemorrhage | Compliment and coagulation cascades |
51 | Syncope | No enriched pathway |
55 | Endometriosis and osteoarthritis | Steroid hormone biosynthesis |
56 | Hallucinations | No enriched pathway |
68 | Hyperkalemia and hypotension | No enriched pathway |
Shared PCOSrps | Non-shared PCOSrps | ||
---|---|---|---|
In subnetwork | a | b | a + b |
Outside subnetwork | c | d | c + d |
a + c | b + d | n1 |
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Ramly, B.; Afiqah-Aleng, N.; Mohamed-Hussein, Z.-A. Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome. Int. J. Mol. Sci. 2019, 20, 2959. https://doi.org/10.3390/ijms20122959
Ramly B, Afiqah-Aleng N, Mohamed-Hussein Z-A. Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome. International Journal of Molecular Sciences. 2019; 20(12):2959. https://doi.org/10.3390/ijms20122959
Chicago/Turabian StyleRamly, Balqis, Nor Afiqah-Aleng, and Zeti-Azura Mohamed-Hussein. 2019. "Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome" International Journal of Molecular Sciences 20, no. 12: 2959. https://doi.org/10.3390/ijms20122959
APA StyleRamly, B., Afiqah-Aleng, N., & Mohamed-Hussein, Z.-A. (2019). Protein–Protein Interaction Network Analysis Reveals Several Diseases Highly Associated with Polycystic Ovarian Syndrome. International Journal of Molecular Sciences, 20(12), 2959. https://doi.org/10.3390/ijms20122959