Background
Methods
Identification of AD-related genes
Functional enrichment analysis of genes related to AD
Analysis of crosstalks among pathways
Compilation of the human protein–protein interaction network
Construction of the AD-specific protein subnetwork
Results
Compilation of genes associated with AD
Biological function enrichment analysis of Alzgset
Biochemical pathway enriched in Alzgset
Pathway |
p valueb
|
p
BH valuec
| Genes included in the pathwayd
|
---|---|---|---|
Cytokines and inflammatory response | 1.03 × 10–9
| 8.79 × 10–8
|
CXCL8, HLA-DRA, HLA-DRB1, IL10, IL12A, IL12B, IL1A, IL4, IL6, TGFB1, TNF
|
cytokine network | 9.89 × 10–9
| 3.84 × 10–7
|
CXCL8, IL10, IL12A, IL12B, IL18, IL1A, IL4, IL6, TNF
|
Hematopoietic cell lineage | 1.92 × 10–7
| 5.46 × 10–6
|
CD14, CD33, CD36, CD44, CR1, HLA-DRA, HLA-DRB1, HLA-DRB5, IL1A, IL1B, IL4, IL6, IL6R, MME, TNF
|
Dendritic cells in regulating TH1 and TH2 Development | 3.11 × 10–7
| 8.29 × 10–6
|
CD33, IL10, IL12A, IL12B, IL4, TLR2, TLR4, TLR9
|
Ovarian steroidogenesis | 5.88 × 10–6
| 1.09 × 10–4
|
ALOX5, CYP19A1, FSHR, IGF1, INS, LDLR, LHCGR, PLA2G4A, PTGS2, STAR
|
IL-5 signaling pathway | 9.00 × 10–6
| 1.60 × 10–4
|
HLA-DRA, HLA-DRB1, IL1B, IL4, IL6
|
Neurotrophin signaling pathway | 1.08 × 10–5
| 1.77 × 10–4
|
BDNF, CAMK2D, GSK3B, IRS1, NGF, NGFR, NTF3, NTRK1, NTRK2, PIK3R1, PSEN1, PSEN2, SOS2, TP53, TP73
|
HIF-1 signaling pathway | 1.12 × 10–5
| 1.77 × 10–4
|
CAMK2D, EIF4EBP1, GAPDH, HMOX1, IGF1, IL6, IL6R, INS, NOS3, PIK3R1, RPS6KB2, TF, TLR4, VEGFA
|
NOD-like receptor signaling pathway | 1.66 × 10–5
| 2.37 × 10–4
|
CARD8, CCL2, CXCL8, IL18, IL1B, IL6, MEFV, NLRP1, NLRP3, TNF
|
Mechanism of gene regulation by peroxisome proliferators via PPARα | 1.95 × 10–5
| 2.69 × 10–4
|
APOA1, CD36, INS, LPL, PIK3R1, PPARA, PTGS2, RXRA, SP1, TNF
|
Th1/Th2 differentiation | 2.54 × 10–5
| 3.19 × 10–4
|
HLA-DRA, HLA-DRB1, IL12A, IL12B, IL18, IL4
|
Antigen-dependent B-cell activation | 2.68 × 10–5
| 3.26 × 10–4
|
FAS, HLA-DRA, HLA-DRB1, IL10, IL4
|
Oxidative phosphorylation | 3.74 × 10–5
| 4.39 × 10–4
|
COX10, COX15, MT-ATP6, MT-ATP8, MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6
|
PI3K-Akt signaling pathway | 3.80 × 10–5
| 4.39 × 10–4
|
COL11A1, EFNA5, EIF4EBP1, FGF1, GNB3, GSK3B, IGF1, IL4, IL6, IL6R, INS, IRS1, NGF, NGFR, NOS3, PCK1, PIK3R1, PPP2R2B, RELN, RPS6KB2, RXRA, SOS2, TLR2, TLR4, TP53, VEGFA, YWHAQ
|
NF-κB signaling pathway | 4.83 × 10–5
| 5.42 × 10–4
|
CD14, CXCL8, ICAM1, IL1B, LCK, PARP1, PLAU, PTGS2, TLR4, TNF, TRAF2, UBE2I
|
Phagosome | 7.77 × 10–5
| 8.29 × 10–4
|
CD14, CD36, CTSS, HLA-A, HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, MBL2, MPO, NOS1, OLR1, RAB7A, TAP2, TLR2, TLR4
|
Erythrocyte differentiation pathway | 9.33 × 10–5
| 9.49 × 10–4
|
CCL3, IGF1, IL1A, IL6, TGFB1
|
IL-10 anti-inflammatory signaling pathway | 1.82 × 10–4
| 1.69 × 10–3
|
HMOX1, IL10, IL1A, IL6, TNF
|
Cells and molecules involved in local acute inflammatory response | 1.82 × 10–4
| 1.69 × 10–3
|
CXCL8, ICAM1, IL1A, IL6, TNF
|
Toll-like receptor signaling pathway | 2.15 × 10–4
| 1.95 × 10–3
|
CCL3, CD14, CXCL8, IL12A, IL12B, IL1B, IL6, PIK3R1, TLR2, TLR4, TLR9, TNF
|
Free radical induced apoptosis | 2.22 × 10–4
| 1.97 × 10–3
|
CXCL8, GPX1, SOD1, TNF
|
Intestinal immune network for IgA production | 2.65 × 10–4
| 2.26 × 10–3
|
HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, IL10, IL4, IL6, TGFB1
|
Selective expression of chemokine receptors during T-cell polarization | 3.35 × 10–4
| 2.68 × 10–3
|
CCL3, CCR2, IL12A, IL12B, IL4, TGFB1
|
B lymphocyte cell surface molecules | 3.39 × 10–4
| 2.68 × 10–3
|
CR1, HLA-DRA, HLA-DRB1, ICAM1
|
Phosphorylation of MEK1 by cdk5/p35 downregulates the MAP kinase pathway | 3.39 × 10–4
| 2.68 × 10–3
|
CDK5, CDK5R1, NGF, NGFR
|
Complement and coagulation cascades | 4.61 × 10–4
| 3.58 × 10–3
|
A2M, C4A, C4B, CFH, CR1, F13A1, MBL2, PLAU, SERPINA1
|
ABC transporters | 5.87 × 10–4
| 4.32 × 10–3
|
ABCA1, ABCA2, ABCA7, ABCC2, ABCG1, ABCG2, TAP2
|
Signal transduction through IL-1R | 6.97 × 10–4
| 5.05 × 10–3
|
IL1A, IL1B, IL1RN, IL6, TGFB1, TNF
|
mTOR signaling pathway | 8.19 × 10–4
| 5.83 × 10–3
|
EIF4EBP1, IGF1, INS, IRS1, PIK3R1, RPS6KB2, TNF, VEGFA
|
Adhesion and diapedesis of granulocytes | 9.49 × 10–4
| 6.65 × 10–3
|
CXCL8, ICAM1, IL1A, TNF
|
TNF signaling pathway | 1.12 × 10–3
| 7.69 × 10–3
|
CCL2, FAS, ICAM1, IL1B, IL6, MAGI2, MMP3, PIK3R1, PTGS2, TNF, TRAF2
|
MAPK signaling pathway | 1.13 × 10–3
| 7.69 × 10–3
|
BDNF, CD14, FAS, FGF1, IL1A, IL1B, MAPK8IP1, MAPT, MEF2C, NGF, NTF3, NTRK1, NTRK2, PLA2G4A, SOS2, TGFB1, TNF, TP53, TRAF2
|
The IGF-1 receptor and longevity | 1.26 × 10–3
| 8.28 × 10–3
|
IGF1, PIK3R1, SOD1, SOD2
|
Glutathione metabolism | 1.45 × 10–3
| 8.95 × 10–3
|
GPX1, GSTM1, GSTM3, GSTO1, GSTO2, GSTP1, GSTT1
|
Cytokine–cytokine receptor interaction | 1.48 × 10–3
| 8.95 × 10–3
|
CCL2, CCL3, CCR2, CXCL8, FAS, IL10, IL12A, IL12B, IL18, IL1A, IL1B, IL23R, IL4, IL6, IL6R, NGFR, TGFB1, TNF, VEGFA
|
Serotonergic synapse | 1.50 × 10–3
| 8.95 × 10–3
|
ALOX5, APP, CYP2D6, GNB3, HTR2A, HTR6, KCNJ6, MAOA, PLA2G4A, PTGS2, SLC6A4
|
Antigen processing and presentation | 1.63 × 10–3
| 9.53 × 10–3
|
CTSS, HLA-A, HLA-DQB1, HLA-DRA, HLA-DRB1, HLA-DRB5, HSPA5, TAP2, TNF
|
Drug metabolism—cytochrome P450 | 1.88 × 10–3
| 1.05 × 10–2
|
CYP2D6, GSTM1, GSTM3, GSTO1, GSTO2, GSTP1, GSTT1, MAOA
|
Cell cycle: G1/S check point | 2.13 × 10–3
| 1.18 × 10–2
|
CDK1, CDKN2A, GSK3B, TGFB1, TP53
|
Fcε RI signaling pathway | 2.26 × 10–3
| 1.23 × 10–2
|
FCER1G, GAB2, IL4, INPP5D, PIK3R1, PLA2G4A, SOS2, TNF
|
Apoptosis | 2.28 × 10–3
| 1.23 × 10–2
|
FAS, IL1A, IL1B, NGF, NTRK1, PIK3R1, TNF, TP53, TRAF2
|
Role of Erk5 in neuronal survival | 2.61 × 10–3
| 1.39 × 10–2
|
MEF2A, MEF2C, NTRK1, PIK3R1
|
Bioactive peptide-induced signaling pathway | 2.90 × 10–3
| 1.52 × 10–2
|
CAMK2D, CDK5, GNA11, MAPT, MYLK, PTK2B
|
Control of skeletal myogenesis by HDAC and calcium/calmodulin-dependent kinase (CaMK) | 2.93 × 10–3
| 1.52 × 10–2
|
IGF1, INS, MEF2A, MEF2C, PIK3R1
|
Metabolism of xenobiotics by cytochrome P450 | 3.22 × 10–3
| 1.62 × 10–2
|
CYP2D6, GSTM1, GSTM3, GSTO1, GSTO2, GSTP1, GSTT1, HSD11B1
|
Ras-independent pathway in NK cell-mediated cytotoxicity | 3.92 × 10–3
| 1.88 × 10–2
|
HLA-A, IL18, PIK3R1, PTK2B
|
Dopaminergic synapse | 4.48 × 10–3
| 2.11 × 10–2
|
CAMK2D, CLOCK, COMT, DRD4, GNB3, GRIN2B, GSK3B, KCNJ6, MAOA, PPP2R2B, SLC6A3
|
Cholinergic synapse | 4.57 × 10–3
| 2.12 × 10–2
|
CAMK2D, CHAT, CHRNA3, CHRNA4, CHRNA7, CHRNB2, GNA11, GNB3, KCNJ6, PIK3R1
|
The co-stimulatory signal during T-cell activation | 4.72 × 10–3
| 2.17 × 10–2
|
HLA-DRA, HLA-DRB1, LCK, PIK3R1
|
Adhesion and diapedesis of lymphocytes | 5.03 × 10–3
| 2.28 × 10–2
|
CXCL8, ICAM1, IL1A
|
Notch signaling pathway | 5.07 × 10–3
| 2.28 × 10–2
|
APH1A, APH1B, NCSTN, PSEN1, PSEN2, PSENEN
|
Role of ERBB2 in signal transduction and oncology | 5.61 × 10–3
| 2.50 × 10–2
|
ESR1, IL6, IL6R, PIK3R1
|
Aminoacyl-tRNA biosynthesis | 6.37 × 10–3
| 2.80 × 10–2
|
MT-TG, MT-TH, MT-TL2, MT-TQ, MT-TR, MT-TS2, MT-TT
|
Trka receptor signaling pathway | 6.55 × 10–3
| 2.80 × 10–2
|
NGF, NTRK1, PIK3R1
|
Rac 1 cell motility signaling pathway | 6.62 × 10–3
| 2.80 × 10–2
|
CDK5, CDK5R1, MYLK, PIK3R1
|
CTCF: first multivalent nuclear factor | 6.62 × 10–3
| 2.80 × 10–2
|
CDKN2A, PIK3R1, TGFB1, TP53
|
Regulation of PGC-1a | 7.74 × 10–3
| 3.21 × 10–2
|
CAMK2D, MEF2A, MEF2C, PPARA
|
Calcium signaling pathway | 7.85 × 10–3
| 3.22 × 10–2
|
ADRB1, ADRB2, ADRB3, CAMK2D, CHRNA7, GNA11, HTR2A, HTR6, LHCGR, MYLK, NOS1, NOS3, PTK2B
|
Lck and Fyn tyrosine kinases in initiation of TCR activation | 8.30 × 10–3
| 3.38 × 10–2
|
HLA-DRA, HLA-DRB1, LCK
|
Adipocytokine signaling pathway | 8.75 × 10–3
| 3.52 × 10–2
|
CD36, IRS1, PCK1, PPARA, RXRA, TNF, TRAF2
|
Ras signaling pathway | 9.43 × 10–3
| 3.76 × 10–2
|
EFNA5, EXOC2, FGF1, GAB2, GNB3, GRIN2B, IGF1, INS, NGF, NGFR, PIK3R1, PLA2G3, PLA2G4A, SOS2, VEGFA
|
Prolactin signaling pathway | 1.02 × 10–2
| 3.96 × 10–2
|
ESR1, ESR2, GSK3B, INS, LHCGR, PIK3R1, SOS2
|
Catecholamine biosynthesis, tyrosine → dopamine → noradrenaline → adrenaline | 1.05 × 10–2
| 3.99 × 10–2
|
DBH, PNMT
|
Fat digestion and absorption | 1.14 × 10–2
| 4.32 × 10–2
|
ABCA1, APOA1, APOA4, CD36, PLA2G3
|
Stress induction of HSP regulation | 1.26 × 10–2
| 4.63 × 10–2
|
FAS, IL1A, TNF
|
Regulation of hematopoiesis by cytokines | 1.26 × 10–2
| 4.63 × 10–2
|
CXCL8, IL4, IL6
|
CTL-mediated immune response against target cells | 1.26 × 10–2
| 4.63 × 10–2
|
FAS, HLA-A, ICAM1
|
Osteoclast differentiation | 1.32 × 10–2
| 4.81 × 10–2
|
GAB2, IL1A, IL1B, LCK, PIK3R1, PPARG, TGFB1, TNF, TRAF2, TREM2
|
Crosstalks among significantly enriched pathways
AD-specific protein network
Gene symbol | Gene name |
---|---|
ABCG5
| ATP binding cassette subfamily G member 5 |
ACHE
| Acetylcholinesterase (Yt blood group) |
ADAMTSL4
| ADAMTS-like 4 |
ADRA1D
| Adrenoceptor alpha 1D |
ALB
| Albumin |
ARFGAP3
| ADP-ribosylation factor GTPase activating protein 3 |
ARG1
| Arginase 1 |
ATP1B2
| ATPase, Na+/K+ transporting, beta 2 polypeptide |
BEND7
| BEN domain containing 7 |
BMP2
| Bone morphogenetic protein 2 |
BRI3BP
| BRI3 binding protein |
CA8
| Carbonic anhydrase VIII |
CARD16
| Caspase recruitment domain family, member 16 |
CDH2
| Cadherin 2, type 1, N-cadherin (neuronal) |
CGB
| Chorionic gonadotropin, beta polypeptide |
CHGB
| Chromogranin B |
CLEC7A
| C-type lectin domain family 7, member A |
COLQ
| Collagen-like tail subunit (single strand of homotrimer) of asymmetric acetylcholinesterase |
COPS5
| COP9 signalosome subunit 5 |
COX6B2
| Cytochrome c oxidase subunit VIb polypeptide 2 (testis) |
CRK
| V-crk avian sarcoma virus CT10 oncogene homolog |
CTAG1B
| Cancer/testis antigen 1B |
CTNNA1
| Catenin (cadherin-associated protein), alpha 1, 102 kDa |
CTSA
| Cathepsin A |
DAO
|
d-amino-acid oxidase |
DDR1
| Discoidin domain receptor tyrosine kinase 1 |
DPYSL5
| Dihydropyrimidinase-like 5 |
DYNC1LI2
| Dynein, cytoplasmic 1, light intermediate chain 2 |
EDN1
| Endothelin 1 |
EFNA1
| Ephrin-A1 |
EGFR
| Epidermal growth factor receptor |
ELF3
| E74-like factor 3 (ets domain transcription factor, epithelial-specific) |
ERAP1
| Endoplasmic reticulum aminopeptidase 1 |
ERP44
| Endoplasmic reticulum protein 44 |
ETNPPL
| Ethanolamine-phosphate phospho-lyase |
FBXO2
| F-box protein 2 |
FCGR2B
| Fc fragment of IgG, low affinity IIb, receptor (CD32) |
FGFBP1
| Fibroblast growth factor binding protein 1 |
FGG
| Fibrinogen gamma chain |
FOXRED2
| FAD-dependent oxidoreductase domain containing 2 |
GNAS
| GNAS complex locus |
GPLD1
| Glycosylphosphatidylinositol specific phospholipase D1 |
GSTM2
| Glutathione S-transferase mu 2 (muscle) |
HCRT
| Hypocretin (orexin) neuropeptide precursor |
HIST1H2AG
| Histone cluster 1, H2ag |
HIST1H2AM
| Histone cluster 1, H2am |
HLA-DQA1
| Major histocompatibility complex, class II, DQ alpha 1 |
HSD17B14
| Hydroxysteroid (17-beta) dehydrogenase 14 |
HSPA1L
| Heat shock 70 kDa protein 1-like |
IFNA5
| Interferon, alpha 5 |
IFNAR2
| Interferon (alpha, beta and omega) receptor 2 |
IL18RAP
| Interleukin-18 receptor accessory protein |
IL1R2
| Interleukin-1 receptor, type II |
IL23A
| Interleukin-23, alpha subunit p19 |
KCNJ9
| Potassium channel, inwardly rectifying subfamily J, member 9 |
KIAA0513
| KIAA0513 |
L3MBTL3
| L(3)mbt-like 3 (Drosophila) |
MAGEA11
| Melanoma antigen family A11 |
MICAL2
| Microtubule associated monooxygenase, calponin and LIM domain containing 2 |
MLLT4
| Myeloid/lymphoid or mixed-lineage leukemia; translocated to, 4 |
MUM1
| Melanoma associated antigen (mutated) 1 |
MYC
| V-myc avian myelocytomatosis viral oncogene homolog |
NRF1
| Nuclear respiratory factor 1 |
NRXN1
| Neurexin 1 |
OCIAD1
| OCIA domain containing 1 |
PIM1
| Pim-1 proto-oncogene, serine/threonine kinase |
PKNOX2
| PBX/knotted 1 homeobox 2 |
PLCZ1
| Phospholipase C, zeta 1 |
PLD1
| Phospholipase D1, phosphatidylcholine-specific |
POR
| P450 (cytochrome) oxidoreductase |
PPP1CA
| Protein phosphatase 1, catalytic subunit, alpha isozyme |
PVR
| Poliovirus receptor |
RAB26
| RAB26, member RAS oncogene family |
REST
| RE1-silencing transcription factor |
RNF19A
| Ring finger protein 19A, RBR E3 ubiquitin protein ligase |
RNF2
| Ring finger protein 2 |
RPSA
| Ribosomal protein SA |
SCNN1A
| Sodium channel, non voltage gated 1 alpha subunit |
SDHA
| Succinate dehydrogenase complex, subunit A, flavoprotein (Fp) |
SEPT12
| Septin 12 |
SEPT6
| Septin 6 |
SFN
| Stratifin |
SIRPB1
| Signal-regulatory protein beta 1 |
SLC40A1
| Solute carrier family 40 member 1 |
SORT1
| Sortilin 1 |
SSTR2
| Somatostatin receptor 2 |
STK11IP
| Serine/threonine kinase 11 interacting protein |
TMEM173
| Transmembrane protein 173 |
TNFRSF11A
| Tumor necrosis factor receptor superfamily, member 11a, NFKB activator |
TNFRSF12A
| Tumor necrosis factor receptor superfamily, member 12A |
TOMM7
| Translocase of outer mitochondrial membrane 7 homolog (yeast) |
TRMT6
| tRNA methyltransferase 6 |
TSPY2
| Testis specific protein, Y-linked 2 |
TYROBP
| TYRO protein tyrosine kinase binding protein |
UBC
| Ubiquitin C |
UBE3A
| Ubiquitin protein ligase E3A |
UBIAD1
| UbiA prenyltransferase domain containing 1 |
VKORC1
| Vitamin K epoxide reductase complex, subunit 1 |
VSTM2L
| V-set and transmembrane domain containing 2 like |
WIPF3
| WAS/WASL interacting protein family, member 3 |
YEATS4
| YEATS domain containing 4 |
ZNF423
| Zinc finger protein 423 |
ZNHIT1
| Zinc finger, HIT-type containing 1 |