CBA
HoliRD REPORT:
Hirschsprung Disease
Marina Esteban Medina
María Peña-Chilet
Carlos Loucera
Joaquín Dopazo
Clinical Bioinformatics Area - FPS
Sevilla, January 13, 2020
Collaborators:
Dra.Salud Borrego ’s group - U702 CIBERER
Research group at IBIS - Instituto de Biomedicina de Sevilla. CBA
Objectives and methodology:
The Holistic Rare Disease project (HoliRD) aims to build Diseases Maps for as many Rare Diseases as possible and to model them to systematize research in drug repurposing. In order to achieve this purpose several databases such as ORPHANET, OMIM, HPO, PubMed, KEGG, STRING, as well as the literature is used to collect all the up-to-date knowledge of the diseases under study and defining a Disease Map that contains the functional relationships among the known disease genes, as well as the functional consequences of their activity. Then, a mechanistic model that accounts for the activity of such map is used. The HiPathia algorithm, which has successfully proven to predict cell activities related to cancer hallmarks (Hidalgo et al., Oncotarget 2017; 8:5160-5178; Hidalgo et al., Biol Direct. 2018;13:16) as well as the effect of protein inhibitions on cell survival (Cubuk et al., Cancer Res. 2018; 78:6059-6072) is used to simulate the activity of the disease map.
Finally, machine learning algorithms are used to find other proteins, already target of drugs with another indication, which display a potential causal effect on the activity of the previously defined disease map. The drugs that target these proteins are potential candidates for repurposing.
Schematic representation of the method used.
Examples of the use of this approach can be found in Esteban-Medina et al., BMC Bioinformatics. 2019, 20(1):370. CBA
Report
This report describes the results of the different steps of the HoliRD approach applied to Hirschsprung Disease
Identification of genes highly related to the rare disease (RD) under study in Orphanet/OMIM
A total of 10 genes annotated as Hirschsprung Disease (HD) were found in the ORPHANET/OMIM database.
HD highly related genes
Disease ID Entrez ID Gene Symbol Disease ID Entrez ID Gene symbol
ORPHA:2151 8929 PHOX2B ORPHA:388 4902 NRTN
ORPHA:388 10512 SEMA3C ORPHA:388 5979 RET
ORPHA:388 1889 ECE1 ORPHA:388 2668 GDNF
ORPHA:388 1908 EDN3 ORPHA:388 223117 SEMA3D
ORPHA:388 1910 EDNRB OMIM:609136 6663 SOX10 CBA
Identification of highly related HPO to the RD under study:
A total of 9 HPO codes associated to HD with specificity >=7 were selected.
HD highly related HPOs
HPO ID HPO term Specificity level
HP:0000407 Sensorineural hearing impairment 10
HP:0001181 Adducted thumb 14
HP:0001249 Intellectual disability 7
HP:0001531 Failure to thrive in infancy 7
HP:0002027 Abdominal pain 8
HP:0002251 Aganglionic megacolon 14
HP:0005214 Intestinal obstruction 11
HP:0100031 Neoplasm of the thyroid gland 9
HP:0200008 Intestinal polyposis 12
Identification of genes that shared at least RD-HPO codes
Genes with >= 4 HD-HPO codes
Gene Symbol Entrez Gene Symbol Entrez Gene Symbol Entrez
APC 324 KRAS 3845 SDHC 6391
ATRX 546 LIMK1 3984 SDHD 6392
BMPR1A 657 MITF 4286 SOX10 6663
CTNNB1 1499 TRNL1 4567 TGFBR2 7048 CBA
ECE1 1889 TRNS1 4574 CLIP2 7461
EDN3 1908 NRTN 4902 BAZ1B 9031
EDNRB 1910 PIK3CA 5290 GTF2IRD1 9569
ELN 2006 PTEN 5728 SEMA3C 10512
GDNF 2668 RET 5979 SETBP1 26040
GNAS 2778 RFC2 5982 TBL2 26608
GTF2I 2969 SDHA 6389 BCOR 54880
KIT 3815 SDHB 6390 SEMA4A 64218
SEMA3D 223117
Genes with >= 6 HD-HPO codes
Gene Symbol Entrez Gene Symbol Entrez
ECE1 1889 NRTN 4902
EDN3 1908 RET 5979
EDNRB 1910 SEMA3C 10512
GDNF 2668 SEMA3D 223117
KRAS 3845 CBA
Genes with >= 8 HD-HPO codes
Gene Symbol Entrez Gene Symbol Entrez
ECE1 1889 NRTN 4902
EDN3 1908 RET 5979
EDNRB 1910 SEMA3C 10512
GDNF 2668 SEMA3D 223117
In order to maintain the specificity and not over expand the Disease Map of action only genes with >=6 HD-HPO codes were selected.
Location of the selected disease related genes in KEGG pathways to define the Disease Map of action.
After locating the RD associated genes within KEGG pathways, a total of 182 circuits belonging to 36 KEGG pathways were found as part of the disease map.
KEGG pathway KEGG-pathway code MAPK signaling pathway hsa04010 ErbB signaling pathway hsa04012 Ras signaling pathway hsa04014 Rap1 signaling pathway hsa04015 Calcium signaling pathway hsa04020 cGMP-PKG signaling pathway hsa04022 Chemokine signaling pathway hsa04062 FoxO signaling pathway hsa04068 Sphingolipid signaling pathway hsa04071 Phospholipase D signaling pathway hsa04072 mTOR signaling pathway hsa04150 PI3K-Akt signaling pathway hsa04151 Apoptosis hsa04210 Longevity regulating pathway - mammal hsa04211 Axon guidance hsa04360 VEGF signaling pathway hsa04370 Tight junction hsa04530 CBA
Gap junction hsa04540 Signaling pathways regulating pluripotency of stem cells hsa04550 Natural killer cell mediated cytotoxicity hsa04650 T cell receptor signaling pathway hsa04660 B cell receptor signaling pathway hsa04662 Fc epsilon RI signaling pathway hsa04664 Neurotrophin signaling pathway hsa04722 Cholinergic synapse hsa04725 Serotonergic synapse hsa04726 Regulation of actin cytoskeleton hsa04810 Insulin signaling pathway hsa04910 GnRH signaling pathway hsa04912 Progesterone-mediated oocyte maturation hsa04914 Estrogen signaling pathway hsa04915 Melanogenesis hsa04916 Prolactin signaling pathway hsa04917 Thyroid hormone signaling pathway hsa04919 Oxytocin signaling pathway hsa04921 Aldosterone-regulated sodium reabsorption hsa04960
HiPathia is a signal propagation algorithm that considers pathways as collections of circuits defined as sub-pathways or sequences of proteins connecting signal receptor proteins to effector proteins. HiPathia uses expression values genes as proxies of the level of activation of the corresponding protein in the circuit. Taking into account the inferred protein activity and the interactions between the proteins (activation or inhibition) defined in the pathway, the level of activity of a circuit is estimated using a signal propagation algorithm. Ultimately, effector proteins are annotated with a cellular function.
In order to enable a better visualization of the RD Map the HiPathia viewer has been used. The circuits that define the RD Map are marked in RED (please ignore the color legend). The pathways that contain these circuits are highlighted in the right window with a red arrow. The only purpose of this report is to represent the components (genes and interaction) and functions of the circuits that compose the RD Map.
Click to access the RD Map Report CBA
HiPathia uses KEGG pathway for the graphical representation of the circuits. The original pathways can also be visualized in the KEGG repository
https://www.genome.jp/kegg/pathway.html
Select prefix: hsa (Organism) Enter keywords: e.g. FoxOsignalingpathway (any HiPathia pathway)
Prediction of relevance of gene targets from approved drugs extracted from DRUGBANK database (release 5.1.4)
The HoliRD approach takes the mechanistic model of the disease map as the proxy for the molecular basis of the disease outcome. Then, a Multi-Output Random Forest (MORF) regressor, a machine learning algorithm that predicts the circuit activities across the whole disease map, is trained on GTEx gene expression data to find proteins (which are targets for drugs with indications for other diseases) that correctly predict the behavior of the disease map. The drugs targeting the best predictor proteins are candidate for drug repurposing. The relevance score accounts for the accuracy of the prediction contributed by each individual protein. Relevance are absolute values and do not account for the direction of the prediction, that is, if the interaction is an activation or an inhibition. CBA
From a total of 683 targets for approved drugs (AT) in the DRUGBANK database (release 5.1.4) the machine learning algorithm selected the 62 most relevant ones (top AT).
Entrez Gene symbol Relevance score Entrez Gene symbol Relevance score 4130 MAP1A 0.1554035565 657 BMPR1A 0.003619209 3561 IL2RG 0.0853983045 3570 IL6R 0.0036092627 2554 GABRA1 0.0591264789 6616 SNAP25 0.0035877724 3767 KCNJ11 0.0372669743 7068 THRB 0.0035538714 1441 CSF3R 0.0301809157 941 CD80 0.0035463019 6093 ROCK1 0.0257452691 1043 CD52 0.003537257 5916 RARG 0.0256825012 7134 TNNC1 0.0034864037 4214 MAP3K1 0.0197904239 4134 MAP4 0.0034379318 57468 SLC12A5 0.0197133066 3563 IL3RA 0.0033721244 9475 ROCK2 0.0151823485 6323 SCN1A 0.0031798254 6261 RYR1 0.0142311972 3688 ITGB1 0.0031312124 645 BLVRB 0.0108550062 3351 HTR1B 0.0031262512 3683 ITGAL 0.0099676683 847 CAT 0.0029671267 2904 GRIN2B 0.0093780568 3849 KRT2 0.0029401554 3725 JUN 0.0081707732 3716 JAK1 0.0029390546 3039 HBA1 0.0073066217 782 CACNB1 0.0027859541 2902 GRIN1 0.0071713071 1583 CYP11A1 0.0027795856 64127 NOD2 0.0052587777 1080 CFTR 0.0027726055 302 ANXA2 0.0052463705 2247 FGF2 0.0025992222 774 CACNA1B 0.0051372524 5698 PSMB9 0.0025055776 55800 SCN3B 0.0050310471 4128 MAOA 0.0024790078 2444 FRK 0.00495984 338442 HCAR2 0.0024740118 7097 TLR2 0.0047835314 6715 SRD5A1 0.002470577 2559 GABRA6 0.0047791421 3737 KCNA2 0.0024400973 695 BTK 0.0046609928 1361 CPB2 0.0024025715 5423 POLB 0.0045240031 2690 GHR 0.0023936546 301 ANXA1 0.0044558809 7048 TGFBR2 0.0023879617 6752 SSTR2 0.0043553951 5468 PPARG 0.0023317997 5139 PDE3A 0.0042249933 5743 PTGS2 0.002313308 786 CACNG1 0.0039811131 7422 VEGFA 0.0023012003 3768 KCNJ12 0.003918914 1956 EGFR 0.0022066809 CBA
Relevance plot depicting the 62 most relevant gene targets (top AT).
Drugs from DRUGBANK db (release 5.1.4) that target top AT.
And the list of drugs that target the 62 most relevant genes follows:
You can click on the hyperlink of the Drug ID to see more detailed information about the drug in DrugBank DB.
Associated Relevance Drug ID Drug Name Drug Effect Target condition score
DB01196 Estramustine antagonist MAP1A 0,1554
High Risk DB00041 Aldesleukin agonist IL2RG 0,0854 Neuroblastoma
positive allosteric DB00186 Lorazepam GABRA1 Agitation 0,05913 modulator
positive allosteric DB00228 Enflurane GABRA1 0,05913 modulator
DB00231 Temazepam potentiator GABRA1 0,05913
DB00231 Temazepam positive allosteric GABRA1 0,05913 CBA
modulator
positive allosteric DB00237 Butabarbital GABRA1 0,05913 modulator
Headache, DB00241 Butalbital potentiator GABRA1 0,05913 Tension-Type
positive allosteric Headache, DB00241 Butalbital GABRA1 0,05913 modulator Tension-Type
Alcohol DB00273 Topiramate agonist GABRA1 0,05913 Dependence
positive allosteric Alcohol DB00273 Topiramate GABRA1 0,05913 modulator Dependence
DB00292 Etomidate agonist GABRA1 0,05913
positive allosteric DB00292 Etomidate GABRA1 0,05913 modulator
DB00306 Talbutal potentiator GABRA1 0,05913
positive allosteric DB00306 Talbutal GABRA1 0,05913 modulator
DB00312 Pentobarbital potentiator GABRA1 Insomnia 0,05913
positive allosteric DB00312 Pentobarbital GABRA1 Insomnia 0,05913 modulator
positive allosteric DB00349 Clobazam GABRA1 0,05913 modulator
DB00371 Meprobamate agonist GABRA1 0,05913
positive allosteric DB00371 Meprobamate GABRA1 0,05913 modulator
DB00402 Eszopiclone potentiator GABRA1 0,05913
positive allosteric DB00402 Eszopiclone GABRA1 0,05913 modulator
positive allosteric DB00404 Alprazolam GABRA1 Anxiety 0,05913 modulator
DB00418 Secobarbital potentiator GABRA1 0,05913 CBA
DB00425 Zolpidem agonist GABRA1 0,05913
DB00474 Methohexital antagonist GABRA1 0,05913
Alcohol Chlordiazepoxid positive allosteric DB00475 GABRA1 Withdrawal 0,05913 e modulator Syndrome(AWS)
DB00599 Thiopental potentiator GABRA1 0,05913
positive allosteric Acute Alcohol DB00628 Clorazepic acid GABRA1 0,05913 modulator Withdrawal
positive DB00659 Acamprosate GABRA1 0,05913 modulator
DB00683 Midazolam potentiator GABRA1 Seizures, Epileptic 0,05913
DB00690 Flurazepam potentiator GABRA1 0,05913
DB00753 Isoflurane agonist GABRA1 0,05913
positive allosteric DB00753 Isoflurane GABRA1 0,05913 modulator
Grand mal Generalized DB00794 Primidone potentiator GABRA1 0,05913 tonic-clonic seizure
Grand mal positive allosteric Generalized DB00794 Primidone GABRA1 0,05913 modulator tonic-clonic seizure
positive allosteric DB00818 Propofol GABRA1 0,05913 modulator
Alcohol DB00829 Diazepam potentiator GABRA1 Withdrawal 0,05913 Syndrome(AWS)
Alcohol positive allosteric DB00829 Diazepam GABRA1 Withdrawal 0,05913 modulator Syndrome(AWS)
DB00842 Oxazepam potentiator GABRA1 Alcohol 0,05913 Withdrawal CBA
Syndrome(AWS)
Alcohol positive allosteric DB00842 Oxazepam GABRA1 Withdrawal 0,05913 modulator Syndrome(AWS)
Methylphenoba DB00849 potentiator GABRA1 0,05913 rbital
DB00897 Triazolam potentiator GABRA1 0,05913
positive allosteric DB00897 Triazolam GABRA1 0,05913 modulator
Bacterial DB00898 Ethanol agonist GABRA1 0,05913 Infections
DB00962 Zaleplon potentiator GABRA1 0,05913
DB01028 Methoxyflurane agonist GABRA1 Severe Pain 0,05913
positive allosteric DB01028 Methoxyflurane GABRA1 Severe Pain 0,05913 modulator
positive allosteric DB01068 Clonazepam GABRA1 Akinetic seizures 0,05913 modulator
DB01154 Thiamylal agonist GABRA1 0,05913
positive allosteric DB01159 Halothane GABRA1 0,05913 modulator
Alcohol DB01174 Phenobarbital potentiator GABRA1 Withdrawal 0,05913 Syndrome(AWS)
positive allosteric DB01189 Desflurane GABRA1 0,05913 modulator
DB01198 Zopiclone potentiator GABRA1 0,05913
Anesthesia DB01205 Flumazenil antagonist GABRA1 0,05913 reversal
positive allosteric Anesthesia DB01205 Flumazenil GABRA1 0,05913 modulator reversal
DB01215 Estazolam potentiator GABRA1 0,05913 CBA
positive allosteric DB01215 Estazolam GABRA1 0,05913 modulator
DB01236 Sevoflurane agonist GABRA1 0,05913
positive allosteric DB01236 Sevoflurane GABRA1 0,05913 modulator
Quinidine DB01346 potentiator GABRA1 0,05913 barbiturate
DB01351 Amobarbital potentiator GABRA1 0,05913
DB01353 Butobarbital potentiator GABRA1 0,05913
DB01437 Glutethimide agonist GABRA1 0,05913
positive allosteric DB01437 Glutethimide GABRA1 0,05913 modulator
DB01558 Bromazepam potentiator GABRA1 Acute Anxiety 0,05913
DB01559 Clotiazepam potentiator GABRA1 0,05913
DB01587 Ketazolam potentiator GABRA1 0,05913
DB01588 Prazepam potentiator GABRA1 0,05913
positive allosteric DB01588 Prazepam GABRA1 0,05913 modulator
DB01589 Quazepam potentiator GABRA1 0,05913
positive allosteric DB01589 Quazepam GABRA1 0,05913 modulator
DB01595 Nitrazepam potentiator GABRA1 Insomnia 0,05913
DB01956 Taurine agonist GABRA1 0,05913
agonist,positive DB09118 Stiripentol allosteric GABRA1 0,05913 modulator
positive allosteric DB11859 Brexanolone GABRA1 0,05913 modulator
positive allosteric DB13872 Lormetazepam GABRA1 0,05913 modulator CBA
DB00222 Glimepiride inhibitor KCNJ11 0,03727
DB00922 Levosimendan inducer KCNJ11 0,03727
DB01119 Diazoxide inducer KCNJ11 0,03727
DB01154 Thiamylal inhibitor KCNJ11 0,03727
Chemotherapy DB00019 Pegfilgrastim agonist CSF3R Induced 0,03018 Neutropenia
Hematopoietic Subsyndrome of DB00099 Filgrastim stimulator CSF3R 0,03018 Acute Radiation Syndrome
DB13144 Lenograstim agonist CSF3R 0,03018
Neutropenia, DB13200 Lipegfilgrastim agonist CSF3R 0,03018 Febrile
DB13931 Netarsudil inhibitor ROCK1 0,02575
DB00210 Adapalene agonist RARG Acne Vulgaris 0,02568
Keratinization DB00459 Acitretin agonist RARG 0,02568 disorders
Chronic Eczema of DB00523 Alitretinoin agonist RARG 0,02568 the hand
DB00755 Tretinoin agonist RARG Acne Vulgaris 0,02568
Psoriasis Vulgaris DB00799 Tazarotene agonist RARG 0,02568 (Plaque Psoriasis)
Metastatic DB11967 Binimetinib inhibitor MAP3K1 0,01979 Melanoma
DB00887 Bumetanide inhibitor SLC12A5 0,01971
DB13931 Netarsudil inhibitor ROCK2 0,01518
Malignant DB01219 Dantrolene antagonist RYR1 0,01423 Hyperthermia
DB09085 Tetracaine modulator RYR1 0,01423 CBA
DB00140 Riboflavin product of BLVRB Ariboflavinosis 0,01086
DB00095 Efalizumab antibody ITGAL 0,00997
Antithymocyte Acute cellular DB00098 immunoglobulin #N/A ITGAL 0,00997 rejection (rabbit)
DB11611 Lifitegrast antagonist ITGAL 0,00997
Refractory Partial DB00949 Felbamate antagonist GRIN2B 0,00938 Seizures
DB01956 Taurine inhibitor GRIN2B 0,00938
DB01169 Arsenic trioxide inducer JUN 0,00817
Plasmodium DB00358 Mefloquine antagonist HBA1 0,00731 Infections
DB00893 Iron Dextran activator HBA1 0,00731
Pentaerythritol DB06154 agonist HBA1 0,00731 tetranitrate
DB09112 Nitrous acid oxidizer HBA1 0,00731
Hyperphosphatae DB09146 Iron saccharate component of HBA1 0,00731 mia
Ferric DB13995 pyrophosphate binder HBA1 0,00731 citrate
DB00659 Acamprosate antagonist GRIN1 0,00717
Mild Vascular DB01043 Memantine antagonist GRIN1 0,00717 dementia
DB01173 Orphenadrine antagonist GRIN1 Muscle Spasms 0,00717
High-grade, DB13615 Mifamurtide ligand NOD2 nonmetastatic 0,00526 Osteosarcoma
Fluocinolone Atopic Dermatitis DB00591 inducer ANXA2 0,00525 acetonide (AD)
DB00996 Gabapentin inhibitor CACNA1B Partial-Onset 0,00514 CBA
Seizures
DB01202 Levetiracetam inhibitor CACNA1B Epilepsies 0,00514
DB00909 Zonisamide inhibitor SCN3B 0,00503
Metastatic DB08896 Regorafenib inhibitor FRK Gastrointestinal 0,00496 Stromal Tumor
DB00231 Temazepam potentiator GABRA6 0,00478
Headache, DB00241 Butalbital potentiator GABRA6 0,00478 Tension-Type
DB00306 Talbutal potentiator GABRA6 0,00478
DB00312 Pentobarbital potentiator GABRA6 Insomnia 0,00478
DB00371 Meprobamate agonist GABRA6 0,00478
DB00418 Secobarbital potentiator GABRA6 0,00478
DB00599 Thiopental potentiator GABRA6 0,00478
DB00683 Midazolam potentiator GABRA6 Seizures, Epileptic 0,00478
DB00690 Flurazepam potentiator GABRA6 0,00478
Grand mal Generalized DB00794 Primidone potentiator GABRA6 0,00478 tonic-clonic seizure
Alcohol DB00842 Oxazepam potentiator GABRA6 Withdrawal 0,00478 Syndrome(AWS)
Methylphenoba DB00849 potentiator GABRA6 0,00478 rbital
DB00897 Triazolam potentiator GABRA6 0,00478
DB01351 Amobarbital potentiator GABRA6 0,00478
DB01353 Butobarbital potentiator GABRA6 0,00478
DB01544 Flunitrazepam potentiator GABRA6 0,00478
DB01558 Bromazepam potentiator GABRA6 Acute Anxiety 0,00478 CBA
DB01595 Nitrazepam potentiator GABRA6 Insomnia 0,00478
Tuberculin DB11601 Purified Protein ligand TLR2 0,00478 Derivative
Chronic DB09053 Ibrutinib inhibitor BTK Lymphocytic 0,00466 Leukaemia (CLL)
DB11703 Acalabrutinib inhibitor BTK 0,00466
Acute Lymphocytic DB00987 Cytarabine inhibitor POLB 0,00452 Leukemia (ALL)
Fluocinolone Atopic Dermatitis DB00591 inducer ANXA1 0,00446 acetonide (AD)
Acute Gouty DB00741 Hydrocortisone agonist ANXA1 0,00446 Arthritis
Hydrocortisone Adrenal cortical DB14539 #N/A ANXA1 0,00446 acetate hypofunctions
Hydrocortisone Atopic Dermatitis DB14540 #N/A ANXA1 0,00446 butyrate (AD)
Hydrocortisone DB14541 #N/A ANXA1 0,00446 cypionate
Hydrocortisone DB14542 #N/A ANXA1 0,00446 phosphate
Hydrocortisone DB14543 #N/A ANXA1 Itching 0,00446 probutate
Hydrocortisone DB14544 #N/A ANXA1 0,00446 valerate
DB00104 Octreotide binder SSTR2 Acromegaly 0,00436
DB09099 Somatostatin agonist SSTR2 0,00436
Dotatate DB13925 binder SSTR2 0,00436 gallium Ga-68
Lutetium Lu 177 DB13985 agonist SSTR2 0,00436 dotatate CBA
DB00235 Milrinone inhibitor PDE3A 0,00422
DB00261 Anagrelide inhibitor PDE3A 0,00422
DB00277 Theophylline inhibitor PDE3A 0,00422
DB01166 Cilostazol inhibitor PDE3A 0,00422
Acute Exacerbation of DB01223 Aminophylline inhibitor PDE3A 0,00422 Chronic Bronchitis (AECB)
DB01303 Oxtriphylline inhibitor PDE3A 0,00422
DB01427 Amrinone inhibitor PDE3A 0,00422
DB04880 Enoximone inhibitor PDE3A 0,00422
DB00343 Diltiazem blocker CACNG1 Anal Fissures 0,00398
DB00381 Amlodipine blocker CACNG1 Anginal Pain 0,00398
DB00528 Lercanidipine inhibitor CACNG1 0,00398
DB01054 Nitrendipine inhibitor CACNG1 0,00398
Symptomatic DB00204 Dofetilide inhibitor KCNJ12 0,00392 Atrial flutter
DB11639 Dibotermin alfa ligand BMPR1A 0,00362
Polyarticular DB06273 Tocilizumab antibody IL6R Juvenile Idiopathic 0,00361 Arthritis
Moderate, active antagonist,antibo DB11767 Sarilumab IL6R Rheumatoid 0,00361 dy arthritis
Botulinum toxin DB00083 inhibitor SNAP25 Blepharospasm 0,00359 type A
Autonomy of DB00279 Liothyronine agonist THRB 0,00355 thyroid gland
DB00451 Levothyroxine agonist THRB Hypothyroidism 0,00355
DB00509 Dextrothyroxine agonist THRB 0,00355 CBA
Moderate Juvenile DB01281 Abatacept antagonist CD80 0,00355 idiopathic arthritis
DB01583 Liotrix agonist THRB 0,00355
Urothelial DB11714 Durvalumab binder CD80 carcinoma ureter 0,00355 metastatic
Autoimmune DB00087 Alemtuzumab antibody CD52 0,00354 Hemolytic Anemia
DB00922 Levosimendan potentiator TNNC1 0,00349
DB01373 Calcium agonist TNNC1 0,00349
Advanced Cervical DB01229 Paclitaxel #N/A MAP4 0,00344 Cancer
Esophageal DB01248 Docetaxel #N/A MAP4 0,00344 Cancers
Bone Marrow DB00020 Sargramostim agonist IL3RA 0,00337 Suppression
DB14731 Tagraxofusp binder IL3RA 0,00337
Complex Partial DB00252 Phenytoin inhibitor SCN1A 0,00318 Seizures
Alcohol DB00273 Topiramate inhibitor SCN1A 0,00318 Dependence
DB00909 Zonisamide inhibitor SCN1A 0,00318
DB01121 Phenacemide inhibitor SCN1A 0,00318
Phenazopyridin DB01438 inhibitor SCN1A 0,00318 e
DB04930 Permethrin inhibitor SCN1A Norwegian scabies 0,00318
DB05541 Brivaracetam inhibitor SCN1A 0,00318
Dichlorobenzyl DB13269 antagonist SCN1A Mouth infection 0,00318 alcohol
Acute cellular DB00098 Antithymocyte #N/A ITGB1 0,00313 immunoglobulin rejection CBA
(rabbit)
DB00216 Eletriptan agonist HTR1B Acute Migraine 0,00313
DB00315 Zolmitriptan agonist HTR1B 0,00313
Dihydroergotam DB00320 agonist HTR1B Cluster Headache 0,00313 ine
DB00669 Sumatriptan agonist HTR1B Acute Migraine 0,00313
DB00696 Ergotamine agonist HTR1B Cluster Headache 0,00313
Migraine with DB00952 Naratriptan agonist HTR1B 0,00313 acute onset aura
Migraine with DB00953 Rizatriptan agonist HTR1B 0,00313 acute onset aura
Menstrual DB00998 Frovatriptan agonist HTR1B 0,00313 Migraines
DB09068 Vortioxetine partial agonist HTR1B 0,00313
Ethylene glycol DB01213 Fomepizole inhibitor CAT 0,00297 poisoning
Post Essential DB08877 Ruxolitinib inhibitor JAK1 Thrombocythemia 0,00294 Myelofibrosis
Moderate DB08895 Tofacitinib inhibitor JAK1 Rheumatoid 0,00294 arthritis
DB11157 Anthralin antagonist KRT2 0,00294
Moderate, active DB11817 Baricitinib inhibitor JAK1 Rheumatoid 0,00294 arthritis
Atrial Fibrillation DB00308 Ibutilide activator CACNB1 0,00279 (AF)
DB00393 Nimodipine inhibitor CACNB1 0,00279
Atrial Fibrillation DB00661 Verapamil inhibitor CACNB1 0,00279 (AF) CBA
Aminoglutethim DB00357 inhibitor CYP11A1 0,00278 ide
DB04941 Crofelemer antagonist CFTR 0,00277
DB08820 Ivacaftor potentiator CFTR 0,00277
DB09280 Lumacaftor modulator CFTR 0,00277
DB11712 Tezacaftor activator CFTR 0,00277
DB00364 Sucralfate agonist,inducer FGF2 Gastric Ulcer (GU) 0,0026
Pentosan DB00686 antagonist FGF2 0,0026 Polysulfate
DB00877 Sirolimus other/unknown FGF2 Chordomas 0,0026
Refractory DB08889 Carfilzomib inhibitor PSMB9 0,00251 Multiple Myeloma
Attention Deficit Disorder With DB00182 Amphetamine inhibitor MAOA 0,00248 Hyperactivity (ADHD)
DB00191 Phentermine antagonist MAOA 0,00248
Tranylcypromin DB00752 inhibitor MAOA 0,00248 e
Exogenous DB00780 Phenelzine antagonist MAOA 0,00248 depression
DB00805 Minaprine inhibitor MAOA 0,00248
DB01168 Procarbazine inhibitor MAOA Non-Hodgkin' 0,00248
antagonist,inhibit DB01171 Moclobemide MAOA 0,00248 or
DB01247 Isocarboxazid inhibitor MAOA 0,00248
Attention Deficit Disorder With DB01577 Metamfetamine inhibitor MAOA 0,00248 Hyperactivity (ADHD)
DB00367 Levonorgestrel inhibitor SRD5A1 Endometrial 0,00247 CBA
Cancers
DB00627 Niacin agonist HCAR2 Atherosclerosis 0,00247
Benign Prostatic DB01126 Dutasteride inhibitor SRD5A1 0,00247 Hyperplasia (BPH)
Abnormal Uterine DB09389 Norgestrel inhibitor SRD5A1 0,00247 Bleeding
DB06637 Dalfampridine antagonist KCNA2 0,00244
DB11311 Prothrombin agonist CPB2 0,0024
Adult Onset DB00052 Somatotropin binder GHR Growth Hormone 0,00239 Deficiency
DB00082 Pegvisomant antagonist GHR 0,00239
Foreskin DB10772 keratinocyte agonist TGFBR2 0,00239 (neonatal)
DB00159 Icosapent agonist PPARG 0,00233
DB00244 Mesalazine agonist PPARG Crohn' 0,00233
DB00412 Rosiglitazone agonist PPARG 0,00233
DB00795 Sulfasalazine agonist PPARG Crohn' 0,00233
Cardiovascular DB00966 Telmisartan partial agonist PPARG 0,00233 Events
Mild Ulcerative DB01014 Balsalazide agonist PPARG 0,00233 Colitis
DB01132 Pioglitazone agonist PPARG 0,00233
Dyslipidemia DB01393 Bezafibrate agonist PPARG (Fredrickson Type 0,00233 Ⅱa)
DB03756 Doconexent ligand PPARG 0,00233
Omega-3 fatty DB11133 ligand PPARG 0,00233 acids CBA
DB00159 Icosapent inhibitor PTGS2 0,00231
DB00210 Adapalene inhibitor PTGS2 Acne Vulgaris 0,00231
DB00244 Mesalazine inhibitor PTGS2 Crohn' 0,00231
DB00316 Acetaminophen inhibitor PTGS2 Fevers 0,00231
Acute Gouty DB00328 Indometacin inhibitor PTGS2 0,00231 Arthritis
Osteoarthritis DB00461 Nabumetone inhibitor PTGS2 0,00231 (OA)
DB00465 Ketorolac inhibitor PTGS2 Acute Migraine 0,00231
DB00469 Tenoxicam inhibitor PTGS2 Backache 0,00231
Ankylosing DB00482 Celecoxib inhibitor PTGS2 0,00231 Spondylitis (AS)
Ankylosing DB00500 Tolmetin inhibitor PTGS2 0,00231 Spondylitis (AS)
Ankylosing DB00554 Piroxicam inhibitor PTGS2 0,00231 Spondylitis (AS)
DB00573 Fenoprofen inhibitor PTGS2 Mild pain 0,00231
Actinic Keratosis DB00586 Diclofenac inhibitor PTGS2 0,00231 (AK)
Acute Gouty DB00605 Sulindac inhibitor PTGS2 0,00231 Arthritis
Ankylosing DB00712 Flurbiprofen inhibitor PTGS2 0,00231 Spondylitis (AS)
Juvenile Idiopathic DB00749 Etodolac inhibitor PTGS2 0,00231 Arthritis (JIA)
DB00784 Mefenamic acid inhibitor PTGS2 Mild pain 0,00231
Acute Gouty DB00788 Naproxen inhibitor PTGS2 0,00231 Arthritis
DB00795 Sulfasalazine inhibitor PTGS2 Crohn' 0,00231
DB00812 Phenylbutazone inhibitor PTGS2 0,00231 CBA
Osteoarthritis DB00814 Meloxicam inhibitor PTGS2 0,00231 (OA)
DB00861 Diflunisal inhibitor PTGS2 Mild pain 0,00231
DB00936 Salicylic acid inhibitor PTGS2 Acne 0,00231
Meclofenamic Acute Gouty DB00939 inhibitor PTGS2 0,00231 acid Arthritis
Acetylsalicylic Acute Coronary DB00945 inhibitor PTGS2 0,00231 acid Syndromes (ACS)
DB00963 Bromfenac inhibitor PTGS2 Ocular Pain 0,00231
Osteoarthritis DB00991 Oxaprozin inhibitor PTGS2 0,00231 (OA)
Ankylosing DB01009 Ketoprofen inhibitor PTGS2 0,00231 Spondylitis (AS)
Mild Ulcerative DB01014 Balsalazide inhibitor PTGS2 0,00231 Colitis
Acute Gouty DB01050 Ibuprofen inhibitor PTGS2 0,00231 Arthritis
DB01283 Lumiracoxib inhibitor PTGS2 0,00231
DB01399 Salsalate inhibitor PTGS2 0,00231
Osteoarthritis DB01600 Tiaprofenic acid inhibitor PTGS2 0,00231 (OA)
DB01628 Etoricoxib inhibitor PTGS2 0,00231
DB06725 Lornoxicam inhibitor PTGS2 0,00231
DB06736 Aceclofenac inhibitor PTGS2 0,00231
DB08439 Parecoxib inhibitor PTGS2 0,00231
DB08910 Pomalidomide inhibitor PTGS2 0,00231
DB09213 Dexibuprofen inhibitor PTGS2 0,00231
DB09216 Tolfenamic Acid antagonist PTGS2 0,00231
Trolamine DB11079 inhibitor PTGS2 0,00231 salicylate CBA
Menthyl DB11201 antagonist PTGS2 0,00231 salicylate
DB11323 Glycol salicylate antagonist PTGS2 0,00231
DB13783 Acemetacin antagonist PTGS2 0,00231
DB13961 Fish oil inhibitor PTGS2 0,00231
DB00112 Bevacizumab #N/A VEGFA Glioblastomas 0,0023
Diabetic Macular DB01270 Ranibizumab #N/A VEGFA 0,0023 Edema (DME)
Cardiovascular DB06779 Dalteparin inhibitor VEGFA 0,0023 Events
Diabetic Macular DB08885 Aflibercept binder VEGFA 0,0023 Edema (DME)
Foreskin DB10772 keratinocyte agonist VEGFA 0,0023 (neonatal)
Metastatic DB00002 Cetuximab antagonist EGFR 0,00221 Colorectal Cancers
DB00317 Gefitinib antagonist EGFR 0,00221
Locally Advanced DB00530 Erlotinib antagonist EGFR Non-Small Cell 0,00221 Lung Cancer
Metastatic Breast DB01259 Lapatinib antagonist EGFR 0,00221 Cancer (MBC)
DB01269 Panitumumab suppressor EGFR 0,00221
Metastatic DB08916 Afatinib inhibitor EGFR Non-Small Cell 0,00221 Lung Cancer
DB09330 Osimertinib inhibitor EGFR 0,00221
DB09559 Necitumumab antagonist EGFR 0,00221
Foreskin DB10772 keratinocyte agonist EGFR 0,00221 (neonatal) CBA
DB11828 Neratinib inhibitor EGFR 0,00221
DB11963 Dacomitinib inhibitor EGFR 0,00221
DB12267 Brigatinib inhibitor EGFR 0,00221
Location of top AT in HiPathia circuits and selection of those circuits shared with the Disease Map. A total of 125/182 circuits from RD Map containing top AT are shown.
Disease Map circuits with top AT
HiPathia pathway: HiPathia pathway: HiPathia pathway: HiPathia pathway: effector gene effector gene effector gene effector gene
Signaling pathways MAPK signaling FoxO signaling PI3K-Akt signaling regulating pathway: ATF4* pathway: CCND1 pathway: CCND1 pluripotency of stem cells: MAPK1*
Natural killer cell MAPK signaling FoxO signaling PI3K-Akt signaling mediated pathway: FOS pathway: CCNG2 pathway: CDKN1B cytotoxicity: TNF
Natural killer cell MAPK signaling FoxO signaling PI3K-Akt signaling mediated pathway: MAPT pathway: CDKN2B pathway: RBL2 cytotoxicity: CSF2
Natural killer cell MAPK signaling FoxO signaling PI3K-Akt signaling mediated pathway: STMN1 pathway: CDKN2D pathway: PCK1 cytotoxicity: FAS
Natural killer cell MAPK signaling FoxO signaling PI3K-Akt signaling mediated pathway: PLA2G4B pathway: CDKN1A pathway: G6PC cytotoxicity: TNFRSF10D
T cell receptor MAPK signaling FoxO signaling PI3K-Akt signaling signaling pathway: pathway: MYC pathway: CDKN1B pathway: FASLG FOS
ErbB signaling FoxO signaling PI3K-Akt signaling B cell receptor pathway: MYC pathway: RBL2 pathway: BCL2L11 signaling pathway: CBA
FOS
ErbB signaling FoxO signaling PI3K-Akt signaling Serotonergic pathway: ELK1 pathway: PLK4 pathway: BCL2L1 synapse: CASP3
Regulation of actin Ras signaling FoxO signaling PI3K-Akt signaling cytoskeleton: ACTB pathway: PLA2G4B pathway: GADD45G pathway: BCL2* ARPC5
Regulation of actin Ras signaling FoxO signaling PI3K-Akt signaling cytoskeleton: CFL1 pathway: ELK1 pathway: FASLG pathway: TP53 ACTB
PI3K-Akt signaling Regulation of actin Ras signaling FoxO signaling pathway: cytoskeleton: pathway: ETS1 pathway: BCL2L11 BCL2L1* MYL12B MYH9 ACTB
Ras signaling FoxO signaling PI3K-Akt signaling Regulation of actin pathway: BCL2L1 pathway: TNFSF10 pathway: MYB cytoskeleton: PXN
PI3K-Akt signaling Regulation of actin Ras signaling FoxO signaling pathway: CCND1 cytoskeleton: pathway: NFKB1 pathway: BCL6 CDK2 IQGAP2
Regulation of actin Ras signaling FoxO signaling PI3K-Akt signaling cytoskeleton: PFN3 pathway: FASLG pathway: BNIP3 pathway: MAPK1 ACTB
Ras signaling FoxO signaling PI3K-Akt signaling Regulation of actin pathway: PAK4 pathway: ATG12 pathway: BCL2 cytoskeleton: VCL*
Ras signaling FoxO signaling PI3K-Akt signaling Regulation of actin pathway: RHOA pathway: GABARAP pathway: MCL1 cytoskeleton: ACTN4
Ras signaling FoxO signaling PI3K-Akt signaling Regulation of actin pathway: MAPK8 pathway: CAT pathway: RXRA cytoskeleton: MSN
Ras signaling FoxO signaling PI3K-Akt signaling GnRH signaling pathway: RAC1* pathway: SOD2 pathway: BCL2** pathway: ELK1
Ras signaling FoxO signaling PI3K-Akt signaling Estrogen signaling pathway: REL pathway: GADD45G* pathway: EIF4E pathway: CREB3
Estrogen signaling Ras signaling FoxO signaling PI3K-Akt signaling pathway: ESR1 pathway: PLD1 pathway: ATM pathway: EIF4B C00951
Ras signaling FoxO signaling PI3K-Akt signaling Estrogen signaling CBA
pathway: PRKCA pathway: PCK1 pathway: RPS6 pathway: ESR1 FOS
Estrogen signaling Ras signaling FoxO signaling PI3K-Akt signaling pathway: ESR1 pathway: C01245 pathway: G6PC pathway: NOS3 C00951*
Thyroid hormone Ras signaling FoxO signaling PI3K-Akt signaling signaling pathway: pathway: ABL1 pathway: BCL6* pathway: CASP9 ATP1B4
Thyroid hormone Ras signaling FoxO signaling PI3K-Akt signaling signaling pathway: pathway: RAB5A pathway: IL7R pathway: PRKCA THRB
Ras signaling FoxO signaling PI3K-Akt signaling Oxytocin signaling pathway: RAP1A pathway: KLF2 pathway: PKN3 pathway: PTGS2
PI3K-Akt signaling Ras signaling FoxO signaling Oxytocin signaling pathway: pathway: RAC1** pathway: S1PR1 pathway: JUN C8orf44-SGK3
Ras signaling FoxO signaling PI3K-Akt signaling Apoptosis: BCL2* pathway: KSR2 pathway: RAG1 pathway: GYS1
Longevity regulating Ras signaling FoxO signaling PI3K-Akt signaling pathway - mammal: pathway: STK4 STK4 pathway: FBXO32 pathway: MYC CAT
Phospholipase D Ras signaling VEGF signaling cGMP-PKG signaling signaling pathway: pathway: MLLT4 pathway: PLA2G4B pathway: MYL9 MAPK1
Phospholipase D Rap1 signaling Gap junction: GJA1 FoxO signaling signaling pathway: pathway: MAPK1 GJA1 pathway: CCNB3 C06124
Phospholipase D Rap1 signaling Gap junction: GJA1 Gap junction: GJA1 signaling pathway: pathway: PLCE1 GJA1* GJA1** MTOR
Gap junction: GJA1 TJP1 CBA
Matrix correlation of the expression of top AT with the activity of the circuits that compose the RD Map.
In order to understand the nature of the interaction (activation or inhibition) between the most relevant targets and the circuits of the disease map a correlation plot was derived. The plot represents the correlation between the expression level of the most relevant targets and the activity levels of the circuits in the disease map inferred by HiPathia across the GTEx data set. Additionally, the top of the figure represents the effect (pharmacological action) of the drugs.
Hint: a drug with an inhibitory effect in a given target will potentially produce an inhibitory effect in circuits positively correlated (and, it is likely that activation in circuits negatively correlated with the target.)
Click to access and download the Correlation Matrix