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 , 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 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 , 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 ID 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 agonist GABRA1 0,05913 Dependence

positive allosteric DB00273 Topiramate GABRA1 0,05913 modulator Dependence

DB00292 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 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 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 GABRA1 0,05913 modulator

Alcohol DB00829 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 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 potentiator GABRA1 Withdrawal 0,05913 Syndrome(AWS)

positive allosteric DB01189 Desflurane GABRA1 0,05913 modulator

DB01198 potentiator GABRA1 0,05913

Anesthesia DB01205 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 agonist GABRA1 0,05913

positive allosteric DB01236 Sevoflurane GABRA1 0,05913 modulator

Quinidine DB01346 potentiator GABRA1 0,05913

DB01351 Amobarbital potentiator GABRA1 0,05913

DB01353 Butobarbital potentiator GABRA1 0,05913

DB01437 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 agonist GABRA1 0,05913

agonist,positive DB09118 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 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 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 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