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HoliRD REPORT:

Ellis-Van Creveld Syndrome

Marina Esteban Medina

María Peña-Chilet

Carlos Loucera

Joaquín Dopazo

Clinical Bioinformatics Area - FPS

Sevilla, January 13, 2020

Collaborators:

Dr.Víctor Ruiz Pérez ’s group - U760 CIBERER

Research group at Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid. 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 Ellis-Van Creveld Syndrome

Identification of genes highly related to the rare disease (RD) under study in Orphanet/OMIM

A total of 2 genes annotated as Ellis-Van Creveld Syndrome (EVC) were found in the OMIM database.

EVC highly related genes

Disease ID Entrez ID Gene Symbol OMIM:225500 132884 EVC2 OMIM:225500 2121 EVC

Identification of highly related HPO to the RD under study:

A total of 32 HPO codes associated to EVC with specificity >=7 were selected.

EVC highly related HPOs

HPO ID HPO term Specificity level

HP:0000008 Abnormality of female internal genitalia 8

HP:0000028 Cryptorchidism 10

HP:0000039 Epispadias 15

HP:0000047 Hypospadias 15

HP:0000072 Hydroureter 8

HP:0000190 Abnormal oral frenulum morphology 9

HP:0000233 Thin vermilion border 10

HP:0000486 Strabismus 7 CBA

HP:0000668 Hypodontia 12

HP:0000684 Delayed eruption of teeth 11

HP:0000691 Microdontia 11

HP:0000774 Narrow chest 8

HP:0001161 Hand polydactyly 18

HP:0001241 Capitate-hamate fusion 21

HP:0001249 Intellectual disability 7

HP:0001629 Ventricular septal defect 9

HP:0001631 Atrial septal defect 9

HP:0001696 Situs inversus totalis 9

HP:0001800 Hypoplastic toenails 10

HP:0001829 Foot polydactyly 16

HP:0002488 Acute leukemia 12

HP:0002857 Genu valgum 19

HP:0002967 Cubitus valgus 10

HP:0002983 Micromelia 9

HP:0005048 Synostosis of carpal bones 19

HP:0006695 Atrioventricular canal defect 7

HP:0008678 Renal hypoplasia/aplasia 8

HP:0008921 Neonatal short-limb short stature 9

HP:0009882 Short distal phalanx of finger 27

HP:0010306 Short thorax 7

HP:0011065 Conical incisor 14

HP:0011830 Abnormal oral mucosa morphology 9 CBA

Identification of genes that shared at least RD-HPO codes

Genes with >= 10 EVC-HPO codes

Gene Symbol Entrez Gene Symbol Entrez Gene Symbol Entrez

ARVCF 421 ROR2 4920 CD96 10225

COMT 1312 PTPN11 5781 CPLX1 10815

CTBP1 1487 RAD21 5885 PIGN 23556

DHCR7 1717 RFC2 5982 NIPBL 25836

DVL1 1855 RREB1 6239 SETBP1 26040

DVL3 1857 TBX1 6899 TCTN3 26123

ELN 2006 HIRA 7290 IFT172 26160

EVC 2121 UFD1 7353 TBL2 26608

FANCB 2187 KDM6A 7403 DYNC2LI1 51626

FGFR1 2260 CLIP2 7461 FGFRL1 53834

FGFR3 2261 WHCR 7467 BCOR 54880

FGFR2 2263 NSD2 7468 SETD5 55209

FLNA 2316 WNT5A 7474 HDAC8 55869

GJA1 2697 MKKS 8195 ARID1B 57492

GLI1 2735 SMC1A 8243 WDR35 57539

GLI3 2737 NAA10 8260 WDR19 57728

GP1BB 2812 OFD1 8481 PIEZO2 63895

GTF2I 2969 TP63 8626 NXN 64359

KRAS 3845 BAZ1B 9031 EVC2 132884 CBA

LETM1 3954 SMC3 9126 B3GLCT 145173

LIMK1 3984 LONP1 9361 CEP120 153241

SMAD4 4089 GTF2IRD1 9569 UBR1 197131

KMT2A 4297 SEC24C 9632 HYLS1 219844

JMJD1C 221037 KIF7 374654

Genes with >= 13 EVC-HPO codes

Gene Symbol Entrez Gene Symbol Entrez

DHCR7 1717 TP63 8626

EVC 2121 DYNC2LI1 51626

FGFR3 2261 BCOR 54880

FGFR2 2263 WDR35 57539

FLNA 2316 EVC2 132884

GLI1 2735 KIF7 374654

GLI3 2737

Genes with >= 32 (all) EVC-HPO codes

Gene Symbol Entrez

EVC 2121

GLI1 2735

DYNC2LI1 51626

EVC2 132884

In order to maintain the specificity and not over expand the Disease Map of action only genes with >=13 EVC-HPO codes were selected. CBA

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 101 circuits belonging to 9 KEGG pathways were found as part of the disease map.

KEGG pathway KEGG-pathway code MAPK signaling pathway hsa04010 Ras signaling pathway hsa04014

Rap1 signaling pathway hsa04015

cAMP signaling pathway hsa04024

PI3K-Akt signaling pathway hsa04151

Hedgehog signaling pathway hsa04340

Focal adhesion hsa04510

Signaling pathways regulating pluripotency of hsa04550 stem cells. Regulation of actin cytoskeleton hsa04810

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. CBA

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

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 51 most relevant ones (top AT).

Entrez Gene symbol Relevance score Entrez Gene symbol Relevance score 4921 DDR2 0.1246788241 4915 NTRK2 0.0062247423 558 AXL 0.1055667695 10544 PROCR 0.0062172438 5159 PDGFRB 0.0690853304 6608 SMO 0.0053865627 6560 SLC12A4 0.0465522187 11255 HRH3 0.0049937396 1956 EGFR 0.0431943115 7035 TFPI 0.0045877157 2335 FN1 0.0413354519 2064 ERBB2 0.0044009706 1277 COL1A1 0.0337826148 3351 HTR1B 0.0042685683 3561 IL2RG 0.0317543927 5740 PTGIS 0.0041923015 5627 PROS1 0.0304667474 5156 PDGFRA 0.0041010268 3688 ITGB1 0.025228295 3791 KDR 0.0037065533 6785 ELOVL4 0.0213337609 55800 SCN3B 0.0034422123 775 CACNA1C 0.0210501489 302 ANXA2 0.0030536432 2247 FGF2 0.0186886186 9475 ROCK2 0.0030046783 6093 ROCK1 0.0143943183 6715 SRD5A1 0.0029581293 5916 RARG 0.0139642827 784 CACNB3 0.0028630476 781 CACNA2D1 0.0137847594 8913 CACNA1G 0.0027950197 87 ACTN1 0.0127013274 5241 PGR 0.0026874201 3785 KCNQ2 0.011057306 55 ACPP 0.0026819434 774 CACNA1B 0.0103482963 2152 F3 0.0025191135 2261 FGFR3 0.0088571926 2556 GABRA3 0.0024852433 715 C1R 0.0077938263 64127 NOD2 0.0024850797 5745 PTH1R 0.0072131923 3269 HRH1 0.0024098319 136 ADORA2B 0.0068923465 3459 IFNGR1 0.0023183231 2260 FGFR1 0.0067774556 5578 PRKCA 0.0022983954 716 C1S 0.0066619628 6869 TACR1 0.0022750919 301 ANXA1 0.0062367681 CBA

Relevance plot depicting the 51 most relevant gene targets.

Drugs from DRUGBANK db (release 5.1.4) that target top AT.

And the list of drugs that target the 51 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.

Relevance Drug ID Drug Name Drug Effect Target Associated condition score

Metastatic DB08896 Regorafenib inhibitor DDR2 Gastrointestinal 0,12468 Stromal Tumor

DB12141 Gilteritinib inhibitor AXL 0,10557

DB00102 Becaplermin PDGFRB 0,06909

Advanced Renal Cell DB00398 Sorafenib antagonist PDGFRB 0,06909 Carcinoma

Advanced Renal Cell DB01268 Sunitinib inhibitor PDGFRB 0,06909 Carcinoma

Advanced Renal Cell DB06589 Pazopanib inhibitor PDGFRB 0,06909 Carcinoma CBA

Leukemia Acute antagonist,i DB06595 Midostaurin PDGFRB Myeloid Leukemia 0,06909 nhibitor (AML)

Metastatic DB08896 Regorafenib inhibitor PDGFRB Gastrointestinal 0,06909 Stromal Tumor

DB00887 Bumetanide inhibitor SLC12A4 0,04655

Metastatic Colorectal DB00002 Cetuximab antagonist EGFR 0,04319 Cancers

DB00317 Gefitinib antagonist EGFR 0,04319

Locally Advanced DB00530 Erlotinib antagonist EGFR Non-Small Cell Lung 0,04319 Cancer

Metastatic Breast DB01259 Lapatinib antagonist EGFR 0,04319 Cancer (MBC)

DB01269 Panitumumab suppressor EGFR 0,04319

Metastatic Non-Small DB08916 Afatinib inhibitor EGFR 0,04319 Cell Lung Cancer

DB09330 Osimertinib inhibitor EGFR 0,04319

DB09559 Necitumumab antagonist EGFR 0,04319

Foreskin DB10772 keratinocyte agonist EGFR 0,04319 (neonatal)

DB11828 Neratinib inhibitor EGFR 0,04319

DB11963 Dacomitinib inhibitor EGFR 0,04319

DB12267 Brigatinib inhibitor EGFR 0,04319

DB08888 Ocriplasmin cleavage FN1 0,04134

DB12872 Vonicog Alfa binder COL1A1 0,03378

Von Willebrand DB13133 binder COL1A1 0,03378 Factor Human

DB00041 Aldesleukin agonist IL2RG High Risk 0,03175 CBA

Neuroblastoma

Sodium Tetradecyl DB00464 inhibitor PROS1 0,03047 Sulfate

Antithymocyte DB00098 immunoglobulin ITGB1 Acute cellular rejection 0,02523 (rabbit)

Omega-3-carboxyli DB09568 potentiator ELOVL4 0,02133 c acids

DB00270 Isradipine inhibitor CACNA1C 0,02105

DB00308 Ibutilide activator CACNA1C Atrial Fibrillation (AF) 0,02105

DB00343 Diltiazem blocker CACNA1C Anal Fissures 0,02105

DB00381 Amlodipine inhibitor CACNA1C Anginal Pain 0,02105

DB00393 Nimodipine inhibitor CACNA1C 0,02105

DB00401 Nisoldipine inhibitor CACNA1C 0,02105

DB00568 inhibitor CACNA1C 0,02105

Chronic Stable Angina DB00622 Nicardipine inhibitor CACNA1C 0,02105 Pectoris

DB00661 Verapamil inhibitor CACNA1C Atrial Fibrillation (AF) 0,02105

DB00825 Levomenthol antagonist CACNA1C Coughing 0,02105

DB01023 Felodipine inhibitor CACNA1C 0,02105

DB01054 Nitrendipine inhibitor CACNA1C 0,02105

Chronic Stable Angina DB01115 Nifedipine inhibitor CACNA1C 0,02105 Pectoris

DB01373 Calcium ligand CACNA1C 0,02105

DB06712 Nilvadipine inhibitor CACNA1C 0,02105

Irritable Bowel DB09089 Trimebutine inhibitor CACNA1C 0,02105 Syndrome (IBS)

DB09236 Lacidipine antagonist CACNA1C 0,02105

DB09238 Manidipine blocker CACNA1C 0,02105 CBA

DB12278 Propiverine antagonist CACNA1C Micturition urgency 0,02105

agonist,indu DB00364 Sucralfate FGF2 Gastric Ulcer (GU) 0,01869 cer

Pentosan DB00686 antagonist FGF2 0,01869 Polysulfate

other/unkn DB00877 Sirolimus FGF2 Chordomas 0,01869 own

DB13931 Netarsudil inhibitor ROCK1 0,01439

DB00210 Adapalene agonist RARG Acne Vulgaris 0,01396

Keratinization DB00459 Acitretin agonist RARG 0,01396 disorders

Chronic Eczema of the DB00523 Alitretinoin agonist RARG 0,01396 hand

DB00755 Tretinoin agonist RARG Acne Vulgaris 0,01396

Psoriasis Vulgaris DB00799 Tazarotene agonist RARG 0,01396 (Plaque Psoriasis)

Diabetic Peripheral DB00230 Pregabalin CACNA2D1 Neuropathic Pain 0,01378 (DPN)

DB00270 Isradipine inhibitor CACNA2D1 0,01378

DB00401 Nisoldipine inhibitor CACNA2D1 0,01378

Chronic Stable Angina DB00622 Nicardipine inhibitor CACNA2D1 0,01378 Pectoris

DB00996 Gabapentin inhibitor CACNA2D1 Partial-Onset Seizures 0,01378

DB01023 Felodipine inhibitor CACNA2D1 0,01378

DB01054 Nitrendipine inhibitor CACNA2D1 0,01378

Chronic Stable Angina DB01115 Nifedipine inhibitor CACNA2D1 0,01378 Pectoris

DB06712 Nilvadipine inhibitor CACNA2D1 0,01378

DB06773 Human calcitonin incorporatio ACTN1 0,0127 n into and CBA

destabilizati on

DB00586 Diclofenac other KCNQ2 Actinic Keratosis (AK) 0,01106

DB00996 Gabapentin inhibitor CACNA1B Partial-Onset Seizures 0,01035

DB01202 Levetiracetam inhibitor CACNA1B Epilepsies 0,01035

Advanced Renal Cell DB09078 Lenvatinib inhibitor FGFR3 0,00886 Carcinoma

Decreased Pulmonary DB09079 Nintedanib inhibitor FGFR3 0,00886 Function

Locally Advanced, Susceptible FGFR3 or FGFR2 genetic alterations, Condition has progressed during or following at least one line of prior DB12147 Erdafitinib inhibitor FGFR3 platinum- containing 0,00886 chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy urothelial carcinoma

Human DB06404 C1-esterase inhibitor C1R 0,00779 inhibitor

DB09228 Conestat alfa inhibitor C1R 0,00779

DB05084 Abaloparatide ligand PTH1R 0,00721

DB00277 antagonist ADORA2B 0,00689

Paroxysmal DB00640 Adenosine agonist ADORA2B Supraventricular 0,00689 Tachycardia

DB00824 Enprofylline antagonist ADORA2B 0,00689

DB00398 Sorafenib inhibitor FGFR1 Advanced Renal Cell 0,00678 CBA

Carcinoma

Metastatic DB08896 Regorafenib inhibitor FGFR1 Gastrointestinal 0,00678 Stromal Tumor

Advanced Renal Cell DB09078 Lenvatinib inhibitor FGFR1 0,00678 Carcinoma

Decreased Pulmonary DB09079 Nintedanib inhibitor FGFR1 0,00678 Function

Locally Advanced, Susceptible FGFR3 or FGFR2 genetic alterations, Condition has progressed during or following at least one line of prior DB12147 Erdafitinib inhibitor FGFR1 platinum- containing 0,00678 chemotherapy including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy urothelial carcinoma

Human DB06404 C1-esterase inhibitor C1S 0,00666 inhibitor

DB09228 Conestat alfa inhibitor C1S 0,00666

Fluocinolone DB00591 inducer ANXA1 Atopic Dermatitis (AD) 0,00624 acetonide

DB00741 Hydrocortisone agonist ANXA1 Acute Gouty Arthritis 0,00624

Hydrocortisone Adrenal cortical DB14539 ANXA1 0,00624 acetate hypofunctions

Hydrocortisone DB14540 ANXA1 Atopic Dermatitis (AD) 0,00624 butyrate

Hydrocortisone DB14541 ANXA1 0,00624 cypionate CBA

Hydrocortisone DB14542 ANXA1 0,00624 phosphate

Hydrocortisone DB14543 ANXA1 Itching 0,00624 probutate

Hydrocortisone DB14544 ANXA1 0,00624 valerate

Tetradecyl Gastrointestinal DB11328 hydrogen sulfate antagonist PROCR 0,00622 Bleedings (ester)

DB14723 Larotrectinib inhibitor NTRK2 NTRK1 Fusion Positive 0,00622

Locally Advanced Basal DB08828 Vismodegib antagonist SMO 0,00539 Cell Carcinoma

DB11978 Glasdegib inhibitor SMO 0,00539

DB05381 agonist HRH3 0,00499

DB06698 antagonist HRH3 0,00499

antagonist,i Excessive Daytime DB11642 Pitolisant nverse HRH3 0,00499 Sleepiness agonist

DB06779 Dalteparin inhibitor TFPI Cardiovascular Events 0,00459

DB14562 Andexanet alfa inhibitor TFPI 0,00459

DB00072 Trastuzumab antibody ERBB2 Breast Cancer 0,0044

Metastatic Breast DB01259 Lapatinib antagonist ERBB2 0,0044 Cancer (MBC)

Trastuzumab DB05773 antibody ERBB2 0,0044 emtansine

Inflammatory DB06366 Pertuzumab antibody ERBB2 carcinoma of the 0,0044 breast

Metastatic Non-Small DB08916 Afatinib inhibitor ERBB2 0,0044 Cell Lung Cancer

DB00216 Eletriptan agonist HTR1B Acute Migraine 0,00427 CBA

DB00315 Zolmitriptan agonist HTR1B 0,00427

Dihydroergotamin DB00320 agonist HTR1B Cluster Headache 0,00427 e

DB00669 Sumatriptan agonist HTR1B Acute Migraine 0,00427

DB00696 Ergotamine agonist HTR1B Cluster Headache 0,00427

Migraine with acute DB00952 Naratriptan agonist HTR1B 0,00427 onset aura

Migraine with acute DB00953 Rizatriptan agonist HTR1B 0,00427 onset aura

DB00998 Frovatriptan agonist HTR1B Menstrual Migraines 0,00427

partial DB09068 Vortioxetine HTR1B 0,00427 agonist

DB00812 Phenylbutazone inhibitor PTGIS 0,00419

DB01240 Epoprostenol inducer PTGIS 0,00419

Advanced Renal Cell DB01268 Sunitinib inhibitor PDGFRA 0,0041 Carcinoma

DB06043 Olaratumab antagonist PDGFRA 0,0041

Advanced Renal Cell DB06589 Pazopanib inhibitor PDGFRA 0,0041 Carcinoma

Leukemia Acute antagonist,i DB06595 Midostaurin PDGFRA Myeloid Leukemia 0,0041 nhibitor (AML)

Metastatic DB08896 Regorafenib inhibitor PDGFRA Gastrointestinal 0,0041 Stromal Tumor

Foreskin DB10772 keratinocyte agonist PDGFRA 0,0041 (neonatal)

Advanced Renal Cell DB00398 Sorafenib antagonist KDR 0,00371 Carcinoma

Advanced Renal Cell DB01268 Sunitinib inhibitor KDR 0,00371 Carcinoma CBA

Advanced Gastric DB05578 Ramucirumab antagonist KDR 0,00371 Cancer

Advanced Renal Cell DB06589 Pazopanib inhibitor KDR 0,00371 Carcinoma

Leukemia Acute antagonist,i DB06595 Midostaurin KDR Myeloid Leukemia 0,00371 nhibitor (AML)

Severe Aplastic Anemia DB06626 Axitinib inhibitor KDR 0,00371 (SAA)

Advanced Renal Cell DB08875 Cabozantinib antagonist KDR 0,00371 Carcinoma

Metastatic DB08896 Regorafenib inhibitor KDR Gastrointestinal 0,00371 Stromal Tumor

Advanced Renal Cell DB09078 Lenvatinib inhibitor KDR 0,00371 Carcinoma

Decreased Pulmonary DB09079 Nintedanib inhibitor KDR 0,00371 Function

DB00909 Zonisamide inhibitor SCN3B 0,00344

Fluocinolone DB00591 inducer ANXA2 Atopic Dermatitis (AD) 0,00305 acetonide

DB13931 Netarsudil inhibitor ROCK2 0,003

DB00367 Levonorgestrel inhibitor SRD5A1 Endometrial Cancers 0,00296

Benign Prostatic DB01126 Dutasteride inhibitor SRD5A1 0,00296 Hyperplasia (BPH)

Abnormal Uterine DB09389 Norgestrel inhibitor SRD5A1 0,00296 Bleeding

DB00393 Nimodipine inhibitor CACNB3 0,00286

DB00661 Verapamil inhibitor CACNB3 Atrial Fibrillation (AF) 0,00286

DB00347 Trimethadione inhibitor CACNA1G 0,0028

DB00568 Cinnarizine inhibitor CACNA1G 0,0028 CBA

DB00593 Ethosuximide inhibitor CACNA1G 0,0028

DB00909 Zonisamide inhibitor CACNA1G 0,0028

DB04841 inhibitor CACNA1G 0,0028

DB05246 Methsuximide inhibitor CACNA1G 0,0028

DB09238 Manidipine blocker CACNA1G 0,0028

DB00294 Etonogestrel agonist PGR 0,00269

DB00304 Desogestrel agonist PGR 0,00269

Advanced Breast DB00351 Megestrol acetate agonist PGR 0,00269 Cancer

DB00367 Levonorgestrel binder PGR Endometrial Cancers 0,00269

Abnormal Uterine DB00396 Progesterone agonist PGR 0,00269 Bleeding

Medroxyprogester Abnormal Uterine DB00603 agonist PGR 0,00269 one acetate Bleeding

Ethynodiol Dysfunctional Uterine DB00823 agonist PGR 0,00269 diacetate Bleeding

DB00834 Mifepristone antagonist PGR 0,00269

Dysfunctional Uterine DB00957 Norgestimate agonist PGR 0,00269 Bleeding

DB01395 Drospirenone agonist PGR Acne Vulgaris 0,00269

Autoimmune DB01406 Danazol agonist PGR 0,00269 Hemolytic Anemia

DB06713 Norelgestromin agonist PGR 0,00269

Moderate Uterine DB08867 Ulipristal modulator PGR 0,00269 Fibroids

DB09123 Dienogest agonist PGR Hypermenorrhea 0,00269

DB09124 Medrogestone ligand PGR 0,00269

Abnormal Uterine DB09389 Norgestrel binder PGR 0,00269 Bleeding CBA

Asymptomatic, metastatic DB06688 Sipuleucel-T other ACPP 0,00268 hormone-refractory Prostate cancer

Coagulation factor DB13150 activator F3 0,00252 VII human

DB00231 Temazepam potentiator GABRA3 0,00249

Headache, DB00241 Butalbital potentiator GABRA3 0,00249 Tension-Type

DB00306 Talbutal potentiator GABRA3 0,00249

DB00312 Pentobarbital potentiator GABRA3 Insomnia 0,00249

DB00371 Meprobamate agonist GABRA3 0,00249

DB00418 Secobarbital potentiator GABRA3 0,00249

DB00599 Thiopental potentiator GABRA3 0,00249

DB00683 Midazolam potentiator GABRA3 Seizures, Epileptic 0,00249

DB00690 Flurazepam potentiator GABRA3 0,00249

Grand Generalized DB00794 Primidone potentiator GABRA3 0,00249 tonic-clonic seizure

Alcohol Withdrawal DB00829 Diazepam potentiator GABRA3 0,00249 Syndrome(AWS)

Alcohol Withdrawal DB00842 Oxazepam potentiator GABRA3 0,00249 Syndrome(AWS)

Methylphenobarbi DB00849 potentiator GABRA3 0,00249 tal

DB00897 Triazolam potentiator GABRA3 0,00249

DB01198 Zopiclone potentiator GABRA3 0,00249

DB01215 Estazolam potentiator GABRA3 0,00249

DB01351 Amobarbital potentiator GABRA3 0,00249

DB01353 Butobarbital potentiator GABRA3 0,00249

DB01544 Flunitrazepam potentiator GABRA3 0,00249 CBA

DB01558 Bromazepam potentiator GABRA3 Acute Anxiety 0,00249

DB01559 Clotiazepam potentiator GABRA3 0,00249

DB01588 Prazepam potentiator GABRA3 0,00249

DB01589 Quazepam potentiator GABRA3 0,00249

DB01595 Nitrazepam potentiator GABRA3 Insomnia 0,00249

High-grade, DB13615 Mifamurtide ligand NOD2 nonmetastatic 0,00249 Osteosarcoma

positive DB13872 Lormetazepam allosteric GABRA3 0,00249 modulator

DB00283 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

Chronic Idiopathic DB00341 antagonist HRH1 0,00241 Urticaria

DB00354 antagonist HRH1 0,00241

DB00366 antagonist HRH1 Flu Symptoms 0,00241

Dexbrompheniram DB00405 antagonist HRH1 Allergic Rhinitis (AR) 0,00241 ine

Conjunctivitis, DB00427 antagonist HRH1 0,00241 Seasonal Allergic

DB00434 antagonist HRH1 Allergic Reactions 0,00241

Allergic Dermatologic DB00455 antagonist HRH1 0,00241 Disorders

Acute Intermittent DB00477 antagonist HRH1 0,00241 Porphyria (AIP)

Alcohol Withdrawal DB00557 antagonist HRH1 0,00241 Syndrome(AWS)

DB00568 Cinnarizine antagonist HRH1 0,00241

DB00719 antagonist HRH1 0,00241

DB00737 antagonist HRH1 Motion Sickness 0,00241 CBA

DB00748 antagonist HRH1 Allergic Reactions 0,00241

DB00751 antagonist HRH1 0,00241

Conjunctivitis, DB00768 antagonist HRH1 0,00241 Seasonal Allergic

DB00777 antagonist HRH1 0,00241

DB00792 antagonist HRH1 0,00241

DB00835 antagonist HRH1 Acute nasopharyngitis 0,00241

DB00902 antagonist HRH1 0,00241

DB00920 antagonist HRH1 Asthma, Allergic 0,00241

DB00950 antagonist HRH1 Pollen Allergy 0,00241

Chronic Idiopathic DB00967 antagonist HRH1 0,00241 Urticaria

Conjunctivitis, DB00972 antagonist HRH1 0,00241 Seasonal Allergic

DB00985 antagonist HRH1 Labyrinthine disorder 0,00241

DB01069 antagonist HRH1 Allergic edema 0,00241

DB01075 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

DB01084 antagonist HRH1 0,00241

DB01106 antagonist HRH1 0,00241

DB01114 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

DB01142 antagonist HRH1 Anxiety 0,00241

DB01146 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

DB01173 antagonist HRH1 Muscle Spasms 0,00241

DB01176 antagonist HRH1 Migraine 0,00241

Bromodiphenhydr DB01237 antagonist HRH1 0,00241 amine

DB01246 antagonist HRH1 Coughing 0,00241

DB01619 antagonist HRH1 0,00241 CBA

Conjunctivitis, DB01620 antagonist HRH1 0,00241 Seasonal Allergic

DB04890 antagonist HRH1 0,00241

DB05381 HRH1 0,00241

Mixed manic DB06016 antagonist HRH1 0,00241 depressive episode

antagonist,i Chronic Idiopathic DB06282 HRH1 0,00241 nhibitor Urticaria

DB06691 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

DB06698 Betahistine agonist HRH1 0,00241

DB08799 antagonist HRH1 0,00241

DB08801 antagonist HRH1 0,00241

DB08936 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

DB09016 antagonist HRH1 0,00241

DB09167 antagonist HRH1 0,00241

DB09195 Lorpiprazole antagonist HRH1 0,00241

DB09488 antagonist HRH1 0,00241

Dexchlorphenirami DB09555 antagonist HRH1 Allergic Rhinitis (AR) 0,00241 ne maleate

DB11235 antagonist HRH1 0,00241

DB11591 antagonist HRH1 0,00241

DB11614 antagonist HRH1 Allergic Rhinitis (AR) 0,00241

Chronic Interferon DB00033 binder IFNGR1 Granulomatous 0,00232 gamma-1b Disease (CGD)

Leukemia Acute antagonist,i DB06595 Midostaurin PRKCA Myeloid Leukemia 0,0023 nhibitor (AML)

DB00673 Aprepitant antagonist TACR1 0,00228 CBA

Acute caused and DB09048 Netupitant antagonist TACR1 vomiting caused by 0,00228 Chemotherapy

Location of top AT in HiPathia circuits and selection of those circuits shared with the Disease Map. A total of 90/101 circuits from RD Map containing top AT are shown.

Disease Map circuits with top AT

HiPathia pathway: HiPathia pathway: HiPathia pathway:

effector gene effector gene effector gen

MAPK signaling pathway: PI3K-Akt signaling pathway: Rap1 signaling pathway: RAC1 ATF4* RXRA

PI3K-Akt signaling pathway: MAPK signaling pathway: FOS Rap1 signaling pathway: ITGAL BCL2**

MAPK signaling pathway: Rap1 signaling pathway: PI3K-Akt signaling pathway: MAPT MAPK14 EIF4E

MAPK signaling pathway: Rap1 signaling pathway: PI3K-Akt signaling pathway: STMN1 MAPK1 EIF4B

MAPK signaling pathway: PI3K-Akt signaling pathway: Rap1 signaling pathway: CDH1 PLA2G4B RPS6

PI3K-Akt signaling pathway: MAPK signaling pathway: MYC Rap1 signaling pathway: AKT3 NOS3

Ras signaling pathway: Rap1 signaling pathway: PI3K-Akt signaling pathway: PLA2G4B THBS1 CASP9

Rap1 signaling pathway: PRKCI PI3K-Akt signaling pathway: Ras signaling pathway: ELK1 PARD6A PARD3 PRKCA

PI3K-Akt signaling pathway: Ras signaling pathway: ETS1 Rap1 signaling pathway: PLCE1 PKN3

PI3K-Akt signaling pathway: Ras signaling pathway: BCL2L1 cAMP signaling pathway: GLI1 C8orf44-SGK3 CBA

cAMP signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: NFKB1 PTCH1 GLI1***

Hedgehog signaling pathway: Ras signaling pathway: FASLG cAMP signaling pathway: HHIP PTCH1***

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: PAK4 GYS1 HHIP*

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: RHOA MYC CCND1*

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: MAPK8 CCND1 BCL2*

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: RAC1* CDKN1B PRKACA

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: REL RBL2 GLI1 SUFU*

PI3K-Akt signaling pathway: Hedgehog signaling pathway: Ras signaling pathway: PLD1 PCK1 SUFU

PI3K-Akt signaling pathway: Focal adhesion: FLNA ITGB1 Ras signaling pathway: PRKCA G6PC ITGA11

Signaling pathways regulating PI3K-Akt signaling pathway: Ras signaling pathway: C01245 pluripotency of stem cells: FASLG MAPK1*

Signaling pathways regulating PI3K-Akt signaling pathway: Ras signaling pathway: ABL1 pluripotency of stem cells: BCL2L11 AKT3*

PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: RAB5A BCL2L1 cytoskeleton: ACTB ARPC5

PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: RAP1A BCL2* cytoskeleton: CFL1 ACTB

Regulation of actin PI3K-Akt signaling pathway: Ras signaling pathway: RAC1** cytoskeleton: MYL12B MYH9 TP53 ACTB

PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: KSR2 BCL2L1* cytoskeleton: PXN

Ras signaling pathway: STK4 PI3K-Akt signaling pathway: Regulation of actin CBA

STK4 MYB cytoskeleton: IQGAP2

PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: MLLT4 CCND1 CDK2 cytoskeleton: PFN3 ACTB

PI3K-Akt signaling pathway: Regulation of actin Rap1 signaling pathway: ACTB MAPK1 cytoskeleton: VCL*

Rap1 signaling pathway: PI3K-Akt signaling pathway: Regulation of actin ITGA2B BCL2 cytoskeleton: ACTN4

PI3K-Akt signaling pathway: Regulation of actin Rap1 signaling pathway: RALA MCL1 cytoskeleton: MSN

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