CBA
HoliRD REPORT:
Williams Syndrome
Marina Esteban Medina
María Peña-Chilet
Carlos Loucera
Joaquín Dopazo
Clinical Bioinformatics Area - FPS
Sevilla, January 13, 2020
Collaborators:
Dra.Victoria Campuzano’s group - U735 CIBERER
Research group at Universidad Pompeu Fabra, Barcelona. 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 Williams Syndrome
Identification of genes highly related to the rare disease (RD) under study in Orphanet/OMIM
A total of 9 genes annotated as Williams Syndrome (WS) were found in the OMIM/ORPHANET database.
WS highly related genes
Disease ID Entrez ID Gene Symbol
OMIM:194050 2006 ELN
OMIM:194050 51085 MLXIPL
ORPHA:904 26608 TBL2
ORPHA:904 3984 LIMK1
ORPHA:904 9569 GTF2IRD1
ORPHA:904 7461 CLIP2
ORPHA:904 9031 BAZ1B
ORPHA:904 2969 GTF2I
ORPHA:904 5982 RFC2 CBA
Identification of highly related HPO to the RD under study:
A total of 143 HPO codes associated to WS with specificity >=7 were selected.
WS highly related HPOs
HPO ID HPO term Specificity level
HP:0000010 Recurrent urinary tract infections 10
HP:0000015 Bladder diverticulum 8
HP:0000023 Inguinal hernia 9
HP:0000025 Functional abnormality of male internal genitalia 7
HP:0000028 Cryptorchidism 10
HP:0000044 Hypogonadotrophic hypogonadism 9
HP:0000075 Renal duplication 8
HP:0000076 Vesicoureteral reflux 11
HP:0000083 Renal insufficiency 9
HP:0000089 Renal hypoplasia 9
HP:0000093 Proteinuria 9
HP:0000121 Nephrocalcinosis 8
HP:0000125 Pelvic kidney 10
HP:0000147 Polycystic ovaries 12
HP:0000154 Wide mouth 10
HP:0000158 Macroglossia 15
HP:0000179 Thick lower lip vermilion 12
HP:0000212 Gingival overgrowth 11
HP:0000232 Everted lower lip vermilion 12
HP:0000252 Microcephaly 19
HP:0000275 Narrow face 8 CBA
HP:0000280 Coarse facial features 7
HP:0000286 Epicanthus 10
HP:0000307 Pointed chin 7
HP:0000337 Broad forehead 7
HP:0000343 Long philtrum 12
HP:0000347 Micrognathia 16
HP:0000348 High forehead 7
HP:0000368 Low-set, posteriorly rotated ears 9
HP:0000389 Chronic otitis media 11
HP:0000400 Macrotia 7
HP:0000407 Sensorineural hearing impairment 10
HP:0000411 Protruding ear 7
HP:0000431 Wide nasal bridge 8
HP:0000485 Megalocornea 8
HP:0000486 Strabismus 7
HP:0000518 Cataract 7
HP:0000581 Blepharophimosis 12
HP:0000627 Posterior embryotoxon 8
HP:0000635 Blue irides 9
HP:0000668 Hypodontia 12
HP:0000670 Carious teeth 11
HP:0000682 Abnormality of dental enamel 14
HP:0000689 Dental malocclusion 11
HP:0000691 Microdontia 11
HP:0000716 Depressivity 7
HP:0000717 Autism 7 CBA
HP:0000739 Anxiety 8
HP:0000767 Pectus excavatum 8
HP:0000787 Nephrolithiasis 8
HP:0000938 Osteopenia 9
HP:0000939 Osteoporosis 9
HP:0000960 Sacral dimple 14
HP:0001052 Nevus flammeus 9
HP:0001081 Cholelithiasis 9
HP:0001136 Retinal arteriolar tortuosity 20
HP:0001181 Adducted thumb 14
HP:0001249 Intellectual disability 7
HP:0001257 Spasticity 11
HP:0001260 Dysarthria 7
HP:0001297 Stroke 10
HP:0001310 Dysmetria 8
HP:0001337 Tremor 7
HP:0001347 Hyperreflexia 7
HP:0001361 Nystagmus-induced head nodding 8
HP:0001387 Joint stiffness 7
HP:0001531 Failure to thrive in infancy 7
HP:0001537 Umbilical hernia 10
HP:0001582 Redundant skin 9
HP:0001618 Dysphonia 8
HP:0001629 Ventricular septal defect 9
HP:0001631 Atrial septal defect 9
HP:0001634 Mitral valve prolapse 9 CBA
HP:0001636 Tetralogy of Fallot 13
HP:0001639 Hypertrophic cardiomyopathy 8
HP:0001642 Pulmonic stenosis 7
HP:0001643 Patent ductus arteriosus 9
HP:0001645 Sudden cardiac death 8
HP:0001647 Bicuspid aortic valve 9
HP:0001653 Mitral regurgitation 8
HP:0001800 Hypoplastic toenails 10
HP:0001822 Hallux valgus 16
HP:0001969 Tubulointerstitial abnormality 10
HP:0002020 Gastroesophageal reflux 11
HP:0002024 Malabsorption 8
HP:0002027 Abdominal pain 8
HP:0002035 Rectal prolapse 11
HP:0002120 Cerebral cortical atrophy 14
HP:0002141 Gait imbalance 7
HP:0002150 Hypercalciuria 10
HP:0002183 Phonophobia 7
HP:0002205 Recurrent respiratory infections 11
HP:0002253 Colonic diverticula 10
HP:0002308 Arnold-Chiari malformation 11
HP:0002575 Tracheoesophageal fistula 13
HP:0002623 Overriding aorta 10
HP:0002637 Cerebral ischemia 15
HP:0002650 Scoliosis 8
HP:0002808 Kyphosis 8 CBA
HP:0002857 Genu valgum 19
HP:0002974 Radioulnar synostosis 21
HP:0002999 Patellar dislocation 13
HP:0003028 Abnormality of the ankles 9
HP:0003072 Hypercalcemia 9
HP:0003196 Short nose 8
HP:0003236 Elevated serum creatine kinase 8
HP:0003298 Spina bifida occulta 11
HP:0003307 Hyperlordosis 8
HP:0003312 Abnormal form of the vertebral bodies 8
HP:0003422 Vertebral segmentation defect 8
HP:0004209 Clinodactyly of the 5th finger 19
HP:0004295 Abnormality of the gastric mucosa 8
HP:0004381 Supravalvular aortic stenosis 8
HP:0004398 Peptic ulcer 7
HP:0004428 Elfin facies 7
HP:0004969 Peripheral pulmonary artery stenosis 15
HP:0005113 Aortic arch aneurysm 13
HP:0005344 Abnormal carotid artery morphology 8
HP:0005562 Multiple renal cysts 9
HP:0005692 Joint hyperflexibility 7
HP:0005978 Type II diabetes mellitus 9
HP:0007018 Attention deficit hyperactivity disorder 9
Atrophy/Degeneration involving the corticospinal HP:0007372 9 tracts
HP:0007477 Abnormal dermatoglyphics 7 CBA
HP:0007495 Prematurely aged appearance 7
HP:0007720 Flat cornea 8
HP:0007957 Corneal opacity 7
HP:0008053 Aplasia/Hypoplasia of the iris 12
HP:0008499 High hypermetropia 7
HP:0008661 Urethral stenosis 13
HP:0008736 Hypoplasia of penis 12
HP:0010526 Dysgraphia 7
HP:0010662 Abnormality of the diencephalon 8
HP:0010669 Hypoplasia of the zygomatic bone 12
HP:0010780 Hyperacusis 7
HP:0010807 Open bite 11
HP:0010880 Increased nuchal translucency 8
HP:0011001 Increased bone mineral density 8
HP:0100025 Overfriendliness 7
HP:0100539 Periorbital edema 13
HP:0100785 Insomnia 7
HP:0100817 Renovascular hypertension 14
HP:0200021 Down-sloping shoulders 9 CBA
Identification of genes that shared at least HPO-RD codes
Genes with >= 25 WS-HPO codes
Gene Symbol Entrez Gene Symbol Entrez Gene Symbol Entrez
ACTB 60 COX2 4513 SMC1A 8243
ARVCF 421 COX3 4514 NAA10 8260
RERE 473 ND1 4535 OFD1 8481
ATP6V1A 523 ND4 4538 TP63 8626
ATRX 546 ND5 4540 BAZ1B 9031
BRCA1 672 ND6 4541 SMC3 9126
BRAF 673 TRNF 4558 GTF2IRD1 9569
COMT 1312 TRNH 4564 SEC24C 9632
DHCR7 1717 TRNL1 4567 SEMA3E 9723
DVL1 1855 TRNQ 4572 MED12 9968
DVL3 1857 TRNS1 4574 CPLX1 10815
ELN 2006 TRNS2 4575 POLR3A 11128
ERCC2 2068 TRNW 4578 KAT6B 23522
ERCC3 2071 NOTCH2 4853 PIGN 23556
ERCC4 2072 NOTCH3 4854 RAB3GAP2 25782
ERCC6 2074 NRAS 4893 NIPBL 25836
FBN1 2200 ROR2 4920 SETBP1 26040
FGFR1 2260 OCRL 4952 TBL2 26608
FGFR3 2261 PIK3CA 5290 MLXIPL 51085
FGFR2 2263 MAP2K1 5604 BCOR 54880
FLNA 2316 PTCH1 5727 NSUN2 54888
GABRD 2563 PTEN 5728 SETD5 55209 CBA
GATA4 2626 PTPN11 5781 FANCI 55215
GJA1 2697 ALDH18A1 5832 CHD7 55636
GP1BB 2812 RAD21 5885 HDAC8 55869
GTF2E2 2961 RAF1 5894 ARID1B 57492
GTF2I 2969 RFC2 5982 PIEZO2 63895
HRAS 3265 RPS6KA3 6197 PRDM16 63976
HSPG2 3339 RREB1 6239 NSD1 64324
KRAS 3845 SKI 6497 NXN 64359
LETM1 3954 TBX1 6899 MPLKIP 136647
LIG4 3981 HIRA 7290 B3GLCT 145173
LIMK1 3984 UFD1 7353 ARX 170302
LMNA 4000 CLIP2 7461 ARID2 196528
MECP2 4204 NSD2 7468 JMJD1C 221037
KMT2A 4297 RNF113A 7737 GTF2H5 404672
COX1 4512
Genes with >= 50 WS-HPO codes
Gene Symbol Entrez Gene Symbol Entrez
ELN 2006 CLIP2 7461
GTF2I 2969 BAZ1B 9031
KRAS 3845 GTF2IRD1 9569
LIMK1 3984 TBL2 26608
RFC2 5982 MLXIPL 51085 CBA
Genes with >= 143 (all) WS-HPO codes
Gene Symbol Entrez
ELN 2006
GTF2I 2969
LIMK1 3984
RFC2 5982
CLIP2 7461
BAZ1B 9031
GTF2IRD1 9569
TBL2 26608
In order to maintain the specificity and not over expand the Disease Map of action only genes with >= 50 WS-HPO codes were selected.
**Take into account that not all genes can be found in HiPathia pathways. We have selected those genes that expand the affected HiPathia circuits within a certain threshold for the model**
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 177 circuits belonging to 36 KEGG pathways were found as part of the disease map.
KEGG-pathway KEGG-pathway KEGG pathway KEGG pathway code code
Natural killer cell MAPK signaling pathway hsa04010 hsa04650 mediated cytotoxicity
T cell receptor signaling ErbB signaling pathway hsa04012 hsa04660 pathway
Ras signaling pathway hsa04014 B cell receptor signaling hsa04662 CBA
pathway
Fc epsilon RI signaling Rap1 signaling pathway hsa04015 hsa04664 pathway
Fc gamma R-mediated cGMP-PKG signaling pathway hsa04022 hsa04666 phagocytosis
Neurotrophin signaling Chemokine signaling pathway hsa04062 hsa04722 pathway
FoxO signaling pathway hsa04068 Cholinergic synapse hsa04725
Sphingolipid signaling pathway hsa04071 Serotonergic synapse hsa04726
Phospholipase D signaling Regulation of actin hsa04072 hsa04810 pathway cytoskeleton
mTOR signaling pathway hsa04150 Insulin signaling pathway hsa04910
PI3K-Akt signaling pathway hsa04151 GnRH signaling pathway hsa04912
Progesterone-mediated Apoptosis hsa04210 hsa04914 oocyte maturation
Longevity regulating pathway - Estrogen signaling hsa04211 hsa04915 mammal pathway
Axon guidance hsa04360 Melanogenesis hsa04916
Prolactin signaling VEGF signaling pathway hsa04370 hsa04917 pathway
Thyroid hormone Tight junction hsa04530 hsa04919 signaling pathway
Oxytocin signaling Gap junction hsa04540 hsa04921 pathway
Signaling pathways regulating Aldosterone-regulated hsa04550 hsa04960 pluripotency of stem cells sodium reabsorption CBA
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
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) CBA
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.
From a total of 683 targets for approved drugs in the DRUGBANK database (release 5.1.4) the machine learning algorithm selected the 42 most relevant ones.
Gene Relevance Gene Relevance Entrez Entrez symbol score symbol score
4130 MAP1A 0.1862461569 6752 SSTR2 0.0054895269
3561 IL2RG 0.1157282118 57468 SLC12A5 0.0053501722
3767 KCNJ11 0.0471714731 2559 GABRA6 0.0051113188
6093 ROCK1 0.0413994575 4134 MAP4 0.0047096497
2554 GABRA1 0.0401520545 1043 CD52 0.0044266396
5916 RARG 0.0288142277 3849 KRT2 0.0043812025
4214 MAP3K1 0.0267365376 5423 POLB 0.0041474196
1956 EGFR 0.0243311451 774 CACNA1B 0.004140814
645 BLVRB 0.0186379067 301 ANXA1 0.0040539
6261 RYR1 0.0105278514 3570 IL6R 0.0039603732
2904 GRIN2B 0.009753303 2185 PTK2B 0.0038901026
3725 JUN 0.0096092073 941 CD80 0.0036146845
9475 ROCK2 0.0080924813 1080 CFTR 0.0034272957
3563 IL3RA 0.0075245839 3351 HTR1B 0.0034199425
64127 NOD2 0.0075005729 5139 PDE3A 0.0031023276 CBA
3683 ITGAL 0.0072311135 775 CACNA1C 0.0029840774
695 BTK 0.0071332571 3768 KCNJ12 0.0027991261
7134 TNNC1 0.0064529938 55107 ANO1 0.0026857803
2444 FRK 0.0062537682 2690 GHR 0.0026688871
7097 TLR2 0.006142283 1131 CHRM3 0.002563458
87 ACTN1 0.0056871128 786 CACNG1 0.0024225012
Relevance plot depicting the 42 most relevant gene targets. CBA
Drugs from DRUGBANK db (release 5.1.4) that target top AT.
And the list of drugs that target the 42most 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 0,18625
High Risk DB00041 Aldesleukin agonist IL2RG 0,11573 Neuroblastoma
DB00222 Glimepiride inhibitor KCNJ11 0,04717
DB00922 Levosimendan inducer KCNJ11 0,04717
DB01119 Diazoxide inducer KCNJ11 0,04717
DB01154 Thiamylal inhibitor KCNJ11 0,04717
DB13931 Netarsudil inhibitor ROCK1 0,0414
positive allosteric DB00186 Lorazepam GABRA1 Agitation 0,04015 modulator
positive allosteric DB00228 Enflurane GABRA1 0,04015 modulator
DB00231 Temazepam potentiator GABRA1 0,04015
positive allosteric DB00231 Temazepam GABRA1 0,04015 modulator
positive allosteric DB00237 Butabarbital GABRA1 0,04015 modulator
Headache, DB00241 Butalbital potentiator GABRA1 0,04015 Tension-Type
positive allosteric Headache, DB00241 Butalbital GABRA1 0,04015 modulator Tension-Type
Alcohol DB00273 Topiramate agonist GABRA1 0,04015 Dependence
DB00273 Topiramate positive allosteric GABRA1 Alcohol 0,04015 CBA
modulator Dependence
DB00292 Etomidate agonist GABRA1 0,04015
positive allosteric DB00292 Etomidate GABRA1 0,04015 modulator
DB00306 Talbutal potentiator GABRA1 0,04015
positive allosteric DB00306 Talbutal GABRA1 0,04015 modulator
DB00312 Pentobarbital potentiator GABRA1 Insomnia 0,04015
positive allosteric DB00312 Pentobarbital GABRA1 Insomnia 0,04015 modulator
positive allosteric DB00349 Clobazam GABRA1 0,04015 modulator
DB00371 Meprobamate agonist GABRA1 0,04015
positive allosteric DB00371 Meprobamate GABRA1 0,04015 modulator
DB00402 Eszopiclone potentiator GABRA1 0,04015
positive allosteric DB00402 Eszopiclone GABRA1 0,04015 modulator
positive allosteric DB00404 Alprazolam GABRA1 Anxiety 0,04015 modulator
DB00418 Secobarbital potentiator GABRA1 0,04015
DB00425 Zolpidem agonist GABRA1 0,04015
DB00474 Methohexital antagonist GABRA1 0,04015
Chlordiazepoxid positive allosteric Alcohol Withdrawal DB00475 GABRA1 0,04015 e modulator Syndrome(AWS)
DB00599 Thiopental potentiator GABRA1 0,04015
positive allosteric Acute Alcohol DB00628 Clorazepic acid GABRA1 0,04015 modulator Withdrawal
DB00659 Acamprosate positive modulator GABRA1 0,04015
DB00683 Midazolam potentiator GABRA1 Seizures, Epileptic 0,04015 CBA
DB00690 Flurazepam potentiator GABRA1 0,04015
DB00753 Isoflurane agonist GABRA1 0,04015
positive allosteric DB00753 Isoflurane GABRA1 0,04015 modulator
Grand mal DB00794 Primidone potentiator GABRA1 Generalized 0,04015 tonic-clonic seizure
Grand mal positive allosteric DB00794 Primidone GABRA1 Generalized 0,04015 modulator tonic-clonic seizure
positive allosteric DB00818 Propofol GABRA1 0,04015 modulator
Alcohol Withdrawal DB00829 Diazepam potentiator GABRA1 0,04015 Syndrome(AWS)
positive allosteric Alcohol Withdrawal DB00829 Diazepam GABRA1 0,04015 modulator Syndrome(AWS)
Alcohol Withdrawal DB00842 Oxazepam potentiator GABRA1 0,04015 Syndrome(AWS)
positive allosteric Alcohol Withdrawal DB00842 Oxazepam GABRA1 0,04015 modulator Syndrome(AWS)
Methylphenobar DB00849 potentiator GABRA1 0,04015 bital
DB00897 Triazolam potentiator GABRA1 0,04015
positive allosteric DB00897 Triazolam GABRA1 0,04015 modulator
DB00898 Ethanol agonist GABRA1 Bacterial Infections 0,04015
DB00962 Zaleplon potentiator GABRA1 0,04015
DB01028 Methoxyflurane agonist GABRA1 Severe Pain 0,04015
positive allosteric DB01028 Methoxyflurane GABRA1 Severe Pain 0,04015 modulator
positive allosteric DB01068 Clonazepam GABRA1 Akinetic seizures 0,04015 modulator CBA
DB01154 Thiamylal agonist GABRA1 0,04015
positive allosteric DB01159 Halothane GABRA1 0,04015 modulator
Alcohol Withdrawal DB01174 Phenobarbital potentiator GABRA1 0,04015 Syndrome(AWS)
positive allosteric DB01189 Desflurane GABRA1 0,04015 modulator
DB01198 Zopiclone potentiator GABRA1 0,04015
DB01205 Flumazenil antagonist GABRA1 Anesthesia reversal 0,04015
positive allosteric DB01205 Flumazenil GABRA1 Anesthesia reversal 0,04015 modulator
DB01215 Estazolam potentiator GABRA1 0,04015
positive allosteric DB01215 Estazolam GABRA1 0,04015 modulator
DB01236 Sevoflurane agonist GABRA1 0,04015
positive allosteric DB01236 Sevoflurane GABRA1 0,04015 modulator
Quinidine DB01346 potentiator GABRA1 0,04015 barbiturate
DB01351 Amobarbital potentiator GABRA1 0,04015
DB01353 Butobarbital potentiator GABRA1 0,04015
DB01437 Glutethimide agonist GABRA1 0,04015
positive allosteric DB01437 Glutethimide GABRA1 0,04015 modulator
DB01558 Bromazepam potentiator GABRA1 Acute Anxiety 0,04015
DB01559 Clotiazepam potentiator GABRA1 0,04015
DB01587 Ketazolam potentiator GABRA1 0,04015
DB01588 Prazepam potentiator GABRA1 0,04015
positive allosteric DB01588 Prazepam GABRA1 0,04015 modulator CBA
DB01589 Quazepam potentiator GABRA1 0,04015
positive allosteric DB01589 Quazepam GABRA1 0,04015 modulator
DB01595 Nitrazepam potentiator GABRA1 Insomnia 0,04015
DB01956 Taurine agonist GABRA1 0,04015
agonist,positive DB09118 Stiripentol allosteric GABRA1 0,04015 modulator
positive allosteric DB11859 Brexanolone GABRA1 0,04015 modulator
positive allosteric DB13872 Lormetazepam GABRA1 0,04015 modulator
DB00210 Adapalene agonist RARG Acne Vulgaris 0,02881
Keratinization DB00459 Acitretin agonist RARG 0,02881 disorders
Chronic Eczema of DB00523 Alitretinoin agonist RARG 0,02881 the hand
DB00755 Tretinoin agonist RARG Acne Vulgaris 0,02881
Psoriasis Vulgaris DB00799 Tazarotene agonist RARG 0,02881 (Plaque Psoriasis)
Metastatic DB11967 Binimetinib inhibitor MAP3K1 0,02674 Melanoma
Metastatic DB00002 Cetuximab antagonist EGFR 0,02433 Colorectal Cancers
DB00317 Gefitinib antagonist EGFR 0,02433
Locally Advanced DB00530 Erlotinib antagonist EGFR Non-Small Cell Lung 0,02433 Cancer
Metastatic Breast DB01259 Lapatinib antagonist EGFR 0,02433 Cancer (MBC)
DB01269 Panitumumab suppressor EGFR 0,02433 CBA
Metastatic DB08916 Afatinib inhibitor EGFR Non-Small Cell Lung 0,02433 Cancer
DB09330 Osimertinib inhibitor EGFR 0,02433
DB09559 Necitumumab antagonist EGFR 0,02433
Foreskin DB10772 keratinocyte agonist EGFR 0,02433 (neonatal)
DB11828 Neratinib inhibitor EGFR 0,02433
DB11963 Dacomitinib inhibitor EGFR 0,02433
DB12267 Brigatinib inhibitor EGFR 0,02433
DB00140 Riboflavin product of BLVRB Ariboflavinosis 0,01864
Malignant DB01219 Dantrolene antagonist RYR1 0,01053 Hyperthermia
DB09085 Tetracaine modulator RYR1 0,01053
Refractory Partial DB00949 Felbamate antagonist GRIN2B 0,00975 Seizures
DB01956 Taurine inhibitor GRIN2B 0,00975
DB01169 Arsenic trioxide inducer JUN 0,00961
DB13931 Netarsudil inhibitor ROCK2 0,00809
Bone Marrow DB00020 Sargramostim agonist IL3RA 0,00752 Suppression
DB14731 Tagraxofusp binder IL3RA 0,00752
High-grade, DB13615 Mifamurtide ligand NOD2 nonmetastatic 0,0075 Osteosarcoma
DB00095 Efalizumab antibody ITGAL 0,00723
Antithymocyte Acute cellular DB00098 immunoglobulin ITGAL 0,00723 rejection (rabbit) CBA
DB11611 Lifitegrast antagonist ITGAL 0,00723
Chronic DB09053 Ibrutinib inhibitor BTK Lymphocytic 0,00713 Leukaemia (CLL)
DB11703 Acalabrutinib inhibitor BTK 0,00713
DB00922 Levosimendan potentiator TNNC1 0,00645
DB01373 Calcium agonist TNNC1 0,00645
Metastatic DB08896 Regorafenib inhibitor FRK Gastrointestinal 0,00625 Stromal Tumor
Tuberculin DB11601 Purified Protein ligand TLR2 0,00614 Derivative
Human incorporation into DB06773 ACTN1 0,00569 calcitonin and destabilization
DB00104 Octreotide binder SSTR2 Acromegaly 0,00549
DB09099 Somatostatin agonist SSTR2 0,00549
Dotatate gallium DB13925 binder SSTR2 0,00549 Ga-68
Lutetium Lu 177 DB13985 agonist SSTR2 0,00549 dotatate
DB00887 Bumetanide inhibitor SLC12A5 0,00535
DB00231 Temazepam potentiator GABRA6 0,00511
Headache, DB00241 Butalbital potentiator GABRA6 0,00511 Tension-Type
DB00306 Talbutal potentiator GABRA6 0,00511
DB00312 Pentobarbital potentiator GABRA6 Insomnia 0,00511
DB00371 Meprobamate agonist GABRA6 0,00511
DB00418 Secobarbital potentiator GABRA6 0,00511
DB00599 Thiopental potentiator GABRA6 0,00511 CBA
DB00683 Midazolam potentiator GABRA6 Seizures, Epileptic 0,00511
DB00690 Flurazepam potentiator GABRA6 0,00511
Grand mal DB00794 Primidone potentiator GABRA6 Generalized 0,00511 tonic-clonic seizure
Alcohol Withdrawal DB00842 Oxazepam potentiator GABRA6 0,00511 Syndrome(AWS)
Methylphenobar DB00849 potentiator GABRA6 0,00511 bital
DB00897 Triazolam potentiator GABRA6 0,00511
DB01351 Amobarbital potentiator GABRA6 0,00511
DB01353 Butobarbital potentiator GABRA6 0,00511
DB01544 Flunitrazepam potentiator GABRA6 0,00511
DB01558 Bromazepam potentiator GABRA6 Acute Anxiety 0,00511
DB01595 Nitrazepam potentiator GABRA6 Insomnia 0,00511
Advanced Cervical DB01229 Paclitaxel MAP4 0,00471 Cancer
DB01248 Docetaxel MAP4 Esophageal Cancers 0,00471
Autoimmune DB00087 Alemtuzumab antibody CD52 0,00443 Hemolytic Anemia
DB11157 Anthralin antagonist KRT2 0,00438
Acute Lymphocytic DB00987 Cytarabine inhibitor POLB 0,00415 Leukemia (ALL)
Partial-Onset DB00996 Gabapentin inhibitor CACNA1B 0,00414 Seizures
DB01202 Levetiracetam inhibitor CACNA1B Epilepsies 0,00414
Fluocinolone Atopic Dermatitis DB00591 inducer ANXA1 0,00405 acetonide (AD)
Acute Gouty DB00741 Hydrocortisone agonist ANXA1 0,00405 Arthritis CBA
Hydrocortisone Adrenal cortical DB14539 ANXA1 0,00405 acetate hypofunctions
Hydrocortisone Atopic Dermatitis DB14540 ANXA1 0,00405 butyrate (AD)
Hydrocortisone DB14541 ANXA1 0,00405 cypionate
Hydrocortisone DB14542 ANXA1 0,00405 phosphate
Hydrocortisone DB14543 ANXA1 Itching 0,00405 probutate
Hydrocortisone DB14544 ANXA1 0,00405 valerate
Polyarticular DB06273 Tocilizumab antibody IL6R Juvenile Idiopathic 0,00396 Arthritis
Moderate, active antagonist,antibod DB11767 Sarilumab IL6R Rheumatoid 0,00396 y arthritis
Moderate, active DB11817 Baricitinib inhibitor PTK2B Rheumatoid 0,00389 arthritis
Moderate Juvenile DB01281 Abatacept antagonist CD80 0,00361 idiopathic arthritis
Urothelial DB11714 Durvalumab binder CD80 carcinoma ureter 0,00361 metastatic
DB04941 Crofelemer antagonist CFTR 0,00343
DB08820 Ivacaftor potentiator CFTR 0,00343
DB09280 Lumacaftor modulator CFTR 0,00343
DB11712 Tezacaftor activator CFTR 0,00343
DB00216 Eletriptan agonist HTR1B Acute Migraine 0,00342
DB00315 Zolmitriptan agonist HTR1B 0,00342 CBA
Dihydroergotam DB00320 agonist HTR1B Cluster Headache 0,00342 ine
DB00669 Sumatriptan agonist HTR1B Acute Migraine 0,00342
DB00696 Ergotamine agonist HTR1B Cluster Headache 0,00342
Migraine with acute DB00952 Naratriptan agonist HTR1B 0,00342 onset aura
Migraine with acute DB00953 Rizatriptan agonist HTR1B 0,00342 onset aura
Menstrual DB00998 Frovatriptan agonist HTR1B 0,00342 Migraines
DB09068 Vortioxetine partial agonist HTR1B 0,00342
DB00235 Milrinone inhibitor PDE3A 0,0031
DB00261 Anagrelide inhibitor PDE3A 0,0031
DB00277 Theophylline inhibitor PDE3A 0,0031
DB01166 Cilostazol inhibitor PDE3A 0,0031
Acute Exacerbation DB01223 Aminophylline inhibitor PDE3A of Chronic 0,0031 Bronchitis (AECB)
DB01303 Oxtriphylline inhibitor PDE3A 0,0031
DB01427 Amrinone inhibitor PDE3A 0,0031
DB04880 Enoximone inhibitor PDE3A 0,0031
DB00270 Isradipine inhibitor CACNA1C 0,00298
Atrial Fibrillation DB00308 Ibutilide activator CACNA1C 0,00298 (AF)
DB00343 Diltiazem blocker CACNA1C Anal Fissures 0,00298
DB00381 Amlodipine inhibitor CACNA1C Anginal Pain 0,00298
DB00393 Nimodipine inhibitor CACNA1C 0,00298
DB00401 Nisoldipine inhibitor CACNA1C 0,00298
DB00568 Cinnarizine inhibitor CACNA1C 0,00298 CBA
Chronic Stable DB00622 Nicardipine inhibitor CACNA1C 0,00298 Angina Pectoris
Atrial Fibrillation DB00661 Verapamil inhibitor CACNA1C 0,00298 (AF)
DB00825 Levomenthol antagonist CACNA1C Coughing 0,00298
DB01023 Felodipine inhibitor CACNA1C 0,00298
DB01054 Nitrendipine inhibitor CACNA1C 0,00298
Chronic Stable DB01115 Nifedipine inhibitor CACNA1C 0,00298 Angina Pectoris
DB01373 Calcium ligand CACNA1C 0,00298
DB06712 Nilvadipine inhibitor CACNA1C 0,00298
Irritable Bowel DB09089 Trimebutine inhibitor CACNA1C 0,00298 Syndrome (IBS)
DB09236 Lacidipine antagonist CACNA1C 0,00298
DB09238 Manidipine blocker CACNA1C 0,00298
DB12278 Propiverine antagonist CACNA1C Micturition urgency 0,00298
Symptomatic Atrial DB00204 Dofetilide inhibitor KCNJ12 0,0028 flutter
DB04941 Crofelemer antagonist ANO1 0,00269
Adult Onset Growth DB00052 Somatotropin binder GHR Hormone 0,00267 Deficiency
DB00082 Pegvisomant antagonist GHR 0,00267
DB00185 Cevimeline agonist CHRM3 0,00256
DB00332 Ipratropium antagonist CHRM3 Asthma 0,00256
Oxyphencyclimi DB00383 antagonist CHRM3 0,00256 ne
Parkinsonian DB00387 Procyclidine antagonist CHRM3 0,00256 Syndromes
DB00496 Darifenacin antagonist CHRM3 0,00256 CBA
Anisotropine DB00517 antagonist CHRM3 0,00256 methylbromide
DB00572 Atropine antagonist CHRM3 Amblyopia 0,00256
Homatropine DB00725 antagonist CHRM3 0,00256 methylbromide
DB00785 Cryptenamine antagonist CHRM3 0,00256
DB01036 Tolterodine antagonist CHRM3 0,00256
DB01062 Oxybutynin antagonist CHRM3 Bladder Spasms 0,00256
DB01085 Pilocarpine agonist CHRM3 Dry Mouth 0,00256
Acute Exacerbation of Chronic DB01409 Tiotropium antagonist CHRM3 0,00256 Obstructive Pulmonary Disease
DB01591 Solifenacin antagonist CHRM3 0,00256
DB01625 Isopropamide antagonist CHRM3 0,00256
DB04843 Mepenzolate antagonist CHRM3 0,00256
DB06702 Fesoterodine antagonist CHRM3 0,00256
DB06709 Methacholine agonist CHRM3 0,00256
DB06787 Hexocyclium antagonist CHRM3 0,00256
DB08897 Aclidinium antagonist CHRM3 0,00256
DB09076 Umeclidinium antagonist CHRM3 0,00256
Irritable Bowel DB09089 Trimebutine antagonist CHRM3 0,00256 Syndrome (IBS)
DB09167 Dosulepin antagonist CHRM3 0,00256
Gastrointestinal Butylscopolamin spastic and DB09300 antagonist CHRM3 0,00256 e hypermotility disorders
DB11181 Homatropine antagonist CHRM3 0,00256
DB12278 Propiverine antagonist CHRM3 Micturition urgency 0,00256 CBA
DB00343 Diltiazem blocker CACNG1 Anal Fissures 0,00242
DB00381 Amlodipine blocker CACNG1 Anginal Pain 0,00242
DB00528 Lercanidipine inhibitor CACNG1 0,00242
DB01054 Nitrendipine inhibitor CACNG1 0,00242
Location of top AT in HiPathia circuits and selection of those circuits shared with the Disease Map. A total of 118 /177 circuits from RD Map containing top AT are shown.
Disease Map circuits with top AT
HiPathia pathway: Effector HiPathia pathway: Effector HiPathia pathway: Effector gene gene gene
MAPK signaling pathway: FoxO signaling pathway: PI3K-Akt signaling pathway: ATF4* GADD45G BCL2
FoxO signaling pathway: PI3K-Akt signaling pathway: MAPK signaling pathway: FOS FASLG MCL1
MAPK signaling pathway: FoxO signaling pathway: PI3K-Akt signaling pathway: MAPT BCL2L11 RXRA
MAPK signaling pathway: FoxO signaling pathway: PI3K-Akt signaling pathway: STMN1 TNFSF10 BCL2**
MAPK signaling pathway: PI3K-Akt signaling pathway: FoxO signaling pathway: BCL6 PLA2G4B EIF4E
FoxO signaling pathway: PI3K-Akt signaling pathway: MAPK signaling pathway: MYC BNIP3 EIF4B
FoxO signaling pathway: PI3K-Akt signaling pathway: ErbB signaling pathway: MYC ATG12 RPS6
FoxO signaling pathway: PI3K-Akt signaling pathway: ErbB signaling pathway: ELK1 GABARAP NOS3
Ras signaling pathway: PI3K-Akt signaling pathway: FoxO signaling pathway: CAT PLA2G4B CASP9 CBA
FoxO signaling pathway: PI3K-Akt signaling pathway: Ras signaling pathway: ELK1 SOD2 PRKCA
FoxO signaling pathway: PI3K-Akt signaling pathway: Ras signaling pathway: ETS1 GADD45G* PKN3
PI3K-Akt signaling pathway: Ras signaling pathway: BCL2L1 FoxO signaling pathway: ATM C8orf44-SGK3
FoxO signaling pathway: Ras signaling pathway: NFKB1 Apoptosis: BCL2* PCK1
FoxO signaling pathway: Ras signaling pathway: FASLG Gap junction: GJA1 GJA1 G6PC
FoxO signaling pathway: Ras signaling pathway: PAK4 Gap junction: GJA1 GJA1* BCL6*
Ras signaling pathway: RHOA FoxO signaling pathway: IL7R Gap junction: GJA1 TJP1
Ras signaling pathway: MAPK8 FoxO signaling pathway: KLF2 Gap junction: GJA1 GJA1**
FoxO signaling pathway: Natural killer cell mediated Ras signaling pathway: RAC1* S1PR1 cytotoxicity: TNF
FoxO signaling pathway: Natural killer cell mediated Ras signaling pathway: REL RAG1 cytotoxicity: CSF2
FoxO signaling pathway: Natural killer cell mediated Ras signaling pathway: PLD1 FBXO32 cytotoxicity: FAS
Phospholipase D signaling Natural killer cell mediated Ras signaling pathway: PRKCA pathway: MAPK1 cytotoxicity: TNFRSF10D
Ras signaling pathway: Phospholipase D signaling T cell receptor signaling C01245 pathway: C06124 pathway: FOS
Phospholipase D signaling B cell receptor signaling Ras signaling pathway: ABL1 pathway: MTOR pathway: FOS
PI3K-Akt signaling pathway: Ras signaling pathway: RAB5A Serotonergic synapse: CASP3 GYS1
PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: RAP1A MYC cytoskeleton: ACTB ARPC5
Ras signaling pathway: PI3K-Akt signaling pathway: Regulation of actin RAC1** CCND1 cytoskeleton: CFL1 ACTB CBA
Regulation of actin PI3K-Akt signaling pathway: Ras signaling pathway: KSR2 cytoskeleton: MYL12B MYH9 CDKN1B ACTB
Ras signaling pathway: STK4 PI3K-Akt signaling pathway: Regulation of actin STK4 RBL2 cytoskeleton: PXN
PI3K-Akt signaling pathway: Regulation of actin Ras signaling pathway: MLLT4 PCK1 cytoskeleton: IQGAP2
Rap1 signaling pathway: PI3K-Akt signaling pathway: Regulation of actin MAPK1 G6PC cytoskeleton: PFN3 ACTB
Rap1 signaling pathway: PI3K-Akt signaling pathway: Regulation of actin PLCE1 FASLG cytoskeleton: VCL*
FoxO signaling pathway: PI3K-Akt signaling pathway: Regulation of actin CCNB3 BCL2L11 cytoskeleton: ACTN4
FoxO signaling pathway: PI3K-Akt signaling pathway: Regulation of actin CCND1 BCL2L1 cytoskeleton: MSN
FoxO signaling pathway: PI3K-Akt signaling pathway: GnRH signaling pathway: ELK1 CCNG2 BCL2*
FoxO signaling pathway: PI3K-Akt signaling pathway: Estrogen signaling pathway: CDKN2B TP53 CREB3
FoxO signaling pathway: PI3K-Akt signaling pathway: Estrogen signaling pathway: CDKN2D BCL2L1* ESR1 C00951
FoxO signaling pathway: PI3K-Akt signaling pathway: Estrogen signaling pathway: CDKN1A MYB ESR1 FOS
FoxO signaling pathway: PI3K-Akt signaling pathway: Estrogen signaling pathway: CDKN1B CCND1 CDK2 ESR1 C00951*
PI3K-Akt signaling pathway: Oxytocin signaling pathway: FoxO signaling pathway: RBL2 MAPK1 JUN
FoxO signaling pathway: PLK4 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