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Atlas / Disease / Osteonecrosis

Osteonecrosis

disease
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Also known as bone necrosisischaemic bone diseaseischemic bone disease

Summary

Osteonecrosis (MONDO:0005380) is a disease (an umbrella term covering 7 Mondo subtypes) with 20 cohort genes (83 GWAS associations across 21 studies) and 56 clinical trials. Top therapeutic interventions include alendronic acid, oxygen, and ferumoxytol.

At a glance

  • Umbrella term: 7 Mondo subtypes
  • Cohort genes: 20
  • GWAS associations: 83
  • Clinical trials: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical nameosteonecrosis
Mondo IDMONDO:0005380
EFOEFO:0004259
MeSHD010020
Orphanet399158
DOIDDOID:0080008, DOID:10159
ICD-10-CMM87
ICD-11536467755
NCITC34880, C35476
SNOMED CT240196003
UMLSC0029445
MedGen45249
GARD0021657
NORD1537
Is cancer (heuristic)no

Also known as: bone necrosis · ischaemic bone disease · ischemic bone disease · osteonecrosis

Data availability: 83 GWAS associations (21 studies).

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis

Related subtypes (26): bone remodeling disease, disease of bone structure, mucopolysaccharidosis type 1, bone inflammation disease, Baastrup syndrome, periostitis, bone development disease, ainhum, cervical rib disease, coxoauricular syndrome, metachondromatosis, mucopolysaccharidosis type 9, Sagliker syndrome, mixed sclerosing bone dystrophy with extra-skeletal manifestations, GM1 gangliosidosis, skeletal dysplasia, autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome, mucopolysaccharidosis type 3, bone neoplasm, skull disorder, Duane anomaly-myopathy-scoliosis syndrome, mueller-weiss syndrome, SLC10A7-congenital disorder of glycosylation, metabolic bone disorder, proteoglycan-related bone disorder, ACAN-related short stature spectrum

Subtypes (7): Kummell disease, avascular necrosis, osteochondrosis, osteonecrosis of genetic origin, idiopathic phalangeal acro-osteolysis, Dieterich disease, osteoradionecrosis

Genetics & variants

GWAS landscape

83 GWAS associations across 21 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs22245391e-15RN7SL680P - HSPE1P1A0.2
rs5685591481e-13ABCC3C1.02
rs5408627563e-13ELL2P2 - LINC01256G2.55
rs5528047782e-11OSBPL10C1.72
rs27363081e-10FAM167A-AS1C2.74
rs341183831e-08WIPF1A3.2
rs1452667782e-08LINC02305 - MTND4P33?
rs109896923e-08MTND3P4 - ARL2BPP7A
rs767696531e-07LINC00364 - BCRP9A1.1
rs77180642e-07LINC02159 - GABRB2T3.1
rs64516043e-07LINC02996 - GHRC2.9
rs79259085e-07RN7SL167P - NTM?
rs109264525e-07RGS7T1.1
rs79575829e-07NAV3G3.3
rs19349511e-06CYP2C8T12.75
rs22292881e-06ZFHX3-AS1, ZFHX3C
rs21544901e-06GRIK1, BACH1A
rs109178081e-06RNA5SP63 - U3A3.2
rs6704761e-06CYP4F12 - OR10H2G1.1
rs28331621e-06KRTAP11-1 - KRTAP19-8C1.1
rs13889412e-06CSGALNACT1?
rs38142762e-06GPC6C3
rs118172962e-06LINC00841 - LINC03089G2.6
rs801312933e-06CWC27?
rs16967563e-06CBX4 - LINC01979?
rs1924621163e-06PPP1R9A-AS1, PPP1R9A?
rs727339933e-06SNORD81 - RN7SL58PA
rs111445503e-06CDCA7P2 - OTX2P1A
rs766383643e-06PPP2R2BA2.8
rs599500163e-06NMRAL2PT2.6

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST90478973Verma A20242,789446,686Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90478972Verma A20241,381119,811Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480528Verma A20241,381119,811Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90474144UK Biobank Whole-Genome Sequencing Consortium20251,170457,270Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90080565Backman JD2021669387,134Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084551Backman JD2021669387,134Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90436702Zhou W2018542391,041Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651569Liu TY2025495226,631Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90053855Yang G20214444,564Genome-wide Association Study Identified Chromosome 8 Locus Associated with Medication-related Osteonecrosis of the Jaw.
GCST90482415Verma A202431859,416Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding1
Tier 2: splice/UTR1
Tier 3: regulatory2
Tier 4: intronic/intergenic46

MAF distribution

BucketVariants
common (>=0.05)45
low_freq (0.01-0.05)0
rare (<0.01)4
unknown1

Functional consequences

ConsequenceCount
intron_variant28
intergenic_variant16
regulatory_region_variant2
non_coding_transcript_exon_variant2
missense_variant1
splice_region_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs22245392039923465A>T0.377intergenic_variantRN7SL680P - HSPE1P11e-15Tier 4: intronic/intergenic
rs5685591481750688894C>A,T0.003intron_variantABCC31e-13Tier 4: intronic/intergenic
rs5408627564132467038G>T0.001intergenic_variantELL2P2 - LINC012563e-13Tier 4: intronic/intergenic
rs552804778331945876C>T0.001intron_variantOSBPL102e-11Tier 4: intronic/intergenic
rs2736308811390991C>A,G,T0.34intron_variantFAM167A-AS11e-10Tier 4: intronic/intergenic
rs341183832174600804G>A,T0.184intron_variantWIPF11e-08Tier 4: intronic/intergenic
rs1452667781484147082T>Cintergenic_variantLINC02305 - MTND4P332e-08Tier 4: intronic/intergenic
rs109896929101912273G>A0.106intergenic_variantMTND3P4 - ARL2BPP73e-08Tier 4: intronic/intergenic
rs767696531367676868A>G0.106intron_variantLINC00364 - BCRP91e-07Tier 4: intronic/intergenic
rs77180645161129761C>T0.11intergenic_variantLINC02159 - GABRB22e-07Tier 4: intronic/intergenic
rs6451604542253995C>A,G,T0.168intron_variantLINC02996 - GHR3e-07Tier 4: intronic/intergenic
rs792590811131276855T>C0.05intron_variantRN7SL167P - NTM5e-07Tier 4: intronic/intergenic
rs109264521241279227C>A,G,T0.417intron_variantRGS75e-07Tier 4: intronic/intergenic
rs79575821277382454C>G0.1intron_variantNAV39e-07Tier 4: intronic/intergenic
rs19349511095038791C>A,G,T0.12intron_variantCYP2C81e-06Tier 4: intronic/intergenic
rs22292881672794405C>A,G0.002missense_variantZFHX3-AS1, ZFHX31e-06Tier 1: coding
rs21544902129543641A>G0.222intron_variantGRIK1, BACH11e-06Tier 4: intronic/intergenic
rs109178081163594664G>A,C,T0.117intergenic_variantRNA5SP63 - U31e-06Tier 4: intronic/intergenic
rs6704761915702657A>C,G0.4regulatory_region_variantCYP4F12 - OR10H21e-06Tier 3: regulatory
rs28331622130923932T>C0.329intergenic_variantKRTAP11-1 - KRTAP19-81e-06Tier 4: intronic/intergenic
rs1388941819757960A>G0.05regulatory_region_variantCSGALNACT12e-06Tier 3: regulatory
rs38142761393551321A>C0.167intron_variantGPC62e-06Tier 4: intronic/intergenic
rs118172961044069746T>G0.148intron_variantLINC00841 - LINC030892e-06Tier 4: intronic/intergenic
rs80131293564854707C>T0.05intron_variantCWC273e-06Tier 4: intronic/intergenic
rs16967561779854174C>A,T0.05intergenic_variantCBX4 - LINC019793e-06Tier 4: intronic/intergenic
rs192462116795138094G>A0.05intron_variantPPP1R9A-AS1, PPP1R9A3e-06Tier 4: intronic/intergenic
rs72733993518408799G>A0.156non_coding_transcript_exon_variantSNORD81 - RN7SL58P3e-06Tier 4: intronic/intergenic
rs11144550975646632G>A0.137intergenic_variantCDCA7P2 - OTX2P13e-06Tier 4: intronic/intergenic
rs766383645146653600G>A0.119intron_variantPPP2R2B3e-06Tier 4: intronic/intergenic
rs599500163185961746C>T0.201intron_variantNMRAL2P3e-06Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
CWC27Orphanet:166035Brachydactyly-short stature-retinitis pigmentosa syndrome
SEMA3COrphanet:388Hirschsprung disease
SP6Orphanet:100031Hypoplastic amelogenesis imperfecta
CCND2Orphanet:83473Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
CSGALNACT1Orphanet:1425Desbuquois syndrome
KCNMA1Orphanet:664438Gingival fibromatosis-aortic root dilatation-facial dysmorphism-intellectual disability syndrome
KCNMA1Orphanet:79137Generalized epilepsy-paroxysmal dyskinesia syndrome

Cohort genes → proteins

20 cohort genes, 20 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only20

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
CWC27HGNC:10664ENSG00000153015Q6UX04Spliceosome-associated protein CWC27 homologgwas
SEMA3CHGNC:10725ENSG00000075223Q99985Semaphorin-3Cgwas
SOX14HGNC:11193ENSG00000168875O95416Transcription factor SOX-14gwas
SP6HGNC:14530ENSG00000189120Q3SY56Transcription factor Sp6gwas
PPP1R9AHGNC:14946ENSG00000158528Q9ULJ8Neurabin-1gwas
CBX4HGNC:1554ENSG00000141582O00257E3 SUMO-protein ligase CBX4gwas
CCND2HGNC:1583ENSG00000118971P30279G1/S-specific cyclin-D2gwas
GRIN3AHGNC:16767ENSG00000198785Q8TCU5Glutamate receptor ionotropic, NMDA 3Agwas
RAPGEF5HGNC:16862ENSG00000136237Q92565Rap guanine nucleotide exchange factor 5gwas
CDH9HGNC:1768ENSG00000113100Q9ULB4Cadherin-9gwas
RNF138HGNC:17765ENSG00000134758Q8WVD3E3 ubiquitin-protein ligase RNF138gwas
NTMHGNC:17941ENSG00000182667Q9P121Neurotrimingwas
CSGALNACT1HGNC:24290ENSG00000147408Q8TDX6Chondroitin sulfate N-acetylgalactosaminyltransferase 1gwas
CYP2C8HGNC:2622ENSG00000138115P10632Cytochrome P450 2C8gwas
PAG1HGNC:30043ENSG00000076641Q9NWQ8Phosphoprotein associated with glycosphingolipid-enriched microdomains 1gwas
GRIK1HGNC:4579ENSG00000171189P39086Glutamate receptor ionotropic, kainate 1gwas
KCNMA1HGNC:6284ENSG00000156113Q12791Calcium-activated potassium channel subunit alpha-1gwas
KLF12HGNC:6346ENSG00000118922Q9Y4X4Krueppel-like factor 12gwas
ZFHX3HGNC:777ENSG00000140836Q15911Zinc finger homeobox protein 3gwas
PCSK5HGNC:8747ENSG00000099139Q92824Proprotein convertase subtilisin/kexin type 5gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
CWC27Spliceosome-associated protein CWC27 homologAs part of the spliceosome, plays a role in pre-mRNA splicing.
SEMA3CSemaphorin-3CBinds to plexin family members and plays an important role in the regulation of developmental processes.
SOX14Transcription factor SOX-14Acts as a negative regulator of transcription.
SP6Transcription factor Sp6Promotes cell proliferation.
PPP1R9ANeurabin-1Binds to actin filaments (F-actin) and shows cross-linking activity.
CBX4E3 SUMO-protein ligase CBX4E3 SUMO-protein ligase that catalyzes sumoylation of target proteins by promoting the transfer of SUMO from the E2 enzyme to the substrate.
CCND2G1/S-specific cyclin-D2Regulatory component of the cyclin D2-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition.
GRIN3AGlutamate receptor ionotropic, NMDA 3AComponent of a non-conventional N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with low calcium permeability and low voltage-dependent block by Mg(2+).
RAPGEF5Rap guanine nucleotide exchange factor 5Guanine nucleotide exchange factor (GEF) for RAP1A, RAP2A and MRAS/M-Ras-GTP.
CDH9Cadherin-9Cadherins are calcium-dependent cell adhesion proteins.
RNF138E3 ubiquitin-protein ligase RNF138E3 ubiquitin-protein ligase involved in DNA damage response by promoting DNA resection and homologous recombination.
NTMNeurotriminNeural cell adhesion molecule.
CSGALNACT1Chondroitin sulfate N-acetylgalactosaminyltransferase 1Transfers 1,4-N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of glucuronic acid (GlcUA).
CYP2C8Cytochrome P450 2C8A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins.
PAG1Phosphoprotein associated with glycosphingolipid-enriched microdomains 1Negatively regulates TCR (T-cell antigen receptor)-mediated signaling in T-cells and FCER1 (high affinity immunoglobulin epsilon receptor)-mediated signaling in mast cells.
GRIK1Glutamate receptor ionotropic, kainate 1Ionotropic glutamate receptor that functions as a cation-permeable ligand-gated ion channel, gated by L-glutamate and the glutamatergic agonist kainic acid.
KCNMA1Calcium-activated potassium channel subunit alpha-1Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+).
KLF12Krueppel-like factor 12Confers strong transcriptional repression to the AP-2-alpha gene.
ZFHX3Zinc finger homeobox protein 3Transcriptional regulator which can act as an activator or a repressor.
PCSK5Proprotein convertase subtilisin/kexin type 5Serine endoprotease that processes various proproteins by cleavage at paired basic amino acids, recognizing the RXXX[KR]R consensus motif.

Protein-family classification

Druggable: 7 · Difficult: 6 · Unknown: 7 · Druggable fraction: 0.35

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

FamilyGenesFoldFDR
Ion channel15.6×0.385
Antibody/Immunoglobulin22.9×0.385
Transcription factor52.1×0.385
Enzyme (other)31.8×0.403
Protease11.8×0.596
Scaffold/PPI10.9×0.813
Other/Unknown70.6×0.982

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
CWC27Enzyme (other)yes5.2.1.8Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-like_dom_sf
SEMA3CAntibody/ImmunoglobulinyesSemap_dom, Ig_sub, Ig-like_dom
SOX14Transcription factornoHMG_box_dom, SOX_fam, HMG_box_dom_sf
SP6Transcription factornoZnf_C2H2_type, Znf_C2H2_sf
PPP1R9AScaffold/PPInoPDZ, SAM, SAM/pointed_sf
CBX4Other/UnknownnoChromo/chromo_shadow_dom, Chromo-like_dom_sf, Chromo_dom_subgr
CCND2Other/UnknownnoCyclin_C-dom, Cyclin_N, Cyclin-like_dom
GRIN3AOther/UnknownnoIontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
RAPGEF5Other/UnknownnoRas-like_Gua-exchang_fac_N, RASGEF_cat_dom, Ras-like_GEF
CDH9Other/UnknownnoCadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
RNF138Transcription factornoZnf_RING, Di19_Zn-bd, Znf_RING/FYVE/PHD
NTMAntibody/ImmunoglobulinyesIg_sub2, Ig_sub, Ig-like_dom
CSGALNACT1Enzyme (other)yes2.4.1.174Chond_GalNAc, Nucleotide-diphossugar_trans, CS_glycosyltransferase
CYP2C8Enzyme (other)yes1.14.14.1Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
PAG1Other/UnknownnoPAG
GRIK1Other/UnknownnoIontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
KCNMA1Ion channelyesRCK_N, K_chnl_BK_asu, Ion_trans_dom
KLF12Transcription factornoZnf_C2H2_type, Znf_C2H2_sf
ZFHX3Transcription factornoHD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
PCSK5Proteaseyes3.4.21.B26Peptidase_S8/S53_dom, EGF, P_dom

Expression context

Cohort genes with no expression data: 0.

18 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)1
broad (>20)19
unknown0

Top tissues across cohort

TissueCohort genes
synovial joint3
male germ line stem cell (sensu Vertebrata) in testis3
saphenous vein3
lower esophagus mucosa2
placenta2
endothelial cell2
secondary oocyte2
buccal mucosa cell2
globus pallidus1
medial globus pallidus1
tendon of biceps brachii1
calcaneal tendon1
mammary duct1
hypothalamus1
upper arm skin1
Brodmann (1909) area 231
parietal lobe1
mucosa of paranasal sinus1
penis1
upper leg skin1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
CWC27253ubiquitousmarkertendon of biceps brachii, medial globus pallidus, globus pallidus
SEMA3C289ubiquitousmarkermammary duct, synovial joint, calcaneal tendon
SOX1415tissue_specificyesplacenta, hypothalamus, lower esophagus mucosa
SP6140broadyeslower esophagus mucosa, upper arm skin, placenta
PPP1R9A257broadmarkerBrodmann (1909) area 23, endothelial cell, parietal lobe
CBX4264ubiquitousmarkerupper leg skin, penis, mucosa of paranasal sinus
CCND2293ubiquitousmarkeradrenal tissue, seminal vesicle, cauda epididymis
GRIN3A149tissue_specificmarkerBrodmann (1909) area 46, middle temporal gyrus, male germ line stem cell (sensu Vertebrata) in testis
RAPGEF5275broadmarkerinferior vagus X ganglion, pons, inferior olivary complex
CDH9121tissue_specificmarkerendothelial cell, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis
RNF138286ubiquitousmarkerprimordial germ cell in gonad, secondary oocyte, right testis
NTM231ubiquitousmarkerright hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
CSGALNACT1280broadmarkercartilage tissue, cardiac muscle of right atrium, synovial joint
CYP2C8185tissue_specificmarkerright lobe of liver, liver, sperm
PAG1255ubiquitousmarkersecondary oocyte, oocyte, ileal mucosa
GRIK1183broadmarkermale germ line stem cell (sensu Vertebrata) in testis, cingulate cortex, anterior cingulate cortex
KCNMA1275ubiquitousmarkerparotid gland, saphenous vein, tibia
KLF12267ubiquitousmarkercorpus epididymis, superficial temporal artery, pigmented layer of retina
ZFHX3274ubiquitousmarkersaphenous vein, buccal mucosa cell, synovial joint
PCSK5264ubiquitousmarkerbuccal mucosa cell, saphenous vein, sural nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

SymbolInteractor count
CCND23,569
RNF1383,447
CWC272,984
KCNMA12,606
PCSK52,359
CBX41,848
NTM1,777
PPP1R9A1,765
CYP2C81,730
GRIK11,725

Intra-cohort edges

ABSources
PCSK5SP6string_interaction

Structural data

PDB: 11 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
KCNMA1Q1279136
GRIK1P3908611
CWC27Q6UX049
CYP2C8P106325
CBX4O002573
GRIN3AQ8TCU53
ZFHX3Q159113
PPP1R9AQ9ULJ82
NTMQ9P1212
CCND2P302791
RAPGEF5Q925651

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
CSGALNACT1Q8TDX687.71
SEMA3CQ9998585.69
RNF138Q8WVD378.86
CDH9Q9ULB477.60
PCSK5Q9282476.31
SOX14O9541668.13
PAG1Q9NWQ854.93
SP6Q3SY5652.79
KLF12Q9Y4X451.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 74. Enrichment computed across 20 evidence-associated genes (14 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Activation of Na-permeable kainate receptors1407.9×0.082GRIK1
NGF processing1203.9×0.082PCSK5
Acetylcholine inhibits contraction of outer hair cells1163.1×0.082KCNMA1
Drug-mediated inhibition of CDK4/CDK6 activity1163.1×0.082CCND2
Biosynthesis of maresin-like SPMs1135.9×0.082CYP2C8
RUNX3 regulates CDKN1A transcription1116.5×0.082ZFHX3
Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)1102.0×0.082CYP2C8
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)190.6×0.082CYP2C8
Ca2+ activated K+ channels181.6×0.082KCNMA1
Activation of Ca-permeable Kainate Receptor181.6×0.082GRIK1
Transcriptional regulation by RUNX1220.9×0.082CBX4, CCND2
CYP2E1 reactions168.0×0.085CYP2C8
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects162.8×0.085CCND2
Nitric oxide stimulates guanylate cyclase158.3×0.085KCNMA1
cGMP effects151.0×0.085KCNMA1
SUMOylation of DNA methylation proteins148.0×0.085CBX4
Regulation of RUNX1 Expression and Activity148.0×0.085CCND2
GAB1 signalosome145.3×0.085PAG1
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)145.3×0.085CCND2
Assembly of active LPL and LIPC lipase complexes142.9×0.085PCSK5
CS-GAG biosynthesis138.8×0.086CSGALNACT1
Phosphorylation of CD3 and TCR zeta chains138.8×0.086PAG1
Xenobiotics135.5×0.090CYP2C8
Aberrant regulation of mitotic cell cycle due to RB1 defects129.1×0.100CCND2
G1 Phase128.1×0.100CCND2
Diseases of mitotic cell cycle128.1×0.100CCND2
Aspirin ADME122.7×0.116CYP2C8
Sensory processing of sound122.1×0.116KCNMA1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known121.5×0.116CBX4
Platelet homeostasis119.9×0.119KCNMA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
modulation of chemical synaptic transmission327.5×0.025PPP1R9A, GRIN3A, GRIK1
UDP-glucuronate metabolic process1842.6×0.039CSGALNACT1
cardiac endothelial to mesenchymal transition1842.6×0.039SEMA3C
regulation of locomotor rhythm1421.3×0.039ZFHX3
pulmonary myocardium development1280.9×0.039SEMA3C
negative regulation of low-density lipoprotein particle receptor catabolic process1280.9×0.039PCSK5
response to carbon monoxide1280.9×0.039KCNMA1
micturition1280.9×0.039KCNMA1
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis1280.9×0.039SEMA3C
renin secretion into blood stream1210.7×0.039PCSK5
viral life cycle1210.7×0.039PCSK5
UDP-N-acetylgalactosamine metabolic process1210.7×0.039CSGALNACT1
plasma lipoprotein particle remodeling1210.7×0.039PCSK5
peptide biosynthetic process1210.7×0.039PCSK5
smooth muscle contraction involved in micturition1210.7×0.039KCNMA1
dichotomous subdivision of terminal units involved in salivary gland branching1210.7×0.039SEMA3C
neuron recognition1168.5×0.039NTM
respiratory tube development1168.5×0.039PCSK5
regulation of odontogenesis1168.5×0.039SP6
negative regulation of cell volume1168.5×0.039KCNMA1
negative regulation of dendritic spine development1168.5×0.039GRIN3A
cytokine precursor processing1168.5×0.039PCSK5
synaptic transmission, glutamatergic235.9×0.039GRIN3A, GRIK1
entrainment of circadian clock1140.4×0.045SOX14
lipid hydroxylation1120.4×0.048CYP2C8
obsolete organic acid metabolic process1120.4×0.048CYP2C8
DNA double-strand break processing involved in repair via single-strand annealing1105.3×0.049RNF138
oxidative demethylation1105.3×0.049CYP2C8
nervous system development36.9×0.049SOX14, RAPGEF5, GRIK1
regulation of T cell activation193.6×0.051PAG1

Therapeutics

Drugs indicated for this disease

0 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

DrugDevelopment status
AspirinPhase 3 (in late-stage trials)
Ibandronic AcidPhase 3 (in late-stage trials)
Ixmyelocel-TPhase 3 (in late-stage trials)
PentoxifyllinePhase 3 (in late-stage trials)
Vitamin EPhase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Atorvastatin.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 6 · Undrugged: 14

Druggability breadth: 10 of 20 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
CCND2PALBOCICLIB
GRIN3ADEXTROMETHORPHAN
CYP2C8CLOTRIMAZOLE
KCNMA1CANNABIDIOL

Top cohort targets by molecule count

SymbolMoleculesMax phase
CYP2C8624
GRIN3A224
CCND234
GRIK133
KCNMA124
CWC2712
SEMA3C00
SOX1400
SP600
PPP1R9A00

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PALBOCICLIB4CCND2
DEXTROMETHORPHAN4GRIN3A
LEVORPHANOL4GRIN3A
AMANTADINE4GRIN3A
CHLORPROMAZINE4GRIN3A
KETAMINE4GRIN3A
MEMANTINE4GRIN3A
PROCYCLIDINE4GRIN3A
ORPHENADRINE4GRIN3A
CLOTRIMAZOLE4CYP2C8
SIMVASTATIN4CYP2C8
PHENELZINE4CYP2C8
MONTELUKAST SODIUM4CYP2C8
MIFEPRISTONE4CYP2C8
DANAZOL4CYP2C8
NICARDIPINE4CYP2C8
KETOCONAZOLE4CYP2C8
ISRADIPINE4CYP2C8
IBRUTINIB4CYP2C8
LUMACAFTOR4CYP2C8
ANIDULAFUNGIN4CYP2C8
RESMETIROM4CYP2C8
ZANUBRUTINIB4CYP2C8
VOXELOTOR4CYP2C8
NORTRIPTYLINE4CYP2C8
GEMFIBROZIL4CYP2C8
LANSOPRAZOLE4CYP2C8
AMIODARONE4CYP2C8
VERAPAMIL4CYP2C8
MONTELUKAST4CYP2C8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

SymbolAssaysType breakdown
CYP2C81,025ADMET:1005, Binding:19, Toxicity:1
GRIN3A195Binding:183, Functional:7, ADMET:4, Toxicity:1
KCNMA194Binding:91, Functional:2, Toxicity:1
GRIK170Binding:55, Functional:15
CCND228Binding:28
CBX411Binding:11
CSGALNACT19Binding:9
CWC277Binding:7
PCSK54Binding:4
PAG11Binding:1

Cohort enzymes (BRENDA EC)

SymbolEC numbersNames
CWC275.2.1.8peptidylprolyl isomerase
CSGALNACT12.4.1.174, 2.4.1.175glucuronylgalactosylproteoglycan 4-beta-N-acetylgalactosaminyltransferase, glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase
CYP2C81.14.14.1unspecific monooxygenase
PCSK53.4.21.B26

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

SymbolChEMBL assays
GRIN3A195
CYP2C81,025

Pharmacogenomics

Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

SymbolCPIC guidelines
CYP2C81

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

CompoundMax phaseCohort target (bioactivity)
PALBOCICLIB4CCND2
DEXTROMETHORPHAN4GRIN3A
LEVORPHANOL4GRIN3A
AMANTADINE4GRIN3A
CHLORPROMAZINE4GRIN3A
KETAMINE4GRIN3A
MEMANTINE4GRIN3A
PROCYCLIDINE4GRIN3A
ORPHENADRINE4GRIN3A
CLOTRIMAZOLE4CYP2C8
SIMVASTATIN4CYP2C8
PHENELZINE4CYP2C8
MONTELUKAST SODIUM4CYP2C8
MIFEPRISTONE4CYP2C8
DANAZOL4CYP2C8
NICARDIPINE4CYP2C8
KETOCONAZOLE4CYP2C8
ISRADIPINE4CYP2C8
IBRUTINIB4CYP2C8
LUMACAFTOR4CYP2C8
ANIDULAFUNGIN4CYP2C8
RESMETIROM4CYP2C8
ZANUBRUTINIB4CYP2C8
VOXELOTOR4CYP2C8
NORTRIPTYLINE4CYP2C8
GEMFIBROZIL4CYP2C8
LANSOPRAZOLE4CYP2C8
AMIODARONE4CYP2C8
VERAPAMIL4CYP2C8
MONTELUKAST4CYP2C8

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)4CCND2, GRIN3A, CYP2C8, KCNMA1
BPhased (≥1) drug, not yet approved2CWC27, GRIK1
CDruggable family + PDB, no drug1NTM
DDruggable family + AlphaFold only, no drug3SEMA3C, CSGALNACT1, PCSK5
EDifficult family or no structure, no drug10SOX14, SP6, PPP1R9A, CBX4, RAPGEF5, CDH9, RNF138, PAG1, KLF12, ZFHX3

Undrugged target profiles

14 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

SymbolChEMBL assaysDrugged partners (top 3)
SEMA3C0—
SOX140—
SP60—
PPP1R9A0—
CBX411—
RAPGEF50—
CDH90—
RNF1380—
NTM0—
CSGALNACT19—
PAG11—
KLF120—
ZFHX30—
PCSK54—

Clinical trials & evidence

Clinical trials

Clinical trials: 56.

Phase distribution (across all retrieved trials)

PhaseTrials
Not specified35
PHASE29
PHASE44
PHASE14
PHASE32
PHASE1/PHASE21
EARLY_PHASE11

Top trials by phase / activity

NCTPhaseStatusTitle
NCT07240649PHASE4NOT_YET_RECRUITINGOutcomes From Hyperbaric Oxygen (HBO2) Treatment for Emerging Indications
NCT01345097PHASE4COMPLETEDA Short Metaphyseal Fitting Total Hip Arthroplasty in Young and Elderly Patients
NCT01806766PHASE4COMPLETEDComparison of Ceramic-on-Ceramic and Ceramic-on-Highly-Cross-Linked Polyethylene Bearings
NCT02893293PHASE4COMPLETEDImaging of Osteonecrosis With Ferumoxytol-Enhanced MRI
NCT00505219PHASE3COMPLETEDIxmyelocel-T Treatment of Patients With Osteonecrosis of the Femoral Head
NCT01892514PHASE3COMPLETEDRandomized Clinical Trial for the Treatment of Osteonecrosis of the Femoral Head
NCT06016634PHASE2RECRUITINGAlendronate for Osteonecrosis in Adults With Sickle Cell Disease
NCT07471880PHASE2ACTIVE_NOT_RECRUITINGA Phase II Trial of RAB001 (LLP2A-Alendronate) for Steroid-Induced Early-Stage Osteonecrosis of the Femoral Head
NCT00289575PHASE2UNKNOWNMBCP Safety and Performance in the Osteonecrosis of Femur Head
NCT00477217PHASE2WITHDRAWNZoledronic Acid Treatment of Spontaneous Osteonecrosis of the Knee
NCT00781261PHASE2UNKNOWNOsteonecrosis of the Hip and Bisphosphonate Treatment
NCT01336803PHASE2COMPLETEDDifferentiation of Bone Sarcomas and Osteomyelitis With Ferumoxytol-Enhanced MRI
NCT01622465PHASE2COMPLETEDEffect of Cycle Ergometer in the Rehabilitation of Elderly Patients With Total Hip Arthroplasty
NCT02632903PHASE2WITHDRAWNIntravenous Zoledronic Acid for the Treatment of Osteoporosis and Osteonecrosis in Children With Leukemia: A Pilot Study
NCT04233125PHASE1/PHASE2COMPLETEDCore Decompression With or Without Cement Packing for ONFH
NCT04401267PHASE2COMPLETEDHypertension Intervention to Reduce Osteonecrosis in Children With Acute Lymphoblastic Leukemia/Lymphoma
NCT00462098PHASE1COMPLETEDRandomized Controlled Trial of Hyperbaric Oxygen in Patients Who Have Taken Bisphosphonates
NCT01198080PHASE1COMPLETEDEvaluate the Effect of Bone Marrow Derived Cd133+ Cells in Patient With Osteonecrosis of Femoral Head
NCT03197623PHASE1COMPLETEDSafety and Tolerability of Intravenous LLP2A-Alendronate for Osteopenia Secondary to Glucocorticoids
NCT03269409PHASE1TERMINATEDUse of Adipose Derived Regenerative Cells in Bilateral Femoral Head Osteonecrosis
NCT01159899EARLY_PHASE1UNKNOWNTransplantation of Bone Marrow Stem Cells Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee
NCT01458782Not specifiedACTIVE_NOT_RECRUITINGACI-C Versus AMIC. A Randomized Trial Comparing Two Methods for Repair of Cartilage Defects in the Knee
NCT02661139Not specifiedRECRUITINGProspective Registry of Prosthodontic Rehabilitation in Oncology Patients Undergoing Jaw Reconstruction
NCT05002959Not specifiedACTIVE_NOT_RECRUITINGTESS V3 Modular Total Shoulder System PMCF
NCT05283148Not specifiedACTIVE_NOT_RECRUITINGSickle Cell Disease (SCD) Bone Pain Study
NCT05603728Not specifiedRECRUITINGExactech Shoulder Post Market Clinical Follow-up Study
NCT05706909Not specifiedACTIVE_NOT_RECRUITINGThe Use of Genex in the Management of Early-Stage Osteonecrosis of the Femoral Head
NCT05734651Not specifiedRECRUITINGPROMIS Evaluation Study
NCT06823089Not specifiedRECRUITINGEarly Feasibility Study of Cartilage Defect Repair
NCT06931301Not specifiedNOT_YET_RECRUITINGEffect of HBOT on Femoral Head Avascular Necrosis (AVN)
NCT00260897Not specifiedUNKNOWNMolecular Genetic Study of Avascular Necrosis of the Femoral Head
NCT00601068Not specifiedCOMPLETEDProposal For The Development Of A Well Defined Database For Patients With Oral Bisphosphonate-Related Osteonecrosis
NCT00679978Not specifiedCOMPLETEDVertebral Fracture and Osteonecrosis Associated With High-dose Glucocorticoid
NCT00913679Not specifiedCOMPLETEDA Comparison of Two Different Surgical Techniques in Hip Resurfacing Arthroplasty
NCT01048710Not specifiedCOMPLETEDTreatment of Medial Compartmental Osteoarthritis Grade 1-4 With TomoFix™ Small or Conservatively
NCT01104324Not specifiedUNKNOWNOsteonecrosis in Children With Acute Lymphoblastic Leukemia
NCT01325142Not specifiedCOMPLETEDGenetic Risk of Osteonecrosis of the Jaw (ONJ) in Patients With Metastatic Cancer
NCT01463566Not specifiedWITHDRAWNGender Solutions Natural Knee Post-Market Study
NCT01583465Not specifiedCOMPLETEDEfficacy of Aquamantys for Reducing Transfusions With Anterior Supine Intermuscular Approach Total Hip Arthroplasty
NCT01619124Not specifiedUNKNOWNOsteonecroses in Pediatric Patients With ALL

Drugs tested across these trials (top 30)

MoleculeMax phaseTrials referencing
ALENDRONIC ACID42
OXYGEN42
FERUMOXYTOL41
IXMYELOCEL-T31
PLATELETS31

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.2
BioBTree
v2.0.2

Sources 75

This page pulls from 75 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondbsnpdepmapdiamond_similaritydoidefoensemblentrezesm2_similarityfantom5_genefantom5_promotergardgenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncicd10cmicd11intactinterpromedgenmeshmimmondomondochildmondoparentncitnordorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot