Osteoarthritis, hip

Summary

Osteoarthritis, hip (MONDO:0006629) is a disease with 21 cohort genes (828 GWAS associations across 47 studies) and 497 clinical trials. Top therapeutic interventions include celecoxib, mepivacaine, and naproxen.

At a glance

• Cohort genes: 21
• GWAS associations: 828
• Clinical trials: 497

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteoarthritis, hip
Mondo ID	MONDO:0006629
EFO	EFO:1000786
MeSH	D015207
NCIT	C34876
UMLS	C0029410
MedGen	14530
Is cancer (heuristic)	no

Also known as: hip osteoarthritis

Data availability: 828 GWAS associations (47 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone inflammation disease › arthritic joint disease › osteoarthritis › osteoarthritis, hip

Related subtypes (4): osteoarthritis, knee, osteoarthritis, spine, osteoarthritis, toe, osteoarthritis, hand

Genetics & variants

GWAS landscape

828 GWAS associations across 47 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12209223	7e-58	FILIP1	A	1.19
rs10843013	5e-57	RN7SKP15 - PTHLH	A	0.87
rs13107325	2e-52	SLC39A8	T
rs1321917	3e-40	ASTN2, ASTN2-AS1	C	1.1
rs1895062	4e-38	ASTN2, ASTN2-AS1	A	0.93
rs2521349	1e-36	MAP2K6	A	1.09
rs1046934	8e-35	TSEN15	A	1.09
rs11075989	1e-34	FTO	T	1.05
rs2716212	3e-32	MAP2K6	A	0.94
rs4240673	8e-32	XKR6	T
rs66989638	2e-31	ECRG4	A	1.12
rs17257909	2e-30	PIK3R1 - LINC02198	T	0.94
rs3910146	4e-29	ECM1P2 - U6	T	0.93
rs1926872	1e-28	COLGALT2 - TSEN15	T	1.06
rs28685250	3e-28	ECM1P2 - U6	T	1.08
rs1851610	4e-28	TGFA	T	1.06
rs6060401	5e-28	UQCC1 - GDF5-AS1	T	1.05
rs2118540	6e-28	PBRM1	T	0.94
rs2710323	3e-27	ITIH1	T
rs3755384	9e-27	TGFA	A	1.07
rs11750646	3e-26	PIK3R1 - LINC02198	T	0.92
rs2268025	4e-26	NEK4	A	0.93
rs1591637	5e-26	COL11A1	T	1.08
rs11164653	8e-26	COL11A1	T	0.94
rs62576130	1e-25	ASTN2	T	1.12
rs117018441	2e-25	EP300-AS1, EP300	T	5.89
rs532464664	2e-25	CHADL	CGCGCGCC	5.89
rs138793270	2e-25	EP300-AS1	G	5.6
chr12:27862568	2e-25		C	0.12
rs12509303	3e-25	TACC3 - FGFR3	T	1.06

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90566799	Hatzikotoulas K	2025	201,533	901,637	Translational genomics of osteoarthritis in 1,962,069 individuals.
GCST90566798	Hatzikotoulas K	2025	95,395	1,011,691	Translational genomics of osteoarthritis in 1,962,069 individuals.
GCST90034521	Boer CG	2021	88,842	397,208	Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
GCST90566804	Hatzikotoulas K	2025	76,604	771,801	Translational genomics of osteoarthritis in 1,962,069 individuals.
GCST90566802	Hatzikotoulas K	2025	49,733	963,748	Translational genomics of osteoarthritis in 1,962,069 individuals.
GCST90034526	Boer CG	2021	40,887	327,689	Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
GCST90061025	Boer CG	2021	40,887	327,689	Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
GCST90061036	Boer CG	2021	40,887	327,689	Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.
GCST007092	Tachmazidou I	2019	39,427	378,169	Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data.
GCST90833065	Yoshino S	2026	36,445	316,943	Genetic study identifies novel genes in developmental dysplasia of the hip.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	1
Tier 3: regulatory	2
Tier 4: intronic/intergenic	43

MAF distribution

Bucket	Variants
common (>=0.05)	46
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	31
intergenic_variant	7
unknown	4
missense_variant	3
regulatory_region_variant	2
non_coding_transcript_exon_variant	1
frameshift_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1421085	16	53767042	T>C	0.05	intron_variant	FTO		Tier 4: intronic/intergenic
rs12209223	6	75454873	C>A	0.116	intron_variant	FILIP1	7e-58	Tier 4: intronic/intergenic
rs10843013	12	27872263	A>C,T	0.211	intron_variant	RN7SKP15 - PTHLH	5e-57	Tier 4: intronic/intergenic
rs13107325	4	102267552	C>A,T	0.05	missense_variant	SLC39A8	2e-52	Tier 1: coding
rs1321917	9	116562650	G>A,C	0.396	intron_variant	ASTN2, ASTN2-AS1	3e-40	Tier 4: intronic/intergenic
rs1895062	9	116551207	A>G	0.393	intron_variant	ASTN2, ASTN2-AS1	4e-38	Tier 4: intronic/intergenic
rs2521349	17	69507360	G>A,T	0.389	intron_variant	MAP2K6	1e-36	Tier 4: intronic/intergenic
rs1046934	1	184054395	A>C,G,T	0.367	missense_variant	TSEN15	8e-35	Tier 1: coding
rs11075989	16	53785965	C>A,G,T	0.406	intron_variant	FTO	1e-34	Tier 4: intronic/intergenic
rs2716212	17	69507512	A>G	0.393	intron_variant	MAP2K6	3e-32	Tier 4: intronic/intergenic
rs4240673	8	10930102	T>C,G	0.05	intron_variant	XKR6	8e-32	Tier 4: intronic/intergenic
rs66989638	2	106073280	G>A	0.144	intron_variant	ECRG4	2e-31	Tier 4: intronic/intergenic
rs17257909	5	68534530	C>G,T	0.358	intron_variant	PIK3R1 - LINC02198	2e-30	Tier 4: intronic/intergenic
rs3910146	4	13041970	G>A,T	0.374	intergenic_variant	ECM1P2 - U6	4e-29	Tier 4: intronic/intergenic
rs1926872	1	184049341	T>A,C,G	0.359	intergenic_variant	COLGALT2 - TSEN15	1e-28	Tier 4: intronic/intergenic
rs28685250	4	13004948	T>C	0.378	intergenic_variant	ECM1P2 - U6	3e-28	Tier 4: intronic/intergenic
rs1851610	2	70472027	T>A,C,G	0.49	intron_variant	TGFA	4e-28	Tier 4: intronic/intergenic
rs6060401	20	35417411	C>A,G,T	0.386	intergenic_variant	UQCC1 - GDF5-AS1	5e-28	Tier 4: intronic/intergenic
rs2118540	3	52595370	T>C,G	0.401	intron_variant	PBRM1	6e-28	Tier 4: intronic/intergenic
rs2710323	3	52781889	T>A,C,G	0.05	intron_variant	ITIH1	3e-27	Tier 4: intronic/intergenic
rs3755384	2	70477379	A>C,G	0.479	intron_variant	TGFA	9e-27	Tier 4: intronic/intergenic
rs11750646	5	68529768	C>T	0.361	non_coding_transcript_exon_variant	PIK3R1 - LINC02198	3e-26	Tier 4: intronic/intergenic
rs2268025	3	52761208	A>G,T	0.398	intron_variant	NEK4	4e-26	Tier 4: intronic/intergenic
rs1591637	1	103068892	C>A,G,T	0.45	intron_variant	COL11A1	5e-26	Tier 4: intronic/intergenic
rs11164653	1	102998654	T>A,C,G	0.426	intron_variant	COL11A1	8e-26	Tier 4: intronic/intergenic
rs62576130	9	116608596	T>G	0.135	intron_variant	ASTN2	1e-25	Tier 4: intronic/intergenic
rs117018441	22	41157913	G>A,T	0.05	intron_variant	EP300-AS1, EP300	2e-25	Tier 4: intronic/intergenic
rs532464664	22	41238084	A>ACGCGCGCC,ACGCGCGCCCGCGCGCC	0.05	frameshift_variant	CHADL	2e-25	Tier 1: coding
rs138793270	22	41180373	GA>G	0.029	intron_variant	EP300-AS1	2e-25	Tier 4: intronic/intergenic
chr12:27862568							2e-25	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
SMAD3	SMAD3	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RUNX2	Orphanet:1452	Cleidocranial dysplasia
RUNX2	Orphanet:2504	Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
GLT8D1	Orphanet:803	Amyotrophic lateral sclerosis
GLIS3	Orphanet:79118	Neonatal diabetes-congenital hypothyroidism-congenital glaucoma-hepatic fibrosis-polycystic kidneys syndrome
HFE	Orphanet:443057	Sporadic porphyria cutanea tarda
HFE	Orphanet:443062	Familial porphyria cutanea tarda
HFE	Orphanet:465508	Symptomatic form of HFE-related hemochromatosis
HFE	Orphanet:586	Cystic fibrosis
HFE	Orphanet:648581	Digenic hemochromatosis
TNC	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
LMX1B	Orphanet:2613	Nail-patella-like renal disease
LMX1B	Orphanet:2614	Nail-patella syndrome
LMX1B	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
SMAD3	Orphanet:284984	Aneurysm-osteoarthritis syndrome
SMAD3	Orphanet:60030	Loeys-Dietz syndrome
SMAD3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
PTHLH	Orphanet:93387	Brachydactyly type E

Cohort genes → proteins

21 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUNX2	HGNC:10472	ENSG00000124813	Q13950	Runt-related transcription factor 2	gwas
SUPT3H	HGNC:11466	ENSG00000196284	O75486	Transcription initiation protein SPT3 homolog	gwas
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
SMOX	HGNC:15862	ENSG00000088826	Q9NWM0	Spermine oxidase	gwas
ASTN2	HGNC:17021	ENSG00000148219	O75129	Astrotactin-2	gwas
SENP6	HGNC:20944	ENSG00000112701	Q9GZR1	Sentrin-specific protease 6	gwas
FILIP1	HGNC:21015	ENSG00000118407	Q7Z7B0	Filamin-A-interacting protein 1	gwas
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gwas
GLT8D1	HGNC:24870	ENSG00000016864	Q68CQ7	Glycosyltransferase 8 domain-containing protein 1	gwas
CHADL	HGNC:25165	ENSG00000100399	Q6NUI6	Chondroadherin-like protein	gwas
RFLNA	HGNC:27051	ENSG00000178882	Q6ZTI6	Refilin-A	gwas
GLIS3	HGNC:28510	ENSG00000107249	Q8NEA6	Zinc finger protein GLIS3	gwas
KLHL42	HGNC:29252	ENSG00000087448	Q9P2K6	Kelch-like protein 42	gwas
HFE	HGNC:4886	ENSG00000010704	Q30201	Hereditary hemochromatosis protein	gwas
TNC	HGNC:5318	ENSG00000041982	P24821	Tenascin	gwas
IL11	HGNC:5966	ENSG00000095752	P20809	Interleukin-11	gwas
ITIH1	HGNC:6166	ENSG00000055957	P19827	Inter-alpha-trypsin inhibitor heavy chain H1	gwas
LMX1B	HGNC:6654	ENSG00000136944	O60663	LIM homeobox transcription factor 1-beta	gwas
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gwas
SMAD3	HGNC:6769	ENSG00000166949	P84022	SMAD family member 3	gwas
PTHLH	HGNC:9607	ENSG00000087494	P12272	Parathyroid hormone-related protein	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUNX2	Runt-related transcription factor 2	Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis.
SUPT3H	Transcription initiation protein SPT3 homolog	Probable transcriptional activator.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
SMOX	Spermine oxidase	Flavoenzyme which catalyzes the oxidation of spermine to spermidine.
ASTN2	Astrotactin-2	Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons.
SENP6	Sentrin-specific protease 6	Protease that deconjugates SUMO1, SUMO2 and SUMO3 from targeted proteins.
FILIP1	Filamin-A-interacting protein 1	By acting through a filamin-A/F-actin axis, it controls the start of neocortical cell migration from the ventricular zone.
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
GLT8D1	Glycosyltransferase 8 domain-containing protein 1	In vitro, catalyzes the transfer of a galactose residue from UDP-galactose onto GalNAc and GlcNAc structures.
CHADL	Chondroadherin-like protein	Potential negative modulator of chondrocyte differentiation.
RFLNA	Refilin-A	Involved in the regulation of the perinuclear actin network and nuclear shape through interaction with filamins.
GLIS3	Zinc finger protein GLIS3	Acts both as a repressor and an activator of transcription.
KLHL42	Kelch-like protein 42	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis.
HFE	Hereditary hemochromatosis protein	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.
TNC	Tenascin	Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration.
IL11	Interleukin-11	Cytokine that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production.
ITIH1	Inter-alpha-trypsin inhibitor heavy chain H1	May act as a carrier of hyaluronan in serum or as a binding protein between hyaluronan and other matrix protein, including those on cell surfaces in tissues to regulate the localization, synthesis and degradation of hyaluronan which are es…
LMX1B	LIM homeobox transcription factor 1-beta	Transcription factor involved in the regulation of podocyte-expressed genes.
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
SMAD3	SMAD family member 3	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
PTHLH	Parathyroid hormone-related protein	Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport.

Protein-family classification

Druggable: 6 · Difficult: 3 · Unknown: 12 · Druggable fraction: 0.29

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.

Family	Genes	Fold	FDR
Complement	1	12.8×	0.453
Antibody/Immunoglobulin	2	2.8×	0.482
Protease	1	1.7×	0.542
Transcription factor	3	1.2×	0.542
Enzyme (other)	2	1.1×	0.542
Other/Unknown	12	1.0×	0.542

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUNX2	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
SUPT3H	Other/Unknown	no		TFIID_TAF13, Histone-fold
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
SMOX	Enzyme (other)	yes	1.5.3.16	Amino_oxidase, FAD/NAD-bd_sf, Flavin_monoamine_oxidase
ASTN2	Complement	yes		MACPF, Astrotactin, FN3_sf
SENP6	Protease	yes	3.4.22.B74	Peptidase_C48_C, Papain-like_cys_pep_sf, Sentrin-specific_protease
FILIP1	Other/Unknown	no		Cortactin-binding_p2_N, Cortactin-Actin_Reg
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
GLT8D1	Other/Unknown	no		Glyco_trans_8, Nucleotide-diphossugar_trans, Glycosyltrans_8_dom-fam
CHADL	Other/Unknown	no		LRRNT, Cys-rich_flank_reg_C, Leu-rich_rpt
RFLNA	Other/Unknown	no		Refilin
GLIS3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
KLHL42	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
HFE	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
TNC	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
IL11	Other/Unknown	no		4_helix_cytokine-like_core, IL-11_mml, IL-11
ITIH1	Other/Unknown	no		VWF_A, ITI_HC_C, VIT
LMX1B	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
SMAD3	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
PTHLH	Other/Unknown	no		PTH/PTH-rel, PTH-rel

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)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	3
male germ line stem cell (sensu Vertebrata) in testis	3
primordial germ cell in gonad	3
cartilage tissue	3
stromal cell of endometrium	3
secondary oocyte	2
C1 segment of cervical spinal cord	2
buccal mucosa cell	2
periodontal ligament	2
mucosa of paranasal sinus	1
trabecular bone tissue	1
sperm	1
monocyte	1
oocyte	1
amygdala	1
lower esophagus mucosa	1
dorsal root ganglion	1
trigeminal ganglion	1
adrenal tissue	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUNX2	241	ubiquitous	marker	tibia, mucosa of paranasal sinus, trabecular bone tissue
SUPT3H	206	ubiquitous	yes	primordial germ cell in gonad, sperm, male germ line stem cell (sensu Vertebrata) in testis
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
SMOX	258	ubiquitous	marker	amygdala, lower esophagus mucosa, C1 segment of cervical spinal cord
ASTN2	236	ubiquitous	marker	buccal mucosa cell, trigeminal ganglion, dorsal root ganglion
SENP6	290	ubiquitous	marker	calcaneal tendon, adrenal tissue, ventricular zone
FILIP1	226	broad	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
GLT8D1	296	ubiquitous	marker	pituitary gland, bronchial epithelial cell, adenohypophysis
CHADL	179	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, tibia
RFLNA	168	broad	marker	ileal mucosa, body of stomach, stomach
GLIS3	213	ubiquitous	marker	buccal mucosa cell, epithelial cell of pancreas, pancreatic ductal cell
KLHL42	248	ubiquitous	marker	endothelial cell, medial globus pallidus, secondary oocyte
HFE	238	ubiquitous	marker	type B pancreatic cell, olfactory bulb, stromal cell of endometrium
TNC	272	ubiquitous	marker	saphenous vein, tibial artery, popliteal artery
IL11	152	broad	yes	islet of Langerhans, cartilage tissue, stromal cell of endometrium
ITIH1	154	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
LMX1B	74	broad	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
SMAD3	288	ubiquitous	marker	tendon of biceps brachii, cartilage tissue, hindlimb stylopod muscle
PTHLH	202	broad	marker	periodontal ligament, primordial germ cell in gonad, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD3	6,440
RUNX2	4,101
HDAC9	3,047
LTBP2	2,658
COL11A1	2,433
IL11	2,049
SENP6	1,948
GLIS3	1,717
ASTN2	1,610
SUPT3H	1,603

Intra-cohort edges

A	B	Sources
ASTN2	FILIP1	string_interaction
ASTN2	GLT8D1	string_interaction
FILIP1	GLT8D1	string_interaction
FILIP1	KLHL42	string_interaction
FILIP1	SENP6	string_interaction
GLT8D1	KLHL42	string_interaction
GLT8D1	SUPT3H	string_interaction
IL11	PTHLH	string_interaction
KLHL42	PTHLH	string_interaction
PTHLH	RUNX2	string_interaction
RUNX2	SMAD3	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 10 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNC	P24821	21
SMAD3	P84022	12
PTHLH	P12272	11
IL11	P20809	8
RUNX2	Q13950	4
SUPT3H	O75486	4
ASTN2	O75129	3
HDAC9	Q9UKV0	2
SMOX	Q9NWM0	2
HFE	Q30201	2
ITIH1	P19827	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL42	Q9P2K6	85.98
GLT8D1	Q68CQ7	85.35
CHADL	Q6NUI6	84.58
LMX1B	O60663	70.79
FILIP1	Q7Z7B0	68.05
RFLNA	Q6ZTI6	59.78
LTBP2	Q14767	58.33
SENP6	Q9GZR1	55.33
COL11A1	P12107	53.06
GLIS3	Q8NEA6	49.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. Enrichment computed across 21 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
PAOs oxidise polyamines to amines	1	292.8×	0.039	SMOX
Loss of Function of SMAD4 in Cancer	1	292.8×	0.039	SMAD3
SMAD4 MH2 Domain Mutants in Cancer	1	292.8×	0.039	SMAD3
SMAD2/3 MH2 Domain Mutants in Cancer	1	292.8×	0.039	SMAD3
Interconversion of polyamines	1	219.6×	0.039	SMOX
Loss of Function of TGFBR1 in Cancer	1	175.7×	0.039	SMAD3
RUNX2 regulates chondrocyte maturation	1	175.7×	0.039	RUNX2
RUNX2 regulates genes involved in differentiation of myeloid cells	1	175.7×	0.039	RUNX2
RUNX3 regulates BCL2L11 (BIM) transcription	1	175.7×	0.039	SMAD3
Loss of Function of SMAD2/3 in Cancer	1	146.4×	0.039	SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	1	146.4×	0.039	SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	146.4×	0.039	SMAD3
TGFBR1 KD Mutants in Cancer	1	146.4×	0.039	SMAD3
TGF-beta receptor signaling activates SMADs	2	50.2×	0.039	LTBP2, SMAD3
Signaling by TGF-beta Receptor Complex	2	30.8×	0.039	LTBP2, SMAD3
Non-integrin membrane-ECM interactions	2	23.7×	0.039	COL11A1, TNC
Signaling by TGFB family members	2	17.8×	0.039	LTBP2, SMAD3
RUNX3 regulates CDKN1A transcription	1	125.5×	0.043	SMAD3
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	1	109.8×	0.044	RUNX2
RUNX2 regulates genes involved in cell migration	1	109.8×	0.044	RUNX2
RUNX2 regulates bone development	1	62.8×	0.064	RUNX2
Formation of axial mesoderm	1	62.8×	0.064	SMAD3
Signaling by Activin	1	58.6×	0.064	SMAD3
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	58.6×	0.064	RUNX2
Formation of definitive endoderm	1	54.9×	0.064	SMAD3
FOXO-mediated transcription of cell cycle genes	1	51.7×	0.064	SMAD3
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	51.7×	0.064	SMAD3
Germ layer formation at gastrulation	1	51.7×	0.064	SMAD3
Extracellular matrix organization	2	9.7×	0.064	TNC, LTBP2
IL-6-type cytokine receptor ligand interactions	1	48.8×	0.066	IL11

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 term	Cohort genes	Fold	FDR	Sample cohort genes
osteoblast development	3	148.7×	2e-04	RUNX2, SMAD3, PTHLH
negative regulation of chondrocyte development	2	561.7×	5e-04	RFLNA, PTHLH
chondrocyte development	2	93.6×	0.016	RUNX2, COL11A1
positive regulation of chondrocyte differentiation	2	80.2×	0.016	RUNX2, SMAD3
SMAD protein signal transduction	2	73.3×	0.016	RUNX2, SMAD3
negative regulation of chondrocyte differentiation	2	67.4×	0.016	CHADL, PTHLH
embryonic cranial skeleton morphogenesis	2	58.1×	0.018	RUNX2, SMAD3
ligamentous ossification	1	842.6×	0.021	RUNX2
regulation of striated muscle cell differentiation	1	842.6×	0.021	HDAC9
negative regulation of lung blood pressure	1	842.6×	0.021	SMAD3
protein modification by small protein removal	1	842.6×	0.021	SENP6
regulation of miRNA transcription	1	842.6×	0.021	SMAD3
negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I	1	842.6×	0.021	HFE
positive regulation of SMAD protein signal transduction	2	38.3×	0.021	HFE, SMAD3
positive regulation of gene expression	4	7.8×	0.024	RUNX2, HFE, TNC, SMAD3
positive regulation of transforming growth factor beta3 production	1	421.3×	0.026	SMAD3
regulation of iron ion transport	1	421.3×	0.026	HFE
mesenchymal-epithelial cell signaling involved in prostate gland development	1	421.3×	0.026	TNC
adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway	1	421.3×	0.026	PTHLH
negative regulation of collagen fibril organization	1	421.3×	0.026	CHADL
odontogenesis of dentin-containing tooth	2	30.1×	0.026	RUNX2, TNC
bone mineralization	2	27.2×	0.026	RUNX2, PTHLH
osteoblast fate commitment	1	280.9×	0.028	RUNX2
polyamine catabolic process	1	280.9×	0.028	SMOX
spermine catabolic process	1	280.9×	0.028	SMOX
paraxial mesoderm morphogenesis	1	280.9×	0.028	SMAD3
regulation of skeletal muscle fiber development	1	280.9×	0.028	HDAC9
bud outgrowth involved in lung branching	1	280.9×	0.028	TNC
actin filament bundle organization	1	280.9×	0.028	RFLNA
regulation of spindle assembly	1	280.9×	0.028	SENP6

Therapeutics

Drugs indicated for this disease

0 approved, 18 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetaminophen	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Corticosterone	Phase 3 (in late-stage trials)
Diacerein	Phase 3 (in late-stage trials)
Diclofenac	Phase 3 (in late-stage trials)
Fasinumab	Phase 3 (in late-stage trials)
HYLAN G-F 20	Phase 3 (in late-stage trials)
Hydromorphone	Phase 3 (in late-stage trials)
Lumiracoxib	Phase 3 (in late-stage trials)
Naproxcinod	Phase 3 (in late-stage trials)
Naproxen	Phase 3 (in late-stage trials)
Oxycodone	Phase 3 (in late-stage trials)
Polmacoxib	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Tanezumab	Phase 3 (in late-stage trials)
Tapentadol	Phase 3 (in late-stage trials)
Triamcinolone	Phase 3 (in late-stage trials)
Triamcinolone Acetonide	Phase 3 (in late-stage trials)

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

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 18

Druggability breadth: 8 of 21 evidence-associated genes (38%) 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.

Symbol	Example approved molecule
HDAC9	CELECOXIB
SMAD3	FLUORESCEIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC9	28	4
SENP6	2	2
SMAD3	2	4
RUNX2	0	0
SUPT3H	0	0
SMOX	0	0
ASTN2	0	0
FILIP1	0	0
COL11A1	0	0
GLT8D1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
FLUORESCEIN	4	SMAD3
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
STREPTONIGRIN	2	SENP6
IPRIFLAVONE	2	SENP6
ELLAGIC ACID	2	SMAD3
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
SMAD3	24	Binding:18, Functional:6
SMOX	18	Binding:15, ADMET:3
SENP6	6	Functional:3, Binding:3
IL11	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC9	3.5.1.98	histone deacetylase
SMOX	1.5.3.16	spermine oxidase
SENP6	3.4.22.B74

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HDAC9	1,625

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

29 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.

Compound	Max phase	Cohort target (bioactivity)
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
FLUORESCEIN	4	SMAD3
CURCUMIN	3	HDAC9
CAFFEIC ACID	3	HDAC9
PRACINOSTAT	3	HDAC9
TACEDINALINE	3	HDAC9
ENTINOSTAT	3	HDAC9
TUCIDINOSTAT	3	HDAC9
ABEXINOSTAT	3	HDAC9
EBSELEN	3	HDAC9
NANATINOSTAT	2	HDAC9
AR-42	2	HDAC9
CHLOROGENIC ACID	2	HDAC9
DACINOSTAT	2	HDAC9
FIMEPINOSTAT	2	HDAC9
QUISINOSTAT	2	HDAC9
DOMATINOSTAT	2	HDAC9
STREPTONIGRIN	2	SENP6
IPRIFLAVONE	2	SENP6
ELLAGIC ACID	2	SMAD3
PYROXAMIDE	1	HDAC9
CUDC-101	1	HDAC9
R-306465	1	HDAC9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	HDAC9, SMAD3
B	Phased (≥1) drug, not yet approved	1	SENP6
C	Druggable family + PDB, no drug	4	SMOX, ASTN2, HFE, TNC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	14	RUNX2, SUPT3H, FILIP1, COL11A1, GLT8D1, CHADL, RFLNA, GLIS3, KLHL42, IL11 (+4 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FILIP1	0	SENP6
RUNX2	0	—
SUPT3H	0	—
SMOX	18	—
ASTN2	0	—
COL11A1	0	—
GLT8D1	0	—
CHADL	0	—
RFLNA	0	—
GLIS3	0	—
KLHL42	0	—
HFE	0	—
TNC	0	—
IL11	2	—
ITIH1	0	—
LMX1B	0	—
LTBP2	0	—
PTHLH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 497.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	397
PHASE4	40
PHASE3	28
PHASE2	15
PHASE1	8
PHASE2/PHASE3	4
PHASE1/PHASE2	4
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04729686	PHASE4	RECRUITING	The Pericapsular Nerve Block in Total Hip Arthroplasty
NCT05761015	PHASE4	RECRUITING	Helping Osteoarthritis Patients to Walk With NSAID
NCT06608914	PHASE4	NOT_YET_RECRUITING	Peri-Operative Testosterone Administration in Primary Total Hip Arthroplasty
NCT06793982	PHASE4	RECRUITING	Platelet Rich Plasma Versus Corticosteroids in Hip Osteoarthritis Pain
NCT06946277	PHASE4	NOT_YET_RECRUITING	Assessing the Time-Course of Dexmedetomidine-Induced Analgesia Via EEG
NCT07180979	PHASE4	RECRUITING	PENG vs L-ESPB With S-ESPB for Analgesia in Total Hip Arthroplasty
NCT00139776	PHASE4	COMPLETED	Study Of Continuous Use Of Celecoxib Vs. Usual or Intermittent Use
NCT00145730	PHASE4	COMPLETED	Prevention of Ectopic Bone Related Pain and Disability After Hip Replacement Surgery With Peri-Operative Ibuprofen
NCT00174317	PHASE4	COMPLETED	Celecoxib Versus Diclofenac In The Treatment Of Osteoarthritis Of The Hip
NCT00570167	PHASE4	COMPLETED	Comparison of Hip Resurfacing and Cementless Metal-on-metal Total Hip Arthroplasty
NCT01218035	PHASE4	COMPLETED	Efficacy of Zoledronic Acid in Enhancement of Early Stability of Cementless Primary Hip Prosthesis
NCT01496300	PHASE4	COMPLETED	Benefit of Orthopedic Navigation in the ARThroplasty of the Hip
NCT01926158	PHASE4	COMPLETED	Denosumab in Enhancement of Bone Bonding of Hip Prosthesis in Postmenopausal Women
NCT02086474	PHASE4	COMPLETED	Daily Activity and Gait Analysis After Viscosupplement Injection Among Hip Osteoarthritis Patients
NCT02321683	PHASE4	COMPLETED	Evaluation of a New Coating in Cement Less Femoral Stems
NCT02379663	PHASE4	COMPLETED	Prophylaxis of Deep Vein Thrombosis Following Total Hip Arthroplasty
NCT02464176	PHASE4	COMPLETED	Systemic Steroids for Peripheral Nerve Blocks
NCT02933671	PHASE4	TERMINATED	Suprainguinal Fascia Iliaca (SIFI) Block Improves Analgesia Following Total Hip Arthroplasty
NCT03090152	PHASE4	COMPLETED	Minimal Opioid Use After Total Hip Replacement (THR)
NCT03513276	PHASE4	COMPLETED	Effect of Local Infiltration Anesthesia in a Hip Arthroplasty Fast Track Program.
NCT03542617	PHASE4	UNKNOWN	Effect of Preoperative Intravenous Dexamethasone on Postoperative Pain After Primary Total Hip Arthroplasty
NCT03639532	PHASE4	COMPLETED	Ceramic-on-Ceramic Versus Ceramic-on-HXLPE THA
NCT03763760	PHASE4	COMPLETED	High-Dose Steroid for Hip Arthroplasty Patients Expected to Have Postoperative Pain
NCT03801265	PHASE4	COMPLETED	Lumbar Plexus vs Quadratus Lumborum Block in Post-operative Pain Following Total Hip Replacement
NCT03948386	PHASE4	COMPLETED	3 Local Anesthetics for Spinal Anesthesia in Primary Total Hip Arthroplasty
NCT04035902	PHASE4	UNKNOWN	Intraoperative IV Iron on Postoperative Red Blood Cell Recovery
NCT04257682	PHASE4	UNKNOWN	Regional Anesthesia in Total Hip and Knee Arthroplasty
NCT05706844	PHASE4	COMPLETED	Spinal Anaesthesia vs. General Anaesthesia for THA, TKA and UKA
NCT05944380	PHASE4	COMPLETED	PENG Block for Total Hip Arthroplasty
NCT06083428	PHASE4	COMPLETED	Erector Spinae vs. PENG Block for Total Hip Arthroplasty
NCT06087588	PHASE4	COMPLETED	Pericapsular Nerve Group Block Chemical Neurolysis in Advanced Hip Osteoarthritis
NCT06144099	PHASE4	UNKNOWN	Prothrombin Complex Concentrate vs Fresh Frozen Plasma in Goal-directed Bleeding Management in Non-cardiac Surgery
NCT06233604	PHASE4	UNKNOWN	Dexamethasone vs. Dexmedetomidine for ESPB in Pain Management After Hip Arthroplasty
NCT06470139	PHASE4	COMPLETED	Dexamethasone for PENG Block in Total Hip Arthroplasty
NCT06470334	PHASE4	COMPLETED	Dexamethasone With Ropivacaine for PENG Block in Total Hip Arthroplasty
NCT06706193	PHASE4	COMPLETED	HXLPE Vs CPE Cups Under 50 Years
NCT06789042	PHASE4	COMPLETED	Dexamethasone for ESPB in Total Hip Arthroplasty
NCT06789328	PHASE4	COMPLETED	The Effect of Dexamethasone Administration Route on Pain and Inflammatory Response in PENG Block for Total Hip Arthroplasty
NCT07023107	PHASE4	COMPLETED	NLR and PLR Levels Following PENG Block in Hip Arthroplasty
NCT07023120	PHASE4	COMPLETED	PENG Block Optimization: Volume and Dexamethasone Effects

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CELECOXIB	4	5
MEPIVACAINE	4	3
NAPROXEN	4	3
TALC ANHYDROUS	4	3
ZOLEDRONIC ACID ANHYDROUS	4	3
CORTISONE ACETATE	4	2
EPINEPHRINE	4	2
RIVAROXABAN	4	2
SUGAMMADEX	4	2
BUPIVACAINE	4	1
DICLOFENAC	4	1
ENOXAPARIN SODIUM	4	1
ETORICOXIB	4	1
FERRIC CARBOXYMALTOSE	4	1
HYALURONIC ACID	4	1
IBUPROFEN	4	1
LUMIRACOXIB	4	1
NANDROLONE DECANOATE	4	1
ROPIVACAINE	4	1
TAPENTADOL	4	1
TOBRAMYCIN	4	1
TRIAMCINOLONE	4	1
TRIAMCINOLONE ACETONIDE	4	1
FASINUMAB	3	5
TANEZUMAB	3	5
CORTISONE	3	2
DABIGATRAN	3	1
DIACEREIN	3	1
FULRANUMAB	3	1
NAPROXCINOD	3	1