Heroin dependence

Summary

Heroin dependence (MONDO:0005367) is a disease with 5 cohort genes (11 GWAS associations across 3 studies) and 80 clinical trials. Top therapeutic interventions include naltrexone, buprenorphine, and levomethadyl acetate.

At a glance

• Cohort genes: 5
• GWAS associations: 11
• Clinical trials: 80

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heroin dependence
Mondo ID	MONDO:0005367
EFO	EFO:0004240
MeSH	D006556
DOID	DOID:9976
ICD-11	443161089
NCIT	C34694
SNOMED CT	231477003
UMLS	C0019337
MedGen	5532
Is cancer (heuristic)	no

Also known as: Heroin addiction

Data availability: 11 GWAS associations (3 studies).

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › substance-related disorder › substance dependence › drug dependence › opiate dependence › heroin dependence

Related subtypes (1): morphine dependence

Genetics & variants

GWAS landscape

11 GWAS associations across 3 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs147247472	3e-12	AGBL4-IT1, AGBL4	A	0.35
rs2133896	4e-09	ANKS1B	T	0.1
rs10196867	5e-09	CTNNA2	C	0.24
rs4791746	2e-07	MYH10 - CCDC42	?	2.15
rs2288156	3e-07	CCDC42	?	2.56
chr17:8631468	4e-07		?	2.13
rs4739179	4e-06	HIGD1AP18 - PKIA-AS1	?	1.98
rs1881509	4e-06	BRSK2	?	2.02
chr8:78718310	5e-06		?	1.96
chr11:1421138	5e-06		?	2
rs78158938	6e-06	AOAH - NPM1P18	?	4.93

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST008645	Sun Y	2019	521	2,859	Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence.
GCST003878	Kalsi G	2016	370	0	Genome-Wide Association of Heroin Dependence in Han Chinese.
GCST000690	Nielsen DA	2010	200	0	Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	10

MAF distribution

Bucket	Variants
common (>=0.05)	9
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	6
unknown	3
intergenic_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs147247472	1	49441901	G>A	0.017	intron_variant	AGBL4-IT1, AGBL4	3e-12	Tier 4: intronic/intergenic
rs2133896	12	99455122	G>T	0.222	intron_variant	ANKS1B	4e-09	Tier 4: intronic/intergenic
rs10196867	2	79751234	C>A,G,T	0.03	intron_variant	CTNNA2	5e-09	Tier 4: intronic/intergenic
rs4791746	17	8723039	T>A,C,G	0.387	intergenic_variant	MYH10 - CCDC42	2e-07	Tier 4: intronic/intergenic
rs2288156	17	8741536	C>A,T	0.173	missense_variant	CCDC42	3e-07	Tier 1: coding
chr17:8631468				0.38			4e-07	Tier 4: intronic/intergenic
rs4739179	8	77873757	G>A	0.348	intron_variant	HIGD1AP18 - PKIA-AS1	4e-06	Tier 4: intronic/intergenic
rs1881509	11	1404375	A>C,G	0.409	intron_variant	BRSK2	4e-06	Tier 4: intronic/intergenic
chr8:78718310				0.353			5e-06	Tier 4: intronic/intergenic
chr11:1421138				0.41			5e-06	Tier 4: intronic/intergenic
rs78158938	7	36747191	G>A	0.098	intron_variant	AOAH - NPM1P18	6e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRSK2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRSK2	HGNC:11405	ENSG00000174672	Q8IWQ3	Serine/threonine-protein kinase BRSK2	gwas
ANKS1B	HGNC:24600	ENSG00000185046	Q7Z6G8	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	gwas
CTNNA2	HGNC:2510	ENSG00000066032	P26232	Catenin alpha-2	gwas
AGBL4	HGNC:25892	ENSG00000186094	Q5VU57	Cytosolic carboxypeptidase 6	gwas
CCDC42	HGNC:26528	ENSG00000161973	Q96M95	Coiled-coil domain-containing protein 42	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRSK2	Serine/threonine-protein kinase BRSK2	Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion.
ANKS1B	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	Isoform 2 may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells.
CTNNA2	Catenin alpha-2	May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system.
AGBL4	Cytosolic carboxypeptidase 6	Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins.
CCDC42	Coiled-coil domain-containing protein 42	Essential for male fertility.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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
Protease	1	7.3×	0.336
Kinase	1	5.5×	0.336
Scaffold/PPI	1	3.5×	0.344
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRSK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ANKS1B	Scaffold/PPI	no		SAM, Ankyrin_rpt, PTB/PI_dom
CTNNA2	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
AGBL4	Protease	yes		Peptidase_M14, Pepdidase_M14_N, Cytosolic_carboxypeptidase
CCDC42	Other/Unknown	no		DUF4200, CFAP_domain-containing

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
Brodmann (1909) area 23	1
inferior vagus X ganglion	1
primary visual cortex	1
Brodmann (1909) area 46	1
frontal pole	1
superior frontal gyrus	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRSK2	176	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ANKS1B	210	broad	marker	Brodmann (1909) area 23, inferior vagus X ganglion, primary visual cortex
CTNNA2	200	broad	marker	frontal pole, Brodmann (1909) area 46, superior frontal gyrus
AGBL4	149	broad	marker	buccal mucosa cell, tendon of biceps brachii, male germ line stem cell (sensu Vertebrata) in testis
CCDC42	67	tissue_specific	yes	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKS1B	2,428
CTNNA2	2,385
BRSK2	1,918
AGBL4	704
CCDC42	561

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANKS1B	Q7Z6G8	4
CTNNA2	P26232	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGBL4	Q5VU57	87.59
CCDC42	Q96M95	87.54
BRSK2	Q8IWQ3	68.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Myogenesis	1	190.3×	0.017	CTNNA2
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.017	AGBL4
Post-translational protein modification	1	9.6×	0.135	AGBL4
Metabolism of proteins	1	6.2×	0.155	AGBL4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of neuron projection development	2	172.8×	0.002	BRSK2, CTNNA2
regulation of retrograde protein transport, ER to cytosol	1	3370.4×	0.004	BRSK2
anterograde axonal transport of mitochondrion	1	1685.2×	0.004	AGBL4
radial glia guided migration of Purkinje cell	1	1123.5×	0.004	CTNNA2
protein deglutamylation	1	1123.5×	0.004	AGBL4
microtubule cytoskeleton organization involved in establishment of planar polarity	1	1123.5×	0.004	BRSK2
retrograde axonal transport of mitochondrion	1	1123.5×	0.004	AGBL4
regulation of synaptic vesicle clustering	1	1123.5×	0.004	BRSK2
C-terminal protein deglutamylation	1	842.6×	0.004	AGBL4
regulation of synapse structural plasticity	1	842.6×	0.004	CTNNA2
regulation of blastocyst development	1	842.6×	0.004	AGBL4
axonogenesis	2	64.2×	0.004	BRSK2, CTNNA2
protein side chain deglutamylation	1	561.7×	0.006	AGBL4
negative regulation of Arp2/3 complex-mediated actin nucleation	1	481.5×	0.006	CTNNA2
modification of postsynaptic actin cytoskeleton	1	280.9×	0.010	CTNNA2
prepulse inhibition	1	224.7×	0.012	CTNNA2
regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.013	BRSK2
regulation of axonogenesis	1	177.4×	0.013	BRSK2
central nervous system neuron development	1	160.5×	0.014	AGBL4
brain morphogenesis	1	146.5×	0.015	CTNNA2
regulation of neuron migration	1	124.8×	0.016	CTNNA2
central nervous system neuron differentiation	1	120.4×	0.016	BRSK2
positive regulation of ubiquitin-dependent protein catabolic process	1	112.3×	0.017	AGBL4
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	96.3×	0.019	BRSK2
acrosome assembly	1	91.1×	0.019	CCDC42
dendrite morphogenesis	1	86.4×	0.019	CTNNA2
establishment of cell polarity	1	76.6×	0.021	BRSK2
ephrin receptor signaling pathway	1	68.8×	0.022	ANKS1B
centrosome cycle	1	67.4×	0.022	CCDC42
G2/M transition of mitotic cell cycle	1	62.4×	0.023	BRSK2

Therapeutics

Drugs indicated for this disease

0 approved, 8 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Buprenorphine	Phase 3 (in late-stage trials)
Diacetylmorphine	Phase 3 (in late-stage trials)
Hydromorphone	Phase 3 (in late-stage trials)
Methadone	Phase 3 (in late-stage trials)
Minocycline	Phase 3 (in late-stage trials)
Mirtazapine	Phase 3 (in late-stage trials)
Naloxone	Phase 3 (in late-stage trials)
Naltrexone	Phase 3 (in late-stage trials)

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

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
BRSK2	BRIGATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRSK2	10	4
ANKS1B	0	0
CTNNA2	0	0
AGBL4	0	0
CCDC42	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BRIGATINIB	4	BRSK2
SUNITINIB	4	BRSK2
MIDOSTAURIN	4	BRSK2
LESTAURTINIB	3	BRSK2
SU-014813	2	BRSK2
TG100-115	2	BRSK2
BAY-1161909	2	BRSK2
GSK-461364	1	BRSK2
KW-2449	1	BRSK2
BMS-387032	1	BRSK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BRSK2	230	Binding:230
AGBL4	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRSK2	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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)
BRIGATINIB	4	BRSK2
SUNITINIB	4	BRSK2
MIDOSTAURIN	4	BRSK2
LESTAURTINIB	3	BRSK2
SU-014813	2	BRSK2
TG100-115	2	BRSK2
BAY-1161909	2	BRSK2
GSK-461364	1	BRSK2
KW-2449	1	BRSK2
BMS-387032	1	BRSK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRSK2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	AGBL4
E	Difficult family or no structure, no drug	3	ANKS1B, CTNNA2, CCDC42

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANKS1B	0	—
CTNNA2	0	—
AGBL4	1	—
CCDC42	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 80.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	33
PHASE2	16
PHASE3	13
PHASE4	6
PHASE2/PHASE3	5
PHASE1	4
PHASE1/PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00310934	PHASE4	COMPLETED	A Stepwise Strategy Utilizing Buprenorphine and Methadone
NCT00326235	PHASE4	COMPLETED	Effects of Buspirone in Opiate Withdrawal
NCT00750217	PHASE4	UNKNOWN	Transfer From Methadone to Buprenorphine Maintenance Treatment Using Buprenorphine Patches
NCT01471145	PHASE4	COMPLETED	Depot Naltrexone Mechanism of Action in Heroin Dependent Patients Using fMRI and SPECT
NCT01999946	PHASE4	COMPLETED	Extended-Release Naltrexone Opioid Treatment at Jail Re-Entry
NCT02324725	PHASE4	COMPLETED	Biomarkers of Injectable Extended Release Naltrexone Treatment
NCT00000302	PHASE3	COMPLETED	Study Comparing Liquid and Tablet Buprenorphine Formulations - 5
NCT00015171	PHASE3	COMPLETED	Buprenorphine and Naloxone for the Treatment of Opiate Dependence - 1
NCT00032955	PHASE3	COMPLETED	Buprenorphine/Naloxone Versus Clonidine for Inpatient Opiate Detoxification - 1
NCT00032968	PHASE3	COMPLETED	Buprenorphine/Naloxone Versus Clonidine for Outpatient Opiate Detoxification - 1
NCT00218426	PHASE2/PHASE3	COMPLETED	Addiction Treatment in Russia: Oral vs. Naltrexone Implant
NCT00279110	PHASE2/PHASE3	COMPLETED	Directly Administered HIV Therapy in Methadone Clinics
NCT00378079	PHASE3	COMPLETED	Methadone Maintenance for Prisoners
NCT00476242	PHASE2/PHASE3	COMPLETED	Memantine as a Supplement to Naltrexone in Treating Heroin Dependence
NCT00574067	PHASE3	COMPLETED	Buprenorphine for Prisoners
NCT00577408	PHASE3	COMPLETED	Behavioral Naltrexone Therapy for Promoting Adherence to Oral Naltrexone vs Extended Release Injectable Depot Naltrexone
NCT00684554	PHASE2/PHASE3	COMPLETED	Buprenorphine Maintenance Treatment of Opioid Dependence in Primary Care: A Randomized Clinical Trial
NCT00709007	PHASE2/PHASE3	WITHDRAWN	Directly Administered Antiretroviral Therapy (DAART) Among HIV-1infected Injecting Drug Users (IDUs) in Chennai, India
NCT01447212	PHASE3	COMPLETED	Study to Assess Longer-term Opioid Medication Effectiveness (SALOME)
NCT01760473	PHASE3	COMPLETED	Reinforcing Effects of Intranasal (IN) Buprenorphine Versus Buprenorphine/Naloxone
NCT02541500	PHASE3	UNKNOWN	An Open Label Study of Oral Minocycline for the Treatment of Patients With Co-occurring Opioid and ATS Dependence
NCT02541513	PHASE3	UNKNOWN	An Open-label Study of Oral Paliparidone for the Treatment of Patients With Co-occurring Opioid and ATS Dependence
NCT02541526	PHASE3	UNKNOWN	Mirtazapine as a Treatment for Co-Occurring Opioid and ATS Dependence in Malaysia
NCT03711318	PHASE3	TERMINATED	Buprenorphine Stabilization and Induction Onto Vivitrol for Heroin-dependent Individuals
NCT00000210	PHASE2	COMPLETED	Treatment Efficacy for Drug Abuse and AIDS Prevention - 1
NCT00000211	PHASE2	COMPLETED	Treatment Efficacy for Drug Abuse and AIDS Prevention - 2
NCT00000273	PHASE2	COMPLETED	A Laboratory Model for Heroin Abuse Medications - 8
NCT00000326	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment 1 - 1
NCT00000327	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment I(2) - 2
NCT00000328	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment III) - 3
NCT00000329	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment II-1 - 4
NCT00000330	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment II-2 - 5
NCT00000331	PHASE2	WITHDRAWN	Buprenorphine/Naloxone Treatment for Opioid Dependence-Experiment II-3 - 6
NCT00023283	PHASE2	COMPLETED	Counseling Conditions for Buprenorphine in a Primary Care Clinic - 1
NCT00135759	PHASE2	COMPLETED	Addition of Naltrexone to Methadone Taper
NCT00142948	PHASE2	COMPLETED	Naltrexone and Adrenergic Agents to Reduce Heroin Use in Heroin Addicts
NCT00158288	PHASE2	COMPLETED	The Efficacy of Methadyl Acetate (LAAM) and Contingency Management Procedures for Treating Dual Opioid and Cocaine Abuse - 1
NCT00218127	PHASE2	COMPLETED	Treatment of Opioid/Heroin Dependence: Comparison of Three Medication Dosing Regimens
NCT00238914	PHASE2	COMPLETED	Opiate Dependence: Combined Naltrexone/Behavior Therapy - 1
NCT00609089	PHASE1/PHASE2	UNKNOWN	Community Reinforcement and Family Training for Drug Abuse Treatment Retention/HIV Risk Reduction

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NALTREXONE	4	17
BUPRENORPHINE	4	7
LEVOMETHADYL ACETATE	4	5
NALOXONE	4	4
METHADONE	4	2
BUSPIRONE	4	1
FLUPHENAZINE DECANOATE	4	1
HYDROMORPHONE	4	1
LOFEXIDINE	4	1
MEMANTINE	4	1
MINOCYCLINE	4	1
MIRTAZAPINE	4	1
DIACETYLMORPHINE	3	3
CHEMBL452845	0	16
alpha-CYANO-4-HYDROXYCINNAMIC ACID	0	1