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Atlas / Disease / Alcohol and nicotine codependence

Alcohol and nicotine codependence

disease
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Summary

Alcohol and nicotine codependence (MONDO:0005432) is a disease with 12 cohort genes (10 GWAS associations across 3 studies).

At a glance

  • Cohort genes: 12
  • GWAS associations: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namealcohol and nicotine codependence
Mondo IDMONDO:0005432
Is cancer (heuristic)no

Data availability: 10 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 › alcohol and nicotine codependence

Related subtypes (9): barbiturate dependence, hallucinogen dependence, cocaine dependence, methamphetamine dependence, opiate dependence, cannabis dependence, phencyclidine abuse, alcohol dependence, nicotine dependence

Genetics & variants

GWAS landscape

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

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs74458321e-09ISCA1P1 - HTR1AA1.15
rs96364703e-08RGPD2 - NDUFB4P7?
rs13189374e-07CAPN7 - SH3BP5-AS1?
rs100429688e-07ISCA1P1 - HTR1AG1.42
rs174273891e-06PLEKHG1?
rs15709892e-06HIVEP1?
rs14261532e-06PKNOX2?
rs7281154e-06KCND2?
rs5283015e-06LINC01833?
rs60283355e-06LINC01734?

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST007657Xiang B20181,0790GWAS and network analysis of co-occurring nicotine and alcohol dependence identifies significantly associated alleles and network.
GCST001471Zuo L20128181,396Genome-wide search for replicable risk gene regions in alcohol and nicotine co-dependence.
GCST001769Zuo L20128181,396Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR1
Tier 3: regulatory0
Tier 4: intronic/intergenic9

MAF distribution

BucketVariants
common (>=0.05)10
low_freq (0.01-0.05)0
rare (<0.01)0
unknown0

Functional consequences

ConsequenceCount
intron_variant6
intergenic_variant3
3_prime_UTR_variant1

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs7445832563290474T>A0.05intergenic_variantISCA1P1 - HTR1A1e-09Tier 4: intronic/intergenic
rs9636470287866942T>C,G0.05intergenic_variantRGPD2 - NDUFB4P73e-08Tier 4: intronic/intergenic
rs1318937315253857A>G0.05intergenic_variantCAPN7 - SH3BP5-AS14e-07Tier 4: intronic/intergenic
rs10042968563737891A>G0.05intron_variantISCA1P1 - HTR1A8e-07Tier 4: intronic/intergenic
rs174273896150841979G>A,T0.053_prime_UTR_variantPLEKHG11e-06Tier 2: splice/UTR
rs1570989612048594A>C,G,T0.05intron_variantHIVEP12e-06Tier 4: intronic/intergenic
rs142615311125300743A>C,G0.05intron_variantPKNOX22e-06Tier 4: intronic/intergenic
rs7281157120665095G>A,C0.05intron_variantKCND24e-06Tier 4: intronic/intergenic
rs528301244927769G>A,C,T0.05intron_variantLINC018335e-06Tier 4: intronic/intergenic
rs60283352039216834A>G0.05intron_variantLINC017345e-06Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SIX3Orphanet:220386Semilobar holoprosencephaly
SIX3Orphanet:280195Septopreoptic holoprosencephaly
SIX3Orphanet:280200Microform holoprosencephaly
SIX3Orphanet:485275Acquired schizencephaly
SIX3Orphanet:93924Lobar holoprosencephaly
SIX3Orphanet:93925Alobar holoprosencephaly
SIX3Orphanet:93926Midline interhemispheric variant of holoprosencephaly
XKOrphanet:59306McLeod neuroacanthocytosis syndrome
RBSNOrphanet:675775Severe congenital myelofibrosis-pancytopenia-intellectual disability-neurologic and ophthalmic abnormalities syndrome
RBSNOrphanet:675782Progressive hypotonia-intellectual disability-facial dysmorphism syndrome due to FYVE-defective RBSN
HTR1AOrphanet:498251Menstrual cycle-dependent periodic fever

Cohort genes → proteins

12 cohort genes, 12 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only12

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SH3BP5HGNC:10827ENSG00000131370O60239SH3 domain-binding protein 5gwas
SIX3HGNC:10889ENSG00000138083O95343Homeobox protein SIX3gwas
XKHGNC:12811ENSG00000047597P51811Endoplasmic reticulum membrane adapter protein XKgwas
PKNOX2HGNC:16714ENSG00000165495Q96KN3Homeobox protein PKNOX2gwas
IPO11HGNC:20628ENSG00000086200Q9UI26Importin-11gwas
RBSNHGNC:20759ENSG00000131381Q9H1K0Rabenosyn-5gwas
PLEKHG1HGNC:20884ENSG00000120278Q9ULL1Pleckstrin homology domain-containing family G member 1gwas
RGPD2HGNC:32415ENSG00000185304P0DJD1RANBP2-like and GRIP domain-containing protein 2gwas
HIVEP1HGNC:4920ENSG00000095951P15822Zinc finger protein 40gwas
HTR1AHGNC:5286ENSG00000178394P089085-hydroxytryptamine receptor 1Agwas
KCND2HGNC:6238ENSG00000184408Q9NZV8A-type voltage-gated potassium channel KCND2gwas
NR2C2HGNC:7972ENSG00000177463P49116Nuclear receptor subfamily 2 group C member 2gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SH3BP5SH3 domain-binding protein 5Functions as a guanine nucleotide exchange factor (GEF) with specificity for RAB11A and RAB25.
SIX3Homeobox protein SIX3Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.
XKEndoplasmic reticulum membrane adapter protein XKRecruits the lipid transfer protein VPS13A from lipid droplets to the endoplasmic reticulum (ER) membrane.
IPO11Importin-11Functions in nuclear protein import as nuclear transport receptor.
RBSNRabenosyn-5Rab4/Rab5 effector protein acting in early endocytic membrane fusion and membrane trafficking of recycling endosomes.
PLEKHG1Pleckstrin homology domain-containing family G member 1Acts as a guanine nucleotide exchange factor (GEF) for RAC1 and CDC42.
HIVEP1Zinc finger protein 40This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV-1.
HTR1A5-hydroxytryptamine receptor 1AG-protein coupled receptor for 5-hydroxytryptamine (serotonin).
KCND2A-type voltage-gated potassium channel KCND2Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain.
NR2C2Nuclear receptor subfamily 2 group C member 2Orphan nuclear receptor that can act as a repressor or activator of transcription.

Protein-family classification

Druggable: 3 · Difficult: 5 · Unknown: 4 · Druggable fraction: 0.25

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
Nuclear receptor132.2×0.143
Transcription factor42.8×0.143
Ion channel19.3×0.205
GPCR12.0×0.601
Scaffold/PPI11.4×0.613
Other/Unknown40.6×0.969

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SH3BP5Other/UnknownnoSH3BP5
SIX3Transcription factornoHD, Homeodomain-like_sf, SIX1_SD
XKOther/UnknownnoXK-rel, XK-related_adapter
PKNOX2Transcription factornoHD, KN_HD, Homeodomain-like_sf
IPO11Other/UnknownnoImportin-beta_N, ARM-like, ARM-type_fold
RBSNTranscription factornoZnf_FYVE, Znf_FYVE_PHD, Znf_RING/FYVE/PHD
PLEKHG1Scaffold/PPInoDH_dom, PH_domain, PH-like_dom_sf
RGPD2Other/UnknownnoRan_bind_dom, GRIP_dom, TPR-like_helical_dom_sf
HIVEP1Transcription factornoZnf_C2H2_type, Znf_CCHC_HIVEP, Znf_C2H2_sf
HTR1AGPCRyesGPCR_Rhodpsn, 5HT1A_rcpt, 5HT_rcpt
KCND2Ion channelyesBTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
NR2C2Nuclear receptoryesNucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

10 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)0
broad (>20)12
unknown0

Top tissues across cohort

TissueCohort genes
sural nerve4
endothelial cell2
pigmented layer of retina2
male germ line stem cell (sensu Vertebrata) in testis2
adrenal tissue1
germinal epithelium of ovary1
nasal cavity epithelium1
retina1
colonic mucosa1
jejunal mucosa1
trabecular bone tissue1
right frontal lobe1
colonic epithelium1
primordial germ cell in gonad1
cardiac muscle of right atrium1
left ventricle myocardium1
ileal mucosa1
spleen1
left testis1
right testis1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SH3BP5293ubiquitousmarkeradrenal tissue, endothelial cell, germinal epithelium of ovary
SIX392broadmarkerpigmented layer of retina, retina, nasal cavity epithelium
XK221broadmarkertrabecular bone tissue, jejunal mucosa, colonic mucosa
PKNOX2236broadyespigmented layer of retina, sural nerve, right frontal lobe
IPO11241ubiquitousmarkerprimordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
RBSN255ubiquitousmarkerendothelial cell, left ventricle myocardium, cardiac muscle of right atrium
PLEKHG1214ubiquitousmarkersural nerve, ileal mucosa, spleen
RGPD2134markerleft testis, right testis, male germ line stem cell (sensu Vertebrata) in testis
HIVEP1276ubiquitousmarkercalcaneal tendon, cartilage tissue, sural nerve
HTR1A66tissue_specificyesentorhinal cortex, middle temporal gyrus, cortical plate
KCND2187broadmarkercerebellar vermis, paraflocculus, cerebellum
NR2C2266ubiquitousmarkersural nerve, upper leg skin, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
NR2C25,729
KCND22,629
HTR1A1,946
HIVEP11,755
SIX31,536
RBSN1,505
IPO111,218
PKNOX21,093
PLEKHG1991
SH3BP5911

Structural data

PDB: 6 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
HTR1AP0890830
KCND2Q9NZV816
SH3BP5O602396
NR2C2P491165
RBSNQ9H1K03
HIVEP1P158223

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
IPO11Q9UI2693.53
XKP5181181.89
SIX3O9534370.38
RGPD2P0DJD166.27
PKNOX2Q96KN361.38
PLEKHG1Q9ULL150.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 12 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Phase 1 - inactivation of fast Na+ channels1271.9×0.060KCND2
Serotonin receptors1158.6×0.060HTR1A
Amine ligand-binding receptors157.7×0.107HTR1A
Voltage gated Potassium channels140.5×0.107KCND2
Nuclear Receptor transcription pathway133.4×0.107NR2C2
Toll Like Receptor 9 (TLR9) Cascade129.3×0.107RBSN
Potassium Channels122.4×0.110KCND2
Interaction of NuRD complexes with transcription factors121.1×0.110NR2C2
Cardiac conduction118.1×0.112KCND2
Muscle contraction112.9×0.112KCND2
Class A/1 (Rhodopsin-like receptors)112.4×0.112HTR1A
Peptide ligand-binding receptors112.4×0.112XK
CDC42 GTPase cycle112.1×0.112PLEKHG1
Factors involved in megakaryocyte development and platelet production111.1×0.112RBSN
GPCR ligand binding110.7×0.112HTR1A
RAC1 GTPase cycle110.2×0.112PLEKHG1
Neuronal System17.4×0.143KCND2
Signaling by GPCR16.7×0.149HTR1A
Signal Transduction11.7×0.463HTR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
proximal/distal axis specification11404.3×0.024SIX3
optic vesicle morphogenesis1702.2×0.024SIX3
regulation of serotonin secretion1702.2×0.024HTR1A
regulation of neural retina development1468.1×0.024SIX3
forebrain anterior/posterior pattern specification1351.1×0.024SIX3
regulation of hormone secretion1351.1×0.024HTR1A
lens induction in camera-type eye1351.1×0.024SIX3
ribosomal protein import into nucleus1280.9×0.024IPO11
regulation of axon diameter1280.9×0.024XK
neuroblast migration1280.9×0.024SIX3
regulation of neuroblast proliferation1280.9×0.024SIX3
lens fiber cell apoptotic process1280.9×0.024SIX3
protein import into nucleus224.0×0.024SIX3, IPO11
intracellular magnesium ion homeostasis1234.1×0.025XK
telencephalon regionalization1234.1×0.025SIX3
neuroblast differentiation1175.5×0.025SIX3
forebrain dorsal/ventral pattern formation1175.5×0.025SIX3
serotonin receptor signaling pathway1156.0×0.025HTR1A
circadian behavior1156.0×0.025SIX3
regulation of cell cycle phase transition1156.0×0.025SIX3
adenylate cyclase-inhibiting serotonin receptor signaling pathway1140.4×0.025HTR1A
regulation of dopamine metabolic process1140.4×0.025HTR1A
serotonin metabolic process1140.4×0.025HTR1A
apoptotic process involved in development1140.4×0.025SIX3
regulation of neural precursor cell proliferation1140.4×0.025SIX3
epithelial cell maturation1127.7×0.025SIX3
Golgi to lysosome transport1127.7×0.025RBSN
regulation of behavior1117.0×0.026HTR1A
cell proliferation in forebrain1108.0×0.026SIX3
early endosome to Golgi transport1108.0×0.026RBSN

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 9

Druggability breadth: 5 of 12 evidence-associated genes (42%) 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
HTR1AIMIPRAMINE
KCND2VERNAKALANT HYDROCHLORIDE

Top cohort targets by molecule count

SymbolMoleculesMax phase
HTR1A4014
KCND214
NR2C212
SH3BP500
SIX300
XK00
PKNOX200
IPO1100
RBSN00
PLEKHG100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
IMIPRAMINE4HTR1A
CANDESARTAN CILEXETIL4HTR1A
BEXAROTENE4HTR1A
METHYSERGIDE4HTR1A
GLIPIZIDE4HTR1A
MORICIZINE4HTR1A
ACETOPHENAZINE4HTR1A
MESORIDAZINE4HTR1A
PHENELZINE4HTR1A
ARTICAINE4HTR1A
EPINASTINE4HTR1A
ARIPIPRAZOLE4HTR1A
AMOXAPINE4HTR1A
SAQUINAVIR4HTR1A
DESLORATADINE4HTR1A
PRUCALOPRIDE4HTR1A
DULOXETINE4HTR1A
TETRABENAZINE4HTR1A
ZOLMITRIPTAN4HTR1A
TRIMETREXATE4HTR1A
DIHYDROERGOTAMINE MESYLATE4HTR1A
CHLOROXINE4HTR1A
CALCIPOTRIENE4HTR1A
CINACALCET HYDROCHLORIDE4HTR1A
OXYMETAZOLINE HYDROCHLORIDE4HTR1A
METHYSERGIDE MALEATE4HTR1A
THIOTHIXENE4HTR1A
CABERGOLINE4HTR1A
SERTACONAZOLE4HTR1A
PROPIOMAZINE4HTR1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

SymbolAssaysType breakdown
HTR1A1,750Binding:1235, Functional:504, ADMET:10, Toxicity:1
NR2C259Binding:58, ADMET:1
HIVEP126Binding:26
KCND223Binding:22, Toxicity:1
IPO111Binding:1

Cohort genes with high screening signal

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

SymbolChEMBL assays
HTR1A1,750

Pharmacogenomics

Cohort genes with a PharmGKB record: 12; with CPIC/DPWG dosing guidelines: 0.

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

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)
IMIPRAMINE4HTR1A
CANDESARTAN CILEXETIL4HTR1A
BEXAROTENE4HTR1A
METHYSERGIDE4HTR1A
GLIPIZIDE4HTR1A
MORICIZINE4HTR1A
ACETOPHENAZINE4HTR1A
MESORIDAZINE4HTR1A
PHENELZINE4HTR1A
ARTICAINE4HTR1A
EPINASTINE4HTR1A
ARIPIPRAZOLE4HTR1A
AMOXAPINE4HTR1A
SAQUINAVIR4HTR1A
DESLORATADINE4HTR1A
PRUCALOPRIDE4HTR1A
DULOXETINE4HTR1A
TETRABENAZINE4HTR1A
ZOLMITRIPTAN4HTR1A
TRIMETREXATE4HTR1A
DIHYDROERGOTAMINE MESYLATE4HTR1A
CHLOROXINE4HTR1A
CALCIPOTRIENE4HTR1A
CINACALCET HYDROCHLORIDE4HTR1A
OXYMETAZOLINE HYDROCHLORIDE4HTR1A
METHYSERGIDE MALEATE4HTR1A
THIOTHIXENE4HTR1A
CABERGOLINE4HTR1A
SERTACONAZOLE4HTR1A
PROPIOMAZINE4HTR1A

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)2HTR1A, KCND2
BPhased (≥1) drug, not yet approved1NR2C2
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug9SH3BP5, SIX3, XK, PKNOX2, IPO11, RBSN, PLEKHG1, RGPD2, HIVEP1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
SH3BP50—
SIX30—
XK0—
PKNOX20—
IPO111—
RBSN0—
PLEKHG10—
RGPD20—
HIVEP126—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

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
v1.1.4
BioBTree
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Sources 66

This page pulls from 66 datasets indexed by BioBTree:

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