Tobacco addiction, susceptibility to

Summary

Tobacco addiction, susceptibility to (MONDO:0100460) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tobacco addiction, susceptibility to
Mondo ID	MONDO:0100460
OMIM	188890
UMLS	C1861063
MedGen	348778
Is cancer (heuristic)	no

Also known as: cigarette habituation, susceptibility to · nicotine addiction, protection from · nicotine addiction, susceptibility to · nicotine dependence, protection against · nicotine dependence, susceptibility to · smoking habit, susceptibility to · susceptibility to tobacco addiction · tobacco addiction, susceptibility to

Data availability: 40 ClinVar variants.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › tobacco addiction, susceptibility to

Related subtypes (283): microvascular complications of diabetes, susceptibility, Mycobacterium tuberculosis, susceptibility, bacteremia, susceptibility, pregnancy loss, recurrent, susceptibility, autoimmune thyroid disease, susceptibility to, susceptibility to HIV infection, appendicitis, proneness to, atherosclerosis susceptibility, multiple sclerosis, susceptibility to, dyslexia, susceptibility to, 1, endometriosis, susceptibility to, 1, osteoarthritis susceptibility 2, essential hypertension, genetic, osteoarthritis susceptibility 1, otitis media, susceptibility to, pelvic organ prolapse, susceptibility to, pulmonary edema of mountaineers, susceptibility to, sarcoidosis, susceptibility to, 1, strabismus, susceptibility to, thyrotoxic periodic paralysis, susceptibility to, 1, predisposition to invasive fungal disease due to CARD9 deficiency, celiac disease, susceptibility to, 1, hemolytic uremic syndrome, atypical, susceptibility to, 1, hypervitaminosis a, susceptibility to, kuru, susceptibility to, leprosy, susceptibility to, 3, nonarteritic anterior ischemic optic neuropathy, susceptibility to, diabetes mellitus, insulin-dependent, X-linked, susceptibility to, coronary heart disease, susceptibility to, 3, dyslexia, susceptibility to, 9, systemic lupus erythematosus, susceptibility to, 15, Leber optic atrophy, susceptibility to, dyslexia, susceptibility to, 2, Helicobacter pylori infection, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 1, inherited susceptibility to asthma, renal dysplasia, cystic, susceptibility to, systemic lupus erythematosus, susceptibility to, 1, leishmaniasis, tegumentary, susceptibility to, xanthomatosis, susceptibility to, hyperlipidemia, combined, 1, urinary tract infections, recurrent, susceptibility to, hypertension, essential, susceptibility to, 1, hepatic fibrosis, severe, susceptibility to, due to Schistosoma mansoni infection, dyslexia, susceptibility to, 3, Ascaris lumbricoides infection, susceptibility to, hypertension, essential, susceptibility to, 2, epilepsy, idiopathic generalized, susceptibility to, 7, systemic lupus erythematosus, susceptibility to, 2, systemic lupus erythematosus, susceptibility to, 3, nephrolithiasis, uric acid, susceptibility to, atrioventricular septal defect, susceptibility to, 2, vitiligo-associated multiple autoimmune disease susceptibility 1, polysubstance abuse, susceptibility to, dyslexia, susceptibility to, 6, glaucoma, normal tension, susceptibility to, anorexia nervosa, susceptibility to, 1, stroke, susceptibility to, 1, dyslexia, susceptibility to, 5, epilepsy, idiopathic generalized, susceptibility to, 2, familial meningioma, celiac disease, susceptibility to, 5, systemic lupus erythematosus with hemolytic anemia, susceptibility to, 1, hypertension, essential, susceptibility to, 3, coronary heart disease, susceptibility to, 1, bulimia nervosa, susceptibility to, 1, leprosy, susceptibility to, 2, epilepsy, idiopathic generalized, susceptibility to, 9, Parkinson disease 11, autosomal dominant, susceptibility to, focal segmental glomerulosclerosis 3, susceptibility to, autoimmune disease, susceptibility to, 1, osteoarthritis susceptibility 3, systemic lupus erythematosus with nephritis, susceptibility to, 1, systemic lupus erythematosus with nephritis, susceptibility to, 2, systemic lupus erythematosus with nephritis, susceptibility to, 3, coronary heart disease, susceptibility to, 2, coronary heart disease, susceptibility to, 4, autoimmune disease, susceptibility to, 2, autoimmune disease, susceptibility to, 3, systemic lupus erythematosus, susceptibility to, 4, myocardial infarction, susceptibility to, major depressive disorder 1, legionnaire disease, susceptibility to, myocardial infarction, susceptibility to, 2, major depressive disorder 2, hypertension, essential, susceptibility to, 4, epilepsy, idiopathic generalized, susceptibility to, 3, myoclonic epilepsy, juvenile, susceptibility to, 3, orofacial cleft 6, susceptibility to, coronary heart disease, susceptibility to, 5, attention deficit-hyperactivity disorder, susceptibility to, 1, attention deficit-hyperactivity disorder, susceptibility to, 2, attention deficit-hyperactivity disorder, susceptibility to, 3, attention deficit-hyperactivity disorder, susceptibility to, 4, Alzheimer disease 9, susceptibility to respiratory infections associated with CD8alpha chain mutation, dyslexia, susceptibility to, 8, autoimmune disease, susceptibility to, 4, hepatitis C virus, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 4, celiac disease, susceptibility to, 4, celiac disease, susceptibility to, 2, celiac disease, susceptibility to, 3, leprosy, susceptibility to, 1, systemic lupus erythematosus, susceptibility to, 5, systemic lupus erythematosus, susceptibility to, 6, opioid dependence, susceptibility to, 1, systemic lupus erythematosus, susceptibility to, 7, systemic lupus erythematosus, susceptibility to, 8, hypertension, essential, susceptibility to, 5, hypertension, essential, susceptibility to, 6, Parkinson disease 13, autosomal dominant, susceptibility to, West Nile virus, susceptibility to, hepatitis B virus, susceptibility to, Buruli ulcer, susceptibility to, osteoarthritis susceptibility 4, systemic lupus erythematosus, susceptibility to, 9, coronary heart disease, susceptibility to, 7, hypertension, essential, susceptibility to, 7, leprosy, susceptibility to, 4, hypertension, essential, susceptibility to, 8, epilepsy, idiopathic generalized, susceptibility to, 13, coronary heart disease, susceptibility to, 8, myoclonic epilepsy, juvenile, susceptibility to, 4, susceptibility to visceral leishmaniasis, 2, susceptibility to visceral leishmaniasis, 3, celiac disease, susceptibility to, 6, epilepsy, idiopathic generalized, susceptibility to, 5, epilepsy, childhood absence, susceptibility to, 6, celiac disease, susceptibility to, 7, celiac disease, susceptibility to, 8, celiac disease, susceptibility to, 9, celiac disease, susceptibility to, 10, celiac disease, susceptibility to, 11, celiac disease, susceptibility to, 12, celiac disease, susceptibility to, 13, coronary heart disease, susceptibility to, 9, systemic lupus erythematosus, susceptibility to, 10, systemic lupus erythematosus, susceptibility to, 11, systemic lupus erythematosus, susceptibility to, 12, epilepsy, childhood absence, susceptibility to, 5, attention deficit-hyperactivity disorder, susceptibility to, 5, attention deficit-hyperactivity disorder, susceptibility to, 6, systemic lupus erythematosus, susceptibility to, 13, sarcoidosis, susceptibility to, 2, sarcoidosis, susceptibility to, 3, osteoarthritis susceptibility 5, osteoarthritis susceptibility 6, focal segmental glomerulosclerosis 4, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 8, herpes simplex encephalitis, susceptibility to, 2, attention deficit-hyperactivity disorder, susceptibility to, 7, epilepsy, idiopathic generalized, susceptibility to, 10, pelvic organ prolapse, susceptibility to, 2, systemic lupus erythematosus, susceptibility to, 14, leprosy, susceptibility to, 5, thyrotoxic periodic paralysis, susceptibility to, 2, hearing loss, cisplatin-induced, susceptibility to, susceptibility to mononeuropathy of the median nerve, mild, fatty liver disease, nonalcoholic, susceptibility to, 2, leprosy, susceptibility to, 6, autoimmune disease, susceptibility to, 6, Parkinson disease 5, autosomal dominant, susceptibility to, aspergillosis, susceptibility to, sick sinus syndrome 3, susceptibility to, Parkinson disease 18, autosomal dominant, susceptibility to, epilepsy, juvenile myoclonic, susceptibility to, 9, dengue virus, susceptibility to, coronary heart disease, susceptibility to, 6, podoconiosis, susceptibility to, peripartum cardiomyopathy, susceptibility to, influenza, severe, susceptibility to, thyrotoxic periodic paralysis, susceptibility to, 3, human herpesvirus 8, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 12, herpes simplex encephalitis, susceptibility to, 3, herpes simplex encephalitis, susceptibility to, 4, pulmonary hypertension, neonatal, susceptibility to, craniosynostosis 5, susceptibility to, melioidosis, susceptibility to, chronic mountain sickness, susceptibility to, herpes simplex encephalitis, susceptibility to, 7, epilepsy, idiopathic generalized, susceptibility to, 14, hereditary neoplastic syndrome, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR1 deficiency, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency, susceptibility to localized juvenile periodontitis, inherited susceptibility to mycobacterial diseases, neural tube defects, susceptibility to, multiple system atrophy 1, susceptibility to, nephrolithiasis susceptibility caused by SLC26A1, myoclonic epilepsy, juvenile, susceptibility to, 1, epilepsy, childhood absence, susceptibility to, 1, autism, susceptiblity to, susceptibility to visceral leishmaniasis, 1, malaria, susceptibility to, spondyloarthropathy, susceptibility to, herpes simplex encephalitis, susceptibility to, 1, epilepsy, idiopathic generalized, susceptibility to, 18, epilepsy, idiopathic generalized, susceptibility to, 15, hepatitis, fulminant viral, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 16, autosomal recessive mendelian susceptibility to mycobacterial diseases due to partial jak1 deficiency, aortic aneurysm, familial thoracic 11, susceptibility to, craniosynostosis 7, amyotrophic lateral sclerosis, susceptibility to, 24, amyotrophic lateral sclerosis, susceptibility to, 25, epilepsy, juvenile myoclonic, susceptibility to, 10, susceptibility to angioedema induced by ACE inhibitors, epidermodysplasia verruciformis, susceptibility to, exfoliation syndrome, susceptibility to, basal cell carcinoma, susceptibility to, graft-versus-host disease, susceptibility to, narcolepsy, susceptibility to, pulmonary disease, chronic obstructive, susceptibility to, restless legs syndrome, susceptibility to, psoriasis, susceptibility to, age related macular degeneration, susceptibility to, allergic rhinitis, susceptibility to, dermatitis, atopic, susceptibility to, Hirschsprung disease, susceptibility to, diabetes mellitus, ketosis-prone, schizophrenia, susceptibility to, radioulnar synostosis, nonsyndromic, susceptibility to, lumbar disk herniation, susceptibility to, lumbar disk degeneration, susceptibility to, psoriatic arthritis, susceptibility to, migraine with or without aura, susceptibility to, Alzheimer disease, susceptibility to, mitochondrial, Asperger syndrome, susceptibility to, lipodystrophy, partial, acquired, susceptibility to, Graves disease, susceptibility to, 1, epilepsy, idiopathic generalized, susceptibility to, 17, breast-ovarian cancer, familial, susceptibility to, blepharospasm, benign essential, susceptibility to, hemorrhage, intracerebral, susceptibility to, IgA nephropathy, susceptibility to, hemolytic uremic syndrome, atypical, susceptibility to, 7, vitiligo-associated multiple autoimmune disease susceptibility 6, delayed sleep phase syndrome, susceptibility to, encephalitis, acute, infection-induced, susceptibility to, malignant hyperthermia, susceptibility to, multicentric Castleman disease, susceptibility to, pelvic organ prolapse, susceptibility to, 1, amyotrophic lateral sclerosis, susceptibility to, 13, Graves disease, susceptibility to, X-linked 2, autoimmune thyroid disease, susceptibility to, 5, atrioventricular septal defect, susceptibility to, 1, epilepsy, juvenile myoclonic, susceptibility to, 6, autoimmune disease, susceptibility to, 5, epilepsy, idiopathic generalized, susceptibility to, 6, seasonal affective disorder, susceptibility to, ventricular fibrillation during myocardial infarction, susceptibility to, UV-induced skin damage, susceptibility to, antisocial behavior, susceptibility to, aplastic anemia, susceptibility to, cardiomyopathy, familial hypertrophic, 4, susceptibility to, cirrhosis, noncryptogenic, susceptibility to, coronary artery disease, severe, susceptibility to, dengue fever, susceptibility to, dengue hemorrhagic fever, susceptibility to, dengue shock syndrome, susceptibility to, dyslexia, susceptibility to, 4, dyslexia, susceptibility to, 7, efavirenz central nervous system toxicity, susceptibility to, obesity, susceptibility to, bleeding disorder, platelet-type, 13, susceptibility to, Schistosoma mansoni infection, susceptibility/resistance to, Parkinson disease 24, autosomal dominant, susceptibility to, iron overload, susceptibility to, hydrocephalus, congenital, 5, susceptibility to, hearing loss, noise-induced, susceptibility to, hyperemesis gravidarum, susceptibility to, Parkinson disease 26, autosomal dominant, susceptibility to, epilepsy, idiopathic generalized, susceptibility to, 19, polycystic kidney disease 9, susceptibility to, rhabdomyolysis, susceptibility to, scoliosis, isolated, susceptibility to, dystonia 38, susceptibility to, gallbladder disease 4, epilepsy, juvenile absence, susceptibility to, GBA1-related Parkinson disease, susceptibility, SH2B3-related immune system disorder

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

40 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 13 conflicting classifications of pathogenicity, 7 benign/likely benign, 3 likely benign, 2 risk factor, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3331	CCG haplotype		risk factor	no assertion criteria provided
3332	NM_005458.8(GABBR2):c.[1662+5118G>A;1893+21406C>T360=631-18885=]		risk factor	no assertion criteria provided
1303856	NM_000744.7(CHRNA4):c.1742A>G (p.Glu581Gly)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205026	NM_000744.7(CHRNA4):c.1316A>C (p.Lys439Thr)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205030	NM_000744.7(CHRNA4):c.1430C>T (p.Ala477Val)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205031	NM_000744.7(CHRNA4):c.1448G>A (p.Arg483Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205043	NM_000744.7(CHRNA4):c.274G>C (p.Glu92Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205046	NM_000744.7(CHRNA4):c.358C>T (p.Arg120Trp)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452325	NM_000744.7(CHRNA4):c.1667C>G (p.Pro556Arg)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510852	NM_000744.7(CHRNA4):c.138C>T (p.Ser46=)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
854387	NM_000744.7(CHRNA4):c.13G>A (p.Gly5Ser)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
98318	NM_000744.7(CHRNA4):c.1460G>A (p.Arg487Gln)	CHRNA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
964522	NM_005458.8(GABBR2):c.2412+3A>G	GABBR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377082	NM_001044.5(SLC6A3):c.499C>T (p.Leu167Phe)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538065	NM_001044.5(SLC6A3):c.1155C>T (p.Asp385=)	SLC6A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303237	NM_000744.7(CHRNA4):c.448C>A (p.Gln150Lys)	CHRNA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1487245	NM_000744.7(CHRNA4):c.687C>G (p.Ile229Met)	CHRNA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382943	NM_000744.7(CHRNA4):c.487A>G (p.Ile163Val)	CHRNA4	Uncertain significance	criteria provided, single submitter
3587594	NM_000744.7(CHRNA4):c.1310C>T (p.Ala437Val)	CHRNA4	Uncertain significance	criteria provided, single submitter
3587595	NM_000744.7(CHRNA4):c.1195C>G (p.Gln399Glu)	CHRNA4	Uncertain significance	criteria provided, single submitter
420395	NM_000744.7(CHRNA4):c.1792A>G (p.Ile598Val)	CHRNA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
98337	NM_000744.7(CHRNA4):c.799C>T (p.Leu267=)	CHRNA4	Uncertain significance	criteria provided, single submitter
1015213	NM_005458.8(GABBR2):c.131G>A (p.Arg44Gln)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1496079	NM_005458.8(GABBR2):c.121G>T (p.Gly41Cys)	GABBR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022175	NM_001044.5(SLC6A3):c.898G>A (p.Val300Ile)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1408732	NM_001044.5(SLC6A3):c.580C>T (p.Pro194Ser)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1507933	NM_001044.5(SLC6A3):c.149C>T (p.Pro50Leu)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
538067	NM_001044.5(SLC6A3):c.70G>A (p.Val24Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
851586	NM_001044.5(SLC6A3):c.1603G>A (p.Val535Met)	SLC6A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1169560	NM_000744.7(CHRNA4):c.*534C>T	CHRNA4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A3	Orphanet:238455	Infantile dystonia-parkinsonism
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy
GABBR2	Orphanet:3095	Atypical Rett syndrome
GABBR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC6A3	HGNC:11049	ENSG00000142319	Q01959	Sodium-dependent dopamine transporter	clinvar
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar
GABBR2	HGNC:4507	ENSG00000136928	O75899	Gamma-aminobutyric acid type B receptor subunit 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A3	Sodium-dependent dopamine transporter	Mediates sodium- and chloride-dependent transport of dopamine.
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
GABBR2	Gamma-aminobutyric acid type B receptor subunit 2	Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
GPCR	1	8.0×	0.240
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A3	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_dopamine, SNS_sf
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
GABBR2	GPCR	yes		GPCR_3, ANF_lig-bd_rcpt, GPCR3_GABA-B

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
substantia nigra	1
cingulate cortex	1
cortical plate	1
right lobe of liver	1
Brodmann (1909) area 23	1
lateral nuclear group of thalamus	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A3	84	tissue_specific	marker	substantia nigra, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex
GABBR2	193	broad	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC6A3	2,245
CHRNA4	1,989
GABBR2	1,980

Intra-cohort edges

A	B	Sources
CHRNA4	GABBR2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABBR2	O75899	26
SLC6A3	Q01959	17
CHRNA4	P43681	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective neurotransmitter clearance by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	3806.7×	0.003	SLC6A3
Defective transport of neurotransmitters by SLC6A3 causes Parkinsonism-dystonia infantile (PKDYS)	1	3806.7×	0.003	SLC6A3
Dopamine clearance from the synaptic cleft	1	1903.3×	0.003	SLC6A3
Transmission across Chemical Synapses	2	50.8×	0.003	SLC6A3, CHRNA4
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	543.8×	0.007	CHRNA4
Neurotransmitter clearance	1	423.0×	0.007	SLC6A3
Highly calcium permeable nicotinic acetylcholine receptors	1	423.0×	0.007	CHRNA4
Neuronal System	2	29.5×	0.007	SLC6A3, CHRNA4
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	346.1×	0.008	CHRNA4
Presynaptic nicotinic acetylcholine receptors	1	317.2×	0.008	CHRNA4
Acetylcholine binding and downstream events	1	271.9×	0.008	CHRNA4
Postsynaptic nicotinic acetylcholine receptors	1	271.9×	0.008	CHRNA4
GABA B receptor activation	1	181.3×	0.011	GABBR2
SLC-mediated transport of neurotransmitters	1	135.9×	0.012	SLC6A3
Activation of G protein gated Potassium channels	1	131.3×	0.012	GABBR2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	131.3×	0.012	GABBR2
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	97.6×	0.015	GABBR2
SLC transporter disorders	1	68.0×	0.020	SLC6A3
R-HSA-425366	1	60.4×	0.022	SLC6A3
Disorders of transmembrane transporters	1	46.4×	0.027	SLC6A3
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.035	CHRNA4
SLC-mediated transmembrane transport	1	19.7×	0.057	SLC6A3
G alpha (i) signalling events	1	13.0×	0.082	GABBR2
Transport of small molecules	1	8.4×	0.119	SLC6A3
Disease	1	4.4×	0.212	SLC6A3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to nicotine	2	280.9×	8e-04	SLC6A3, CHRNA4
cognition	2	190.4×	9e-04	SLC6A3, CHRNA4
neuron-glial cell signaling	1	1123.5×	0.007	GABBR2
adenohypophysis development	1	802.5×	0.007	SLC6A3
hyaloid vascular plexus regression	1	802.5×	0.007	SLC6A3
dopamine uptake	1	702.2×	0.007	SLC6A3
behavioral response to nicotine	1	624.1×	0.007	CHRNA4
dopamine biosynthetic process	1	624.1×	0.007	SLC6A3
dopamine uptake involved in synaptic transmission	1	624.1×	0.007	SLC6A3
regulation of dopamine metabolic process	1	561.7×	0.007	SLC6A3
dopamine catabolic process	1	561.7×	0.007	SLC6A3
inhibitory postsynaptic potential	1	561.7×	0.007	CHRNA4
chemical synaptic transmission	2	51.5×	0.007	CHRNA4, GABBR2
obsolete dopamine transport	1	510.7×	0.007	SLC6A3
negative regulation of adenylate cyclase activity	1	468.1×	0.007	GABBR2
regulation of dopamine secretion	1	401.2×	0.007	CHRNA4
obsolete monoamine transport	1	401.2×	0.007	SLC6A3
nervous system process	1	401.2×	0.007	CHRNA4
prepulse inhibition	1	374.5×	0.007	SLC6A3
response to iron ion	1	312.1×	0.008	SLC6A3
synaptic transmission, cholinergic	1	267.5×	0.009	CHRNA4
acetylcholine receptor signaling pathway	1	208.1×	0.011	CHRNA4
neuromuscular synaptic transmission	1	200.6×	0.011	CHRNA4
response to cocaine	1	193.7×	0.011	SLC6A3
gamma-aminobutyric acid signaling pathway	1	181.2×	0.011	GABBR2
response to cAMP	1	170.2×	0.011	SLC6A3
membrane depolarization	1	170.2×	0.011	CHRNA4
positive regulation of multicellular organism growth	1	165.2×	0.011	SLC6A3
synaptic transmission, GABAergic	1	165.2×	0.011	GABBR2
B cell activation	1	151.8×	0.011	CHRNA4

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 0

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
SLC6A3	CETIRIZINE
CHRNA4	VARENICLINE
GABBR2	BACLOFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A3	466	4
CHRNA4	64	4
GABBR2	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	CHRNA4, SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	SLC6A3
UMECLIDINIUM	4	SLC6A3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A3	1,043	Binding:993, Functional:24, ADMET:24, Toxicity:2
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
GABBR2	57	Binding:35, Functional:21, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC6A3	1,043
CHRNA4	624

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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.

Compound	Max phase	Cohort target (bioactivity)
CETIRIZINE	4	SLC6A3
BEPRIDIL	4	SLC6A3
CANDESARTAN CILEXETIL	4	SLC6A3
BEXAROTENE	4	SLC6A3
CLOTRIMAZOLE	4	SLC6A3
AMINOCAPROIC ACID	4	SLC6A3
SIMVASTATIN	4	SLC6A3
NABUMETONE	4	SLC6A3
PROPIVERINE	4	SLC6A3
ACETOPHENAZINE	4	SLC6A3
MESORIDAZINE	4	SLC6A3
VALPROIC ACID	4	SLC6A3
NIRAPARIB	4	SLC6A3
INDACATEROL	4	SLC6A3
IMIPRAMINE	4	SLC6A3
HALOFANTRINE	4	SLC6A3
RIMONABANT	4	SLC6A3
ARIPIPRAZOLE	4	SLC6A3
AMOXAPINE	4	SLC6A3
IDARUBICIN	4	SLC6A3
DESVENLAFAXINE	4	SLC6A3
EZETIMIBE	4	SLC6A3
SAQUINAVIR	4	SLC6A3
PONATINIB	4	CHRNA4, SLC6A3
DESLORATADINE	4	SLC6A3
AFATINIB	4	SLC6A3
DULOXETINE	4	SLC6A3
PEMOLINE	4	SLC6A3
CELECOXIB	4	SLC6A3
UMECLIDINIUM	4	SLC6A3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SLC6A3, CHRNA4, GABBR2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.