Alcohol dependence

Summary

Alcohol dependence (MONDO:0007079) is a disease with 75 cohort genes (281 GWAS associations across 52 studies) and 596 clinical trials. The dominant Reactome pathway is Ethanol oxidation (8 cohort genes). Top therapeutic interventions include naltrexone, acamprosate, and prazosin.

At a glance

• Cohort genes: 75
• GWAS associations: 281
• ClinVar variants: 9
• Clinical trials: 596

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	alcohol dependence
Mondo ID	MONDO:0007079
OMIM	103780
DOID	DOID:0050741
ICD-10-CM	F10.2
ICD-11	1580466198
NCIT	C93040
SNOMED CT	66590003
UMLS	C0001973
MedGen	1801
Is cancer (heuristic)	no

Also known as: alcohol dependence · alcoholism

Data availability: 9 ClinVar variants · 281 GWAS associations (52 studies) · 1 GenCC gene-disease record.

Disease family

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

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

Genetics & variants

GWAS landscape

281 GWAS associations across 52 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1229984	5e-85	ADH1B	C	19.54
rs2066702	5e-24	ADH1B	G	1.19
rs2075633	5e-21	ADH1B	?	2.52
rs1612735	8e-19	ADH1C	T	8.86
rs1260326	1e-16	GCKR	C	1.07
rs1154433	1e-14	ADH1B - ADH1C	G	1.07
rs13107325	3e-14	SLC39A8	C	1.13
rs4936277	1e-13	DRD2 - TMPRSS5	A	7.44
rs147247472	3e-12	AGBL4-IT1, AGBL4	A	0.35
rs11066001	7e-12	BRAP	?	4.76
rs139438618	2e-11	SEMA3A	G	0.87
rs1421085	2e-11	FTO	T	6.69
rs540606	9e-11	CAMKMT - LINC01833	A	6.49
rs1437396	1e-10	MTIF2 - PRORSD1P	T
rs570436	2e-10	CAMKMT - LINC01833	T	1.06
rs11075992	2e-10	FTO	T	1.06
rs62313897	8e-10	CCSER1	?
rs5860563	1e-09	ADH4	?	6.21
rs1789882	2e-09	ADH1B	G	1.3
rs1693457	2e-09	ADH1B	T	1.3
rs1867877	2e-09	IGSF22	?
rs7906104	3e-09	LINC02661	T	5.98
rs72900220	3e-09	TSPAN5-DT	A	1.24
rs2133896	4e-09	ANKS1B	T	0.1
rs2168784	5e-09	LINC01324	T	1.46
rs904092	5e-09	ADH1A - ADH1B	G	1.3
rs10196867	5e-09	CTNNA2	C	0.24
rs17125651	8e-09	RN7SKP278 - RNU5B-6P	C	1.07
rs7590720	1e-08	MREG, PECR	G	1.35
rs1789891	1e-08	ADH1B - ADH1C	?	1.46

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST008259	Kranzler HR	2019	34,658	167,346	Genome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations.
GCST009886	Walters RK	2018	11,569	34,999	Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.
GCST90078405	Backman JD	2021	3,191	4,505	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90082391	Backman JD	2021	3,191	4,505	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST004712	Gelernter J	2014	2,415	1,798	Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci.
GCST008284	Lai D	2019	2,411	2,438	Genome-wide association studies of alcohol dependence, DSM-IV criterion count, and individual criteria.
GCST90079790	Backman JD	2021	2,395	384,707	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083776	Backman JD	2021	2,395	384,707	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST001052	Heath AC	2011	2,062	6,692	A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications.
GCST001053	Heath AC	2011	2,062	6,692	A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	7
Tier 2: splice/UTR	0
Tier 3: regulatory	2
Tier 4: intronic/intergenic	41

MAF distribution

Bucket	Variants
common (>=0.05)	45
low_freq (0.01-0.05)	5
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	28
intergenic_variant	12
missense_variant	7
regulatory_region_variant	2
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1229984	4	99318162	T>A,C,G	0.031	missense_variant	ADH1B	5e-85	Tier 1: coding
rs2066702	4	99307860	G>A,C	0.193	missense_variant	ADH1B	5e-24	Tier 1: coding
rs2075633	4	99317841	T>A,C,G	0.05	intron_variant	ADH1B	5e-21	Tier 4: intronic/intergenic
rs1612735	4	99336850	T>C,G	0.344	intron_variant	ADH1C	8e-19	Tier 4: intronic/intergenic
rs1260326	2	27508073	T>A,C,G	0.409	missense_variant	GCKR	1e-16	Tier 1: coding
rs1154433	4	99332551	A>G,T	0.404	intergenic_variant	ADH1B - ADH1C	1e-14	Tier 4: intronic/intergenic
rs13107325	4	102267552	C>A,T	0.079	missense_variant	SLC39A8	3e-14	Tier 1: coding
rs4936277	11	113561238	A>G	0.401	intergenic_variant	DRD2 - TMPRSS5	1e-13	Tier 4: intronic/intergenic
rs147247472	1	49441901	G>A	0.017	intron_variant	AGBL4-IT1, AGBL4	3e-12	Tier 4: intronic/intergenic
rs11066001	12	111681367	T>C	0.05	intron_variant	BRAP	7e-12	Tier 4: intronic/intergenic
rs139438618	7	84008281	A>G	0.05	intron_variant	SEMA3A	2e-11	Tier 4: intronic/intergenic
rs1421085	16	53767042	T>C	0.33	intron_variant	FTO	2e-11	Tier 4: intronic/intergenic
rs540606	2	44911368	A>G	0.409	intergenic_variant	CAMKMT - LINC01833	9e-11	Tier 4: intronic/intergenic
rs1437396	2	55278320	C>A,G,T	0.05	intergenic_variant	MTIF2 - PRORSD1P	1e-10	Tier 4: intronic/intergenic
rs570436	2	44915534	C>G,T	0.423	intergenic_variant	CAMKMT - LINC01833	2e-10	Tier 4: intronic/intergenic
rs11075992	16	53786154	T>C	0.395	intron_variant	FTO	2e-10	Tier 4: intronic/intergenic
rs62313897	4	90215590	G>A	0.058	intron_variant	CCSER1	8e-10	Tier 4: intronic/intergenic
rs5860563	4	99126007	CA>C,CAA	0.278	intron_variant	ADH4	1e-09	Tier 4: intronic/intergenic
rs1789882	4	99313896	A>C,G,T	0.231	missense_variant	ADH1B	2e-09	Tier 1: coding
rs1693457	4	99315605	C>A,G,T	0.232	intron_variant	ADH1B	2e-09	Tier 4: intronic/intergenic
rs1867877	11	18705901	T>C	0.051	missense_variant	IGSF22	2e-09	Tier 1: coding
rs7906104	10	108737343	C>G,T	0.271	intron_variant	LINC02661	3e-09	Tier 4: intronic/intergenic
rs72900220	4	98671846	A>G	0.039	intron_variant	TSPAN5-DT	3e-09	Tier 4: intronic/intergenic
rs2133896	12	99455122	G>T	0.222	intron_variant	ANKS1B	4e-09	Tier 4: intronic/intergenic
rs2168784	3	164872151	C>T	0.11	intron_variant	LINC01324	5e-09	Tier 4: intronic/intergenic
rs904092	4	99293007	A>C,G,T	0.237	intron_variant	ADH1A - ADH1B	5e-09	Tier 4: intronic/intergenic
rs10196867	2	79751234	C>A,G,T	0.03	intron_variant	CTNNA2	5e-09	Tier 4: intronic/intergenic
rs17125651	10	109063325	T>C	0.134	intergenic_variant	RN7SKP278 - RNU5B-6P	8e-09	Tier 4: intronic/intergenic
rs7590720	2	216033935	G>A,C,T	0.29	regulatory_region_variant	MREG, PECR	1e-08	Tier 3: regulatory
rs1789891	4	99329262	C>A,G	0.05	intergenic_variant	ADH1B - ADH1C	1e-08	Tier 4: intronic/intergenic

ClinVar germline variants

9 retrieved; paginated sample, class counts are floors:

4 protective, 3 uncertain significance, 1 pathogenic/likely pathogenic, 1 drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685836	NM_000807.4(GABRA2):c.995C>T (p.Ala332Val)	GABRA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18390	NM_000690.4(ALDH2):c.1510G>A (p.Glu504Lys)	ALDH2	drug response	reviewed by expert panel
18182	NM_000668.5(ADH1B):c.143A= (p.His48=)	ADH1B	protective	no assertion criteria provided
18183	NM_000668.6(ADH1B):c.1108C>T (p.Arg370Cys)	ADH1B	protective	no assertion criteria provided
18179	NM_000669.5(ADH1C):c.815G>A (p.Arg272Gln)	ADH1C	protective	no assertion criteria provided
18180	NM_000669.5(ADH1C):c.1048A>G (p.Ile350Val)	ADH1C	protective	no assertion criteria provided
3391131	NM_000669.5(ADH1C):c.321A>G (p.Pro107=)	ADH1C	Uncertain significance	criteria provided, single submitter
2102687	NM_000807.4(GABRA2):c.166C>T (p.Arg56Trp)	GABRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
5333	NM_016945.3(TAS2R16):c.516T>G (p.Asn172Lys)	TAS2R16	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 28 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

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

Gene	HGNC	Evidence routes
ADH1B	ADH1B	GWAS, GenCC
ADH1C	ADH1C	GWAS
ALDH2	ALDH2	GWAS

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ADH1B	Limited	Autosomal dominant	alcohol dependence

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RHAG	Orphanet:3203	Overhydrated hereditary stomatocytosis
RHAG	Orphanet:71275	Rh deficiency syndrome
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome
SIX3	Orphanet:220386	Semilobar holoprosencephaly
SIX3	Orphanet:280195	Septopreoptic holoprosencephaly
SIX3	Orphanet:280200	Microform holoprosencephaly
SIX3	Orphanet:485275	Acquired schizencephaly
SIX3	Orphanet:93924	Lobar holoprosencephaly
SIX3	Orphanet:93925	Alobar holoprosencephaly
SIX3	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
CAST	Orphanet:444138	Peeling skin-leukonychia-acral punctate keratoses-cheilitis-knuckle pads syndrome
SUGCT	Orphanet:35706	Glutaric acidemia type 3
ERAP1	Orphanet:117	Behçet disease
CAMTA1	Orphanet:157791	Epithelioid hemangioendothelioma
CAMTA1	Orphanet:314647	Non-progressive cerebellar ataxia with intellectual disability
SLC39A8	Orphanet:468699	SLC39A8-CDG
EPS8L3	Orphanet:444	Marie Unna hereditary hypotrichosis
FTO	Orphanet:210144	Lethal polymalformative syndrome, Boissel type
DCC	Orphanet:238722	Familial congenital mirror movements
DCC	Orphanet:2744	Horizontal gaze palsy with progressive scoliosis
DCC	Orphanet:478	Kallmann syndrome
GPD1L	Orphanet:130	Brugada syndrome
DRD2	Orphanet:36899	Myoclonus-dystonia syndrome
ESR1	Orphanet:785	Estrogen resistance syndrome
GABRA2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GNAL	Orphanet:329466	Autosomal dominant focal dystonia, DYT25 type
GSTM3	Orphanet:586	Cystic fibrosis

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	70
gwas_and_clinvar	2
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADH1B	HGNC:250	ENSG00000196616	P00325	All-trans-retinol dehydrogenase [NAD(+)] ADH1B	gwas,gencc,clinvar
ADH1C	HGNC:251	ENSG00000248144	P00326	Alcohol dehydrogenase 1C	gwas,clinvar
ALDH2	HGNC:404	ENSG00000111275	P05091	Aldehyde dehydrogenase, mitochondrial	gwas,clinvar
RHAG	HGNC:10006	ENSG00000112077	Q02094	Ammonium transporter Rh type A	gwas
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	gwas
SH3BP5	HGNC:10827	ENSG00000131370	O60239	SH3 domain-binding protein 5	gwas
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	gwas
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gwas
ZNF124	HGNC:12907	ENSG00000196418	Q15973	Zinc finger protein 124	gwas
WDR7	HGNC:13490	ENSG00000091157	Q9Y4E6	WD repeat-containing protein 7	gwas
SLC6A15	HGNC:13621	ENSG00000072041	Q9H2J7	Sodium-dependent neutral amino acid transporter B(0)AT2	gwas
RGS17	HGNC:14088	ENSG00000091844	Q9UGC6	Regulator of G-protein signaling 17	gwas
TAS2R16	HGNC:14921	ENSG00000128519	Q9NYV7	Taste receptor type 2 member 16	clinvar
CAST	HGNC:1515	ENSG00000153113	P20810	Calpastatin	gwas
ULK4	HGNC:15784	ENSG00000168038	Q96C45	Serine/threonine-protein kinase ULK4	gwas
METAP1	HGNC:15789	ENSG00000164024	P53582	Methionine aminopeptidase 1	gwas
PPP1R16B	HGNC:15850	ENSG00000101445	Q96T49	Protein phosphatase 1 regulatory inhibitor subunit 16B	gwas
GLRX3	HGNC:15987	ENSG00000108010	O76003	Glutaredoxin-3	gwas
SUGCT	HGNC:16001	ENSG00000175600	Q9HAC7	Succinyl-CoA:glutarate CoA-transferase	gwas
SACK1D	HGNC:16122	ENSG00000101447	Q9H4H8	Protein FAM83D	gwas
PKNOX2	HGNC:16714	ENSG00000165495	Q96KN3	Homeobox protein PKNOX2	gwas
MBNL2	HGNC:16746	ENSG00000139793	Q5VZF2	Muscleblind-like protein 2	gwas
ABI3BP	HGNC:17265	ENSG00000154175	Q7Z7G0	Target of Nesh-SH3	gwas
TSPAN5	HGNC:17753	ENSG00000168785	P62079	Tetraspanin-5	gwas
FAM162A	HGNC:17865	ENSG00000114023	Q96A26	Protein FAM162A	gwas
UTP20	HGNC:17897	ENSG00000120800	O75691	Small subunit processome component 20 homolog	gwas
ERAP1	HGNC:18173	ENSG00000164307	Q9NZ08	Endoplasmic reticulum aminopeptidase 1	gwas
PECR	HGNC:18281	ENSG00000115425	Q9BY49	Peroxisomal trans-2-enoyl-CoA reductase	gwas
AOX2P	HGNC:18450	ENSG00000243478		aldehyde oxidase 2, pseudogene	gwas
CAMTA1	HGNC:18806	ENSG00000171735	Q9Y6Y1	Calmodulin-binding transcription activator 1	gwas
NEIL2	HGNC:18956	ENSG00000154328	Q969S2	Endonuclease 8-like 2	gwas
GALNT10	HGNC:19873	ENSG00000164574	Q86SR1	Polypeptide N-acetylgalactosaminyltransferase 10	gwas
USP12	HGNC:20485	ENSG00000152484	O75317	Ubiquitin carboxyl-terminal hydrolase 12	gwas
SLC39A8	HGNC:20862	ENSG00000138821	Q9C0K1	Metal cation symporter ZIP8	gwas
ANKS1A	HGNC:20961	ENSG00000064999	Q92625	Ankyrin repeat and SAM domain-containing protein 1A	gwas
LINGO1	HGNC:21205	ENSG00000169783	Q96FE5	Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1	gwas
EPS8L3	HGNC:21297	ENSG00000198758	Q8TE67	Epidermal growth factor receptor kinase substrate 8-like protein 3	gwas
CNTN5	HGNC:2175	ENSG00000149972	O94779	Contactin-5	gwas
SPATA13	HGNC:23222	ENSG00000182957	Q96N96	Spermatogenesis-associated protein 13	gwas
SERINC2	HGNC:23231	ENSG00000168528	Q96SA4	Serine incorporator 2	gwas
SYT17	HGNC:24119	ENSG00000103528	Q9BSW7	Synaptotagmin-17	gwas
SPATS2L	HGNC:24574	ENSG00000196141	Q9NUQ6	SPATS2-like protein	gwas
ANKS1B	HGNC:24600	ENSG00000185046	Q7Z6G8	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	gwas
FTO	HGNC:24678	ENSG00000140718	Q9C0B1	Alpha-ketoglutarate-dependent dioxygenase FTO	gwas
ADH1A	HGNC:249	ENSG00000187758	P07327	Alcohol dehydrogenase 1A	gwas
CTNNA2	HGNC:2510	ENSG00000066032	P26232	Catenin alpha-2	gwas
TAMM41	HGNC:25187	ENSG00000144559	Q96BW9	Phosphatidate cytidylyltransferase, mitochondrial	gwas
ADH4	HGNC:252	ENSG00000198099	P08319	All-trans-retinol dehydrogenase [NAD(+)] ADH4	gwas
ADH5	HGNC:253	ENSG00000197894	P11766	Alcohol dehydrogenase class-3	gwas
ADH6	HGNC:255	ENSG00000172955	P28332	Alcohol dehydrogenase 6	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADH1B	All-trans-retinol dehydrogenase [NAD(+)] ADH1B	Catalyzes the NAD-dependent oxidation of all-trans-retinol and its derivatives such as all-trans-4-hydroxyretinol and may participate in retinoid metabolism.
ADH1C	Alcohol dehydrogenase 1C	Alcohol dehydrogenase.
ALDH2	Aldehyde dehydrogenase, mitochondrial	Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.
RHAG	Ammonium transporter Rh type A	Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane.
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.
SH3BP5	SH3 domain-binding protein 5	Functions as a guanine nucleotide exchange factor (GEF) with specificity for RAB11A and RAB25.
SIX3	Homeobox protein SIX3	Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes.
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
ZNF124	Zinc finger protein 124	May be involved in transcriptional regulation.
SLC6A15	Sodium-dependent neutral amino acid transporter B(0)AT2	Functions as a sodium-dependent neutral amino acid transporter.
RGS17	Regulator of G-protein signaling 17	Regulates G protein-coupled receptor signaling cascades, including signaling via muscarinic acetylcholine receptor CHRM2 and dopamine receptor DRD2.
TAS2R16	Taste receptor type 2 member 16	Gustducin-coupled receptor implicated in the perception of bitter compounds in the oral cavity and the gastrointestinal tract.
CAST	Calpastatin	Specific inhibition of calpain (calcium-dependent cysteine protease).
ULK4	Serine/threonine-protein kinase ULK4	May be involved in the remodeling of cytoskeletal components, such as alpha-tubulin, and in this way regulates neurite branching and elongation, as well as cell motility.
METAP1	Methionine aminopeptidase 1	Cotranslationally removes the N-terminal methionine from nascent proteins.
PPP1R16B	Protein phosphatase 1 regulatory inhibitor subunit 16B	Regulator of protein phosphatase 1 (PP1) that acts as a positive regulator of pulmonary endothelial cell (EC) barrier function.
GLRX3	Glutaredoxin-3	Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins.
SUGCT	Succinyl-CoA:glutarate CoA-transferase	Coenzyme A (CoA) transferase that reversibly catalyzes the transfer of a CoA moiety from a dicarboxyl-CoA to a dicarboxylate in a metabolite recycling process.
SACK1D	Protein FAM83D	Through the degradation of FBXW7, may act indirectly on the expression and downstream signaling of MTOR, JUN and MYC.
MBNL2	Muscleblind-like protein 2	Mediates pre-mRNA alternative splicing regulation.
TSPAN5	Tetraspanin-5	Part of TspanC8 subgroup, composed of 6 members that interact with the transmembrane metalloprotease ADAM10.
FAM162A	Protein FAM162A	Proposed to be involved in regulation of apoptosis; the exact mechanism may differ between cell types/tissues.
UTP20	Small subunit processome component 20 homolog	Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit.
ERAP1	Endoplasmic reticulum aminopeptidase 1	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.
PECR	Peroxisomal trans-2-enoyl-CoA reductase	Participates in chain elongation of fatty acids.
CAMTA1	Calmodulin-binding transcription activator 1	Transcriptional activator.
NEIL2	Endonuclease 8-like 2	Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents.
GALNT10	Polypeptide N-acetylgalactosaminyltransferase 10	Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor.
USP12	Ubiquitin carboxyl-terminal hydrolase 12	Deubiquitinating enzyme that plays various roles in the regulation of the immune response and inflammation.
SLC39A8	Metal cation symporter ZIP8	Electroneutral divalent metal cation:bicarbonate symporter of the plasma membrane mediating the cellular uptake of zinc and manganese, two divalent metal cations important for development, tissue homeostasis and immunity.
ANKS1A	Ankyrin repeat and SAM domain-containing protein 1A	Regulator of different signaling pathways.
LINGO1	Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1	Functional component of the Nogo receptor signaling complex (RTN4R/NGFR) in RhoA activation responsible for some inhibition of axonal regeneration by myelin-associated factors.
CNTN5	Contactin-5	Contactins mediate cell surface interactions during nervous system development.
SPATA13	Spermatogenesis-associated protein 13	Acts as a guanine nucleotide exchange factor (GEF) for RHOA, RAC1 and CDC42 GTPases.
SERINC2	Serine incorporator 2	Non-ATP-dependent, non-specific lipid transporter for phosphatidylserine, phosphatidylcholine, and phosphatidylethanolamine.
SYT17	Synaptotagmin-17	Plays a role in dendrite formation by melanocytes.
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.
FTO	Alpha-ketoglutarate-dependent dioxygenase FTO	RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.
ADH1A	Alcohol dehydrogenase 1A	Alcohol dehydrogenase.
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.
TAMM41	Phosphatidate cytidylyltransferase, mitochondrial	Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.
ADH4	All-trans-retinol dehydrogenase [NAD(+)] ADH4	Catalyzes the NAD-dependent oxidation of either all-trans-retinol or 9-cis-retinol.
ADH5	Alcohol dehydrogenase class-3	Catalyzes the oxidation of long-chain primary alcohols and the oxidation of S-(hydroxymethyl) glutathione.
ADH6	Alcohol dehydrogenase 6	Alcohol dehydrogenase.
ADH7	All-trans-retinol dehydrogenase [NAD(+)] ADH7	Catalyzes the NAD-dependent oxidation of all-trans-retinol, alcohol, and omega-hydroxy fatty acids and their derivatives.
AGBL4	Cytosolic carboxypeptidase 6	Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins.
DCC	Netrin receptor DCC	Receptor for netrin required for axon guidance.
MICU3	Calcium uptake protein 3, mitochondrial	Tissue-specific calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which specifically regulates MCU channel activity in the central nervous system and skeletal muscle.
GPD1L	Glycerol-3-phosphate dehydrogenase 1-like protein	Plays a role in regulating cardiac sodium current; decreased enzymatic activity with resulting increased levels of glycerol 3-phosphate activating the DPD1L-dependent SCN5A phosphorylation pathway, may ultimately lead to decreased sodium c…
LHPP	Phospholysine phosphohistidine inorganic pyrophosphate phosphatase	Phosphatase that hydrolyzes imidodiphosphate, 3-phosphohistidine and 6-phospholysine.

Protein-family classification

Druggable: 24 · Difficult: 15 · Unknown: 36 · Druggable fraction: 0.32

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	5	2.4×	0.271
Antibody/Immunoglobulin	6	2.3×	0.271
Nuclear receptor	1	5.2×	0.354
Scaffold/PPI	7	1.6×	0.354
Enzyme (other)	9	1.4×	0.354
Transporter	1	1.0×	0.960
Transcription factor	8	0.9×	0.960
Other/Unknown	36	0.9×	0.960
Kinase	1	0.4×	0.960
GPCR	1	0.3×	0.960

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADH1B	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
ADH1C	Enzyme (other)	yes	1.1.1.1	ADH_Zn_CS, GroES-like_sf, ADH-like_C
ALDH2	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
RHAG	Other/Unknown	no		RhesusRHD, NH4_transpt_AmtB-like_dom, Ammonium/urea_transptr
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SH3BP5	Other/Unknown	no		SH3BP5
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
ZNF124	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
WDR7	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
SLC6A15	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
RGS17	Other/Unknown	no		RGS, RGS_sf, RGS_subdomain_2
TAS2R16	Other/Unknown	no		TAS2R
CAST	Other/Unknown	no		Prot_inh_calpain, Calpastatin
ULK4	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, ARM-like
METAP1	Protease	yes	3.4.11.18	Pept_M24, Pept_M24_MAP, Pept_M24A_MAP1
PPP1R16B	Scaffold/PPI	no		Ankyrin_rpt, Pase-1_reg_su_16AB, Ankyrin_rpt-contain_sf
GLRX3	Other/Unknown	no		Glutaredoxin, Monothiol_GRX-rel, Thioredoxin_domain
SUGCT	Enzyme (other)	yes	2.8.3.13	CoA-Trfase_fam_III, CoA-Trfase_III_dom_1_sf, CoA-Trfase_III_dom3_sf
SACK1D	Other/Unknown	no		SACK1, FAM83
PKNOX2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MBNL2	Transcription factor	no		Znf_CCCH, Znf-CCCH_Muscleblind-like
ABI3BP	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
TSPAN5	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
FAM162A	Other/Unknown	no		DUF1075
UTP20	Other/Unknown	no		UTP20_N, ARM-type_fold, UTP20_dom
ERAP1	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
PECR	Enzyme (other)	yes	1.3.1.38	SDR_fam, NAD(P)-bd_dom_sf, Peroxisomal_t2-enoyl-CoA_red
AOX2P	Other/Unknown	no
CAMTA1	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, Ankyrin_rpt, IPT_dom
NEIL2	Transcription factor	no	3.2.2.23	Znf_DNA_glyclase/AP_lyase, Ribosomal_uS13-like_H2TH, FPG_cat
GALNT10	Other/Unknown	no		Ricin_B_lectin, Glyco_trans_2-like, Nucleotide-diphossugar_trans
USP12	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
SLC39A8	Transporter	yes		ZIP, ZIP_Transporter
ANKS1A	Scaffold/PPI	no		SAM, Ankyrin_rpt, PTB/PI_dom
LINGO1	Antibody/Immunoglobulin	yes		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
EPS8L3	Scaffold/PPI	no		SH3_domain, PH-like_dom_sf, PTB
CNTN5	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
SPATA13	Scaffold/PPI	no		DH_dom, SH3_domain, PH_domain
SERINC2	Other/Unknown	no		TDE1/TMS
SYT17	Other/Unknown	no		C2_dom, Synaptotagmin, Syt17_C2B
SPATS2L	Other/Unknown	no		UBA-like_sf, SPATS2-like
ANKS1B	Scaffold/PPI	no		SAM, Ankyrin_rpt, PTB/PI_dom
FTO	Enzyme (other)	yes	1.14.11.53	FTO_C, FTO_cat_dom, FTO
ADH1A	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
CTNNA2	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
TAMM41	Other/Unknown	no		Tam41
ADH4	Enzyme (other)	yes	1.1.1.1	ADH_Zn_CS, GroES-like_sf, ADH-like_C
ADH5	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
ADH6	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	1
broad (>20)	73
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	9
male germ line stem cell (sensu Vertebrata) in testis	9
left testis	8
endothelial cell	7
buccal mucosa cell	7
right testis	6
right lobe of liver	5
mucosa of transverse colon	5
calcaneal tendon	5
jejunal mucosa	4
liver	4
Brodmann (1909) area 23	4
middle temporal gyrus	4
tendon of biceps brachii	4
primordial germ cell in gonad	4
lower lobe of lung	3
colonic epithelium	3
adrenal tissue	3
pigmented layer of retina	3
secondary oocyte	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADH1B	244	broad	marker	right lobe of liver, right coronary artery, lower lobe of lung
ADH1C	199	tissue_specific	marker	mucosa of transverse colon, jejunal mucosa, nasal cavity epithelium
ALDH2	301	ubiquitous	marker	right lobe of liver, liver, lower lobe of lung
RHAG	140	tissue_specific	marker	trabecular bone tissue, bone marrow, bone marrow cell
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium
SH3BP5	293	ubiquitous	marker	adrenal tissue, endothelial cell, germinal epithelium of ovary
SIX3	92	broad	marker	pigmented layer of retina, retina, nasal cavity epithelium
BRAP	286	ubiquitous	marker	left testis, right testis, testis
ZNF124	234	tissue_specific	yes	colonic epithelium, secondary oocyte, calcaneal tendon
WDR7	288	ubiquitous	yes	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
SLC6A15	204	ubiquitous	marker	cortical plate, pigmented layer of retina, retina
RGS17	227	ubiquitous	marker	cortical plate, buccal mucosa cell, tendon of biceps brachii
TAS2R16	4		yes	tibialis anterior, pancreatic ductal cell, ileal mucosa
CAST	301	tissue_specific	marker	calcaneal tendon, bronchial epithelial cell, colonic epithelium
ULK4	203	ubiquitous	marker	decidua, secondary oocyte, buccal mucosa cell
METAP1	293	ubiquitous	marker	esophagus squamous epithelium, left testis, epithelium of esophagus
PPP1R16B	257	broad	marker	CA1 field of hippocampus, lateral globus pallidus, orbitofrontal cortex
GLRX3	287	ubiquitous	marker	buccal mucosa cell, islet of Langerhans, adrenal tissue
SUGCT	191	ubiquitous	marker	right adrenal gland cortex, oocyte, right coronary artery
SACK1D	199	ubiquitous	marker	esophagus squamous epithelium, pharyngeal mucosa, mucosa of stomach
PKNOX2	236	broad	yes	pigmented layer of retina, sural nerve, right frontal lobe
MBNL2	292	ubiquitous	marker	endothelial cell, lateral globus pallidus, heart right ventricle
ABI3BP	256	ubiquitous	marker	decidua, synovial joint, calcaneal tendon
TSPAN5	274	ubiquitous	marker	secondary oocyte, cerebellar vermis, middle temporal gyrus
FAM162A	287	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, tongue squamous epithelium
UTP20	215	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, minor salivary gland
ERAP1	286	ubiquitous	marker	jejunal mucosa, rectum, monocyte
PECR	264	ubiquitous	marker	renal medulla, buccal mucosa cell, nipple
AOX2P	76		marker	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, primordial germ cell in gonad
CAMTA1	287	ubiquitous	marker	parotid gland, postcentral gyrus, heart right ventricle

Protein interactions among cohort

Intra-cohort edges: 37.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ESR1	12,382
EIF4E	5,888
ALDH2	4,554
METAP1	4,378
PECR	3,667
GLRX3	3,187
DRD2	3,148
SNRNP40	2,776
GPD1L	2,618
FTO	2,496

Intra-cohort edges

A	B	Sources
ADH1A	ADH1B	biogrid_interaction, intact, string_interaction
ADH1A	ALDH2	string_interaction
ADH1A	TAS2R16	string_interaction
ADH1B	ADH1C	biogrid_interaction, intact
ADH1B	ALDH2	string_interaction
ADH1B	GABRA2	string_interaction
ADH1B	TAS2R16	string_interaction
ADH1C	ALDH2	string_interaction
ADH4	ALDH2	string_interaction
ADH4	GABRA2	string_interaction
ADH5	ALDH2	string_interaction
ADH5	TAS2R16	string_interaction
ADH6	ALDH2	string_interaction
ADH6	TAS2R16	string_interaction
ADH7	ALDH2	string_interaction
ADH7	GABRA2	string_interaction
ADH7	TAS2R16	string_interaction
AGBL4	SYT17	string_interaction
ALDH2	GABRA2	string_interaction
CAST	ERAP1	string_interaction
DRD2	GABRA2	string_interaction
ERAP1	METAP1	string_interaction
ESR1	METAP1	intact
ESR1	SPATS2L	intact
GLRX3	METAP1	intact
GSTM3	GSTM4	biogrid_interaction, intact
KIAA0040	PKNOX2	string_interaction
KIAA0040	SERINC2	string_interaction
KIAA0040	TAS2R16	string_interaction
NKAIN1	SERINC2	string_interaction
NKAIN1	SNRNP40	string_interaction
NKAIN1	ZCCHC17	string_interaction
PECR	PKNOX2	string_interaction
PPP1R16B	SACK1D	string_interaction
SERINC2	SNRNP40	string_interaction
SERINC2	ZCCHC17	string_interaction
SNRNP40	ZCCHC17	string_interaction

Structural data

PDB: 47 · AlphaFold-only: 26 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESR1	P03372	478
FABP3	P05413	70
SNRNP40	Q96DI7	54
EIF4E	P06730	45
METAP1	P53582	41
ALDH2	P05091	29
FTO	Q9C0B1	28
ERAP1	Q9NZ08	23
FAF1	Q9UNN5	16
DRD2	P14416	11
ADH5	P11766	10
GNAL	P38405	10
ADH1B	P00325	9
DCC	P43146	9
RHAG	Q02094	8
GABRA2	P47869	8
SH3BP5	O60239	6
USP12	O75317	5
TAS2R16	Q9NYV7	4
GLRX3	O76003	4
ANKS1B	Q7Z6G8	4
UTP20	O75691	3
ANKS1A	Q92625	3
ADH7	P40394	3
ADH1C	P00326	2
RGS17	Q9UGC6	2
ULK4	Q96C45	2
SUGCT	Q9HAC7	2
SACK1D	Q9H4H8	2
MBNL2	Q5VZF2	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADH6	P28332	95.87
TSPAN5	P62079	89.48
AGBL4	Q5VU57	87.59
SEMA3A	Q14563	84.50
NEIL2	Q969S2	81.95
SLC6A15	Q9H2J7	80.15
SERINC2	Q96SA4	79.46
BRAP	Q7Z569	76.92
ZNF124	Q15973	76.71
NKAIN1	Q4KMZ8	75.75
WDR7	Q9Y4E6	74.31
SLC39A8	Q9C0K1	73.46
TAMM41	Q96BW9	73.42
SPATA13	Q96N96	72.49
PPP1R16B	Q96T49	70.73
SIX3	O95343	70.38
KIAA0040	Q15053	69.05
PRSS54	Q6PEW0	67.53
ZNF697	Q5TEC3	65.99
FAM162A	Q96A26	64.21
SPATS2L	Q9NUQ6	63.72
PKNOX2	Q96KN3	61.38
CAST	P20810	59.67
ABI3BP	Q7Z7G0	54.33
CCSER1	Q9C0I3	47.56
C15orf32	Q32M92	40.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 242. Enrichment computed across 92 evidence-associated genes (59 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 59 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ethanol oxidation	8	129.0×	4e-14	ADH1B, ADH1C, ALDH2, ADH1A, ADH4, ADH5, ADH6, ADH7
Phase I - Functionalization of compounds	8	29.8×	2e-08	ADH1B, ADH1C, ALDH2, ADH1A, ADH4, ADH5, ADH6, ADH7
Biological oxidations	8	17.6×	1e-06	ADH1B, ADH1C, ALDH2, ADH1A, ADH4, ADH5, ADH6, ADH7
RA biosynthesis pathway	3	24.2×	0.015	ADH1C, ADH1A, ADH4
Signaling by Retinoic Acid	3	20.7×	0.019	ADH1C, ADH1A, ADH4
Signaling by Nuclear Receptors	4	6.9×	0.106	ADH1C, ADH1A, ADH4, MYC
Metabolism	12	2.4×	0.135	ADH1B, ADH1C, ALDH2, SERINC2, ADH1A, ADH4, ADH5, ADH6 (+4 more)
Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN)	1	193.6×	0.156	RHAG
Glutathione conjugation	2	16.8×	0.166	GSTM3, GSTM4
Metabolism of serotonin	1	96.8×	0.227	ALDH2
Biosynthesis of maresin conjugates in tissue regeneration (MCTR)	1	96.8×	0.227	GSTM4
Rhesus glycoproteins mediate ammonium transport	1	64.5×	0.249	RHAG
Pyrophosphate hydrolysis	1	64.5×	0.249	LHPP
Abacavir metabolism	1	48.4×	0.249	ADH1A
Serotonin clearance from the synaptic cleft	1	48.4×	0.249	ALDH2
Biosynthesis of D-series resolvins	1	48.4×	0.249	HPGD
p75NTR regulates axonogenesis	1	38.7×	0.249	LINGO1
DSCAM interactions	1	38.7×	0.249	DCC
Dopamine receptors	1	38.7×	0.249	DRD2
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	38.7×	0.249	MYC
Biosynthesis of E-series 18(S)-resolvins	1	38.7×	0.249	HPGD
NR1H2 & NR1H3 regulate gene expression linked to gluconeogenesis	1	38.7×	0.249	NRIP1
Biosynthesis of Lipoxins (LX)	1	32.3×	0.249	HPGD
Vasopressin-like receptors	1	32.3×	0.249	OXTR
Alpha-oxidation of phytanate	1	32.3×	0.249	PECR
RUNX1 regulates estrogen receptor mediated transcription	1	32.3×	0.249	ESR1
RUNX1 regulates transcription of genes involved in WNT signaling	1	32.3×	0.249	ESR1
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	27.6×	0.249	NEIL2
Reversal of alkylation damage by DNA dioxygenases	1	27.6×	0.249	FTO
Abacavir ADME	1	24.2×	0.249	ADH1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 83 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinol metabolic process	6	35.8×	8e-06	ADH1B, ADH1C, ADH1A, ADH4, ADH6, ADH7
retinoic acid metabolic process	5	48.3×	1e-05	ADH1B, ADH1C, ADH1A, ADH6, ADH7
fatty acid omega-oxidation	3	101.5×	4e-04	ADH4, ADH5, ADH7
alcohol metabolic process	3	87.0×	6e-04	ALDH2, ADH1A, ADH4
ethanol metabolic process	2	203.0×	0.002	ALDH2, ADH4
retinoid metabolic process	4	23.9×	0.002	ADH1B, ADH4, ADH5, ADH7
formaldehyde catabolic process	2	135.4×	0.006	ADH4, ADH5
nitrobenzene metabolic process	2	101.5×	0.009	GSTM3, GSTM4
regulation of synapse structural plasticity	2	101.5×	0.009	CTNNA2, DRD2
response to amphetamine	3	17.9×	0.036	RGS17, DRD2, GNAL
ovarian follicle rupture	1	203.0×	0.072	NRIP1
proximal/distal axis specification	1	203.0×	0.072	SIX3
nitroglycerin metabolic process	1	203.0×	0.072	ALDH2
protein kinase C deactivation	1	203.0×	0.072	ULK4
negative regulation of circadian sleep/wake cycle, sleep	1	203.0×	0.072	DRD2
alcohol catabolic process	1	203.0×	0.072	ADH4
leukocyte adhesion to arterial endothelial cell	1	203.0×	0.072	SLC39A8
regulation of white fat cell proliferation	1	203.0×	0.072	FTO
methylammonium transmembrane transport	1	203.0×	0.072	RHAG
positive regulation of metanephric cap mesenchymal cell proliferation	1	203.0×	0.072	MYC
plasma membrane selenite transport	1	203.0×	0.072	SLC39A8
neurotransmitter receptor transport	1	203.0×	0.072	HIP1
positive regulation of long-chain fatty acid import into cell	1	203.0×	0.072	FABP3
quinone metabolic process	1	203.0×	0.072	ADH4
regulation of dopamine biosynthetic process	1	203.0×	0.072	ALDH2
regulation of epithelial cell apoptotic process	1	203.0×	0.072	ESR1
regulation of cholangiocyte proliferation	1	203.0×	0.072	PKHD1
positive regulation of acinar cell proliferation	1	203.0×	0.072	MYC
regulation of serotonin biosynthetic process	1	203.0×	0.072	ALDH2
regulation of prostaglandin catabolic process	1	203.0×	0.072	HPGD

Therapeutics

Drug target analysis

Approved (phase 4): 9 · Phase ≥3: 10 · Phased (≥1): 14 · Undrugged: 61

Druggability breadth: 40 of 92 evidence-associated genes (43%) 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
ALDH2	DISULFIRAM
SLC6A15	LORATADINE
TAS2R16	ISOPROTERENOL
METAP1	CLIOQUINOL
FTO	FLUORESCEIN
DRD2	CABERGOLINE
EIF4E	RIBAVIRIN
ESR1	CANDESARTAN CILEXETIL
GABRA2	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DRD2	298	4
ESR1	162	4
GABRA2	46	4
FTO	18	4
METAP1	4	4
EIF4E	4	4
ALDH2	3	4
RGS17	2	2
ERAP1	2	2
SLC6A15	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DISULFIRAM	4	ALDH2, DRD2
LORATADINE	4	SLC6A15
ISOPROTERENOL	4	DRD2, TAS2R16
CLIOQUINOL	4	METAP1
THIABENDAZOLE	4	METAP1
FLUORESCEIN	4	FTO
DEMECLOCYCLINE	4	FTO
ROXADUSTAT	4	FTO
MECLOFENAMIC ACID	4	FTO
AMILORIDE	4	FTO
TACRINE	4	FTO
ENTACAPONE	4	FTO
CABERGOLINE	4	DRD2
APOMORPHINE	4	DRD2, ESR1
HALOPERIDOL	4	DRD2
ROPINIROLE	4	DRD2
DOPAMINE	4	DRD2
BEPRIDIL	4	DRD2
CLOTRIMAZOLE	4	DRD2
METHYSERGIDE	4	DRD2
OXAPROZIN	4	DRD2
ACETOPHENAZINE	4	DRD2, ESR1
IMIPRAMINE	4	DRD2
DROPERIDOL	4	DRD2
ARIPIPRAZOLE	4	DRD2, ESR1
AMOXAPINE	4	DRD2
IDARUBICIN	4	DRD2
SAQUINAVIR	4	DRD2
PONATINIB	4	DRD2
DESLORATADINE	4	DRD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
DRD2	2,636	Binding:2064, Functional:517, ADMET:54, Unclassified:1
ESR1	2,435	Binding:2037, Functional:363, ADMET:35
GABRA2	385	Binding:327, Functional:52, ADMET:3, Toxicity:3
FTO	153	Binding:153
EIF4E	136	Binding:136
ERAP1	88	Binding:85, Functional:2, ADMET:1
METAP1	79	Binding:75, ADMET:4
ALDH2	71	Binding:66, Functional:5
TAS2R16	56	Functional:54, Binding:2
FABP3	45	Binding:39, ADMET:5, Toxicity:1
RGS17	20	Binding:20
ADH5	19	Binding:19
ADH1A	18	Binding:17, Functional:1
ADH7	14	Binding:14
ADH1B	13	Binding:13
ADH4	13	Binding:13
ADH1C	12	Binding:12
ADH6	11	Binding:11
UTP20	7	Binding:7
SLC6A15	5	Binding:5
USP12	3	Binding:3
BRAP	2	Binding:2
FAF1	2	Binding:2
GLRX3	1	Binding:1
FAM162A	1	Binding:1
NEIL2	1	Functional:1
GALNT10	1	Binding:1
SPATS2L	1	Binding:1
AGBL4	1	Binding:1
LHPP	1	Binding:1
GSTM3	1	ADMET:1
GSTM4	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADH1C	1.1.1.1	alcohol dehydrogenase
ALDH2	1.2.1.3	aldehyde dehydrogenase (NAD+)
METAP1	3.4.11.18	methionyl aminopeptidase
SUGCT	2.8.3.13	succinate-hydroxymethylglutarate CoA-transferase
ERAP1	3.4.11.1, 3.4.11.22	leucyl aminopeptidase, aminopeptidase I
PECR	1.3.1.38	trans-2-enoyl-CoA reductase (NADPH)
NEIL2	3.2.2.23	DNA-formamidopyrimidine glycosylase
FTO	1.14.11.53	mRNA N6-methyladenine demethylase
ADH4	1.1.1.1	alcohol dehydrogenase
LHPP	3.9.1.3	phosphohistidine phosphatase
GSTM3	2.5.1.18	glutathione transferase
GSTM4	2.5.1.18	glutathione transferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
FTO	153
DRD2	2,636
EIF4E	136
ESR1	2,435
GABRA2	385

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

27 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)
LORATADINE	4	SLC6A15
ISOPROTERENOL	4	DRD2, TAS2R16
CLIOQUINOL	4	METAP1
THIABENDAZOLE	4	METAP1
FLUORESCEIN	4	FTO
DEMECLOCYCLINE	4	FTO
ROXADUSTAT	4	FTO
MECLOFENAMIC ACID	4	FTO
AMILORIDE	4	FTO
TACRINE	4	FTO
ENTACAPONE	4	FTO
CABERGOLINE	4	DRD2
HALOPERIDOL	4	DRD2
ROPINIROLE	4	DRD2
DOPAMINE	4	DRD2
BEPRIDIL	4	DRD2
CLOTRIMAZOLE	4	DRD2
METHYSERGIDE	4	DRD2
OXAPROZIN	4	DRD2
ACETOPHENAZINE	4	DRD2, ESR1
IMIPRAMINE	4	DRD2
DROPERIDOL	4	DRD2
AMOXAPINE	4	DRD2
IDARUBICIN	4	DRD2
SAQUINAVIR	4	DRD2
PONATINIB	4	DRD2
DESLORATADINE	4	DRD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	9	ALDH2, SLC6A15, TAS2R16, METAP1, FTO, DRD2, EIF4E, ESR1, GABRA2
B	Phased (≥1) drug, not yet approved	5	RGS17, UTP20, ERAP1, ADH5, FABP3
C	Druggable family + PDB, no drug	13	ADH1C, ULK4, SUGCT, PECR, CAMTA1, USP12, LINGO1, CNTN5, ADH4, DCC (+3 more)
D	Druggable family + AlphaFold only, no drug	5	SEMA3A, ABI3BP, SLC39A8, AGBL4, PRSS54
E	Difficult family or no structure, no drug	43	ADH1B, RHAG, SH3BP5, SIX3, BRAP, ZNF124, WDR7, CAST, PPP1R16B, GLRX3 (+33 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADH1B	13	ALDH2
ADH1C	12	ALDH2
ADH1A	18	ALDH2
ADH4	13	ALDH2
ADH6	11	ALDH2
ADH7	14	ALDH2, TAS2R16
RHAG	0	—
SEMA3A	0	—
SH3BP5	0	—
SIX3	0	—
BRAP	2	—
ZNF124	0	—
WDR7	0	—
CAST	0	—
ULK4	0	—
PPP1R16B	0	—
GLRX3	1	—
SUGCT	0	—
SACK1D	0	—
PKNOX2	0	—
MBNL2	0	—
ABI3BP	0	—
TSPAN5	0	—
FAM162A	1	—
PECR	0	—
AOX2P	0	—
CAMTA1	0	—
NEIL2	1	—
GALNT10	1	—
USP12	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 596.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	247
PHASE2	128
PHASE4	91
PHASE3	58
PHASE1	33
PHASE2/PHASE3	18
PHASE1/PHASE2	12
EARLY_PHASE1	9

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05028062	PHASE4	RECRUITING	Naltrexone in AUD Reward Drinkers
NCT00000437	PHASE4	COMPLETED	Tobacco Dependence in Alcoholism Treatment (Nicotine Patch/Naltrexone)
NCT00000438	PHASE4	COMPLETED	Naltrexone Treatment for Alcoholism
NCT00000441	PHASE4	COMPLETED	Drug Therapy for Alcohol Detoxification
NCT00000442	PHASE4	COMPLETED	Naltrexone for Relapse Prevention
NCT00000444	PHASE4	COMPLETED	Timing of Smoking Intervention in Alcohol Treatment (Nicotine Patch)
NCT00000445	PHASE4	COMPLETED	Use of Naltrexone in a Clinical Setting
NCT00000447	PHASE4	COMPLETED	Behavioral/Drug Therapy for Alcohol-Nicotine Dependence (Naltrexone/Nicotine Patch)
NCT00000448	PHASE4	COMPLETED	Naltrexone Treatment for Alcoholic Women
NCT00000449	PHASE4	COMPLETED	Behavior and Naltrexone Treatment for Alcoholics
NCT00000450	PHASE4	COMPLETED	Naltrexone Maintenance Treatment of Alcoholism
NCT00000452	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Dependence
NCT00000454	PHASE4	COMPLETED	Smoking Cessation in Alcoholism Treatment
NCT00000455	PHASE4	COMPLETED	Naltrexone for Early Problem Drinkers
NCT00000456	PHASE4	COMPLETED	Behavioral Therapy Plus Naltrexone for Alcoholism
NCT00004551	PHASE4	COMPLETED	Behavioral Counseling for Alcohol Dependent Smokers (Nicotine Patch)
NCT00004554	PHASE4	COMPLETED	Sertraline for Alcohol Dependence and Depression
NCT00006203	PHASE4	COMPLETED	Naltrexone, Craving, and Drinking
NCT00006204	PHASE4	COMPLETED	Drug Treatment for Depressed Alcoholics (Naltrexone/Fluoxetine)
NCT00006449	PHASE4	COMPLETED	Post-Treatment Effects of Naltrexone
NCT00006489	PHASE4	COMPLETED	Treatment for Alcoholism and Post-Traumatic Stress Disorder (Naltrexone)
NCT00018824	PHASE4	COMPLETED	Treating Alcohol Use In Older Adults With Depression
NCT00044434	PHASE4	COMPLETED	Bupropion as a Smoking Cessation Aid in Alcoholics
NCT00064844	PHASE4	COMPLETED	Combination Nicotine Replacement for Alcoholic Smokers
NCT00082199	PHASE4	COMPLETED	Study of Aripiprazole in Subjects With Alcoholism
NCT00115037	PHASE4	COMPLETED	Managing Alcoholism in People Who Do Not Respond to Naltrexone
NCT00120601	PHASE4	UNKNOWN	Trial for the Treatment of Alcohol Dependence
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148031	PHASE4	COMPLETED	Improving Hepatitis C Treatment in Injection Drug Users
NCT00159107	PHASE4	COMPLETED	Integrative Therapy in Alcoholism
NCT00167687	PHASE4	COMPLETED	Prazosin Alcohol Dependence IVR Study
NCT00223275	PHASE4	COMPLETED	Naltrexone for Bipolar Disorder and Alcohol Dependence
NCT00226109	PHASE4	SUSPENDED	Clinical Trial Studying the Effects of Spironolactone on Heart and Skeletal Muscle Function in Chronic Alcoholics
NCT00246441	PHASE4	COMPLETED	Paroxetine for Comorbid Social Anxiety Disorder and Alcoholism
NCT00249379	PHASE4	TERMINATED	Study of Acamprosate to Prevent Alcohol Relapse in Criminal Justice Supervisees
NCT00261872	PHASE4	COMPLETED	Treatment of Patients With Alcoholism and Attention Deficit Disorder
NCT00317031	PHASE4	COMPLETED	Individually Adapted Therapy of Alcoholism
NCT00325182	PHASE4	COMPLETED	The Effects of Levetiracetam on Alcohol Dependent Subjects
NCT00329407	PHASE4	COMPLETED	The Effects of Topiramate on Alcohol Use in Alcohol Dependent Subjects
NCT00330174	PHASE4	COMPLETED	Acamprosate in Alcoholics With Comorbid Anxiety or Depression

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NALTREXONE	4	157
ACAMPROSATE	4	22
PRAZOSIN	4	18
NALMEFENE	4	13
BACLOFEN	4	12
ALCOHOL	4	11
FLUOXETINE	4	9
VALPROIC ACID	4	8
BUPROPION	4	6
DOXAZOSIN	4	6
MECAMYLAMINE	4	6
ONDANSETRON	4	6
TOPIRAMATE	4	6
ZONISAMIDE	4	6
QUETIAPINE FUMARATE	4	5
DUTASTERIDE	4	4
PAROXETINE	4	4
VARENICLINE	4	4
DISULFIRAM	4	3
LORAZEPAM	4	3
APREPITANT	4	2
DESIPRAMINE	4	2
ESCITALOPRAM	4	2
LAMOTRIGINE	4	2
LEVETIRACETAM	4	2
MIRTAZAPINE	4	2
NIACIN	4	2
SERTRALINE	4	2
APOMORPHINE	4	1
ARIPIPRAZOLE	4	1