Major depressive disorder

Summary

Major depressive disorder (MONDO:0002009) is a disease with 75 cohort genes (4,177 GWAS associations across 377 studies) and 2,270 clinical trials. The dominant Reactome pathway is Negative regulation of activity of TFAP2 (AP-2) family transcription factors (3 cohort genes). Top therapeutic interventions include escitalopram, fluoxetine, and bupropion.

At a glance

• Cohort genes: 75
• GWAS associations: 4,177
• ClinVar variants: 5
• Clinical trials: 2,270

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	major depressive disorder
Mondo ID	MONDO:0002009
EFO	EFO:0003761
MeSH	D003865
OMIM	608516
DOID	DOID:1470
NCIT	C35094
SNOMED CT	370143000
UMLS	C1269683
MedGen	266123
Is cancer (heuristic)	no

Also known as: major depression · major depressive disorder · major depressive disorder 1 · major depressive disorder 2 · major depressive disorder and accelerated response to antidepressant drug treatment · major depressive disorder, response to citalopram therapy in · unipolar depression · unipolar depression, susceptibility to

Data availability: 5 ClinVar variants · 4,177 GWAS associations (377 studies) · 35 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › mood disorder › depressive disorder › major depressive disorder

Related subtypes (6): seasonal affective disorder, melancholia, postpartum depression, bipolar depression, neurotic depression, mixed anxiety and depressive disorder

Subtypes (1): endogenous depression

Genetics & variants

GWAS landscape

4,177 GWAS associations across 377 studies. Top hits map to 37 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2568958	4e-52	LINC02796	A	1.03
rs30266	2e-45	NIHCOLE - RNU6-334P	A	1.03
rs1568452	3e-40	ACTG1P22 - VRK2	T	1.03
rs61902811	4e-39	DRD2 - TMPRSS5	G	1.03
rs1095626	6e-39	RSRC1	C	1.03
rs200949	2e-37	H1-5 - H3C11	A	1.04
rs5995992	3e-35	ACTBP15 - EP300	C	1.03
rs10890020	3e-34	RN7SKP19 - LINC01360	G	1.03
rs61990288	2e-31	LRFN5-DT	G	1.03
rs301799	4e-31	RERE, RERE-AS1	C	1.03
rs11135349	2e-30	LINC03000	C	1.03
rs7030813	9e-30	PAX5	T	1.02
rs9592461	1e-28	PCDH9	A	1.02
rs7227069	2e-28	DCC	A	1.02
rs7200826	3e-28	SHISA9	T	1.03
rs12967143	2e-27	TCF4	G	1.03
rs3823624	2e-26	MAD1L1	T	1.03
rs1343605	2e-25	OLFM4 - LINC01065	A	1.02
rs7932640	3e-25	GRM5	T	1.02
rs1045430	4e-25	AREL1	G	1.02
rs12923444	2e-24	METTL9	C	1.02
rs2043539	8e-24	TMEM106B	A	1.02
rs1021363	4e-23	SORCS3	A	1.02
rs7198928	4e-23	RBFOX1	T	1.02
rs62057061	2e-22	LINC02210-CRHR1	G	0.03
rs12052908	4e-22	LINC01830	T	1.02
rs7807677	5e-22	CTTNBP2	T	1.02
rs10061069	5e-22	POU5F2, ARB2A	G	1.03
rs3793577	6e-22	ELAVL2	G	1.02
rs10149470	7e-22	RNU7-160P - BAG5	G	1.02

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005839	Wray NR	2018	135,458	344,901	Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.
GCST005902	Howard DM	2018	113,769	208,811	Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.
GCST005907	Li X	2018	84,847	241,266	Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder.
GCST006041	Hyde CL	2016	84,847	241,266	Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.
GCST005904	Howard DM	2018	30,603	143,916	Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.
GCST003769	Okbay A	2016	16,471	58,835	Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses.
GCST004024	Direk N	2016	9,240	9,519	An Analysis of Two Genome-wide Association Meta-analyses Identifies a New Locus for Broad Depression Phenotype.
GCST001469	Sullivan PF	2012	9,240	9,519	A mega-analysis of genome-wide association studies for major depressive disorder.
GCST005903	Howard DM	2018	8,276	209,308	Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.
GCST003813	Li QS	2016	7,795	191,173	Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	5
Tier 3: regulatory	2
Tier 4: intronic/intergenic	42

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	33
intergenic_variant	7
3_prime_UTR_variant	4
regulatory_region_variant	2
non_coding_transcript_exon_variant	2
missense_variant	1
splice_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2568958	1	72299433	G>A,C,T	0.384	intron_variant	LINC02796	4e-52	Tier 4: intronic/intergenic
rs30266	5	104636656	G>A,C	0.33	intron_variant	NIHCOLE - RNU6-334P	2e-45	Tier 4: intronic/intergenic
rs1568452	2	57785698	C>G,T	0.385	intron_variant	ACTG1P22 - VRK2	3e-40	Tier 4: intronic/intergenic
rs61902811	11	113500036	G>A,C	0.368	intergenic_variant	DRD2 - TMPRSS5	4e-39	Tier 4: intronic/intergenic
rs1095626	3	158260173	T>A,C,G	0.42	intron_variant	RSRC1	6e-39	Tier 4: intronic/intergenic
rs200949	6	27867657	A>C,G,T	0.126	regulatory_region_variant	H1-5 - H3C11	2e-37	Tier 3: regulatory
rs5995992	22	41091214	T>C	0.284	intron_variant	ACTBP15 - EP300	3e-35	Tier 4: intronic/intergenic
rs10890020	1	73203153	A>G,T	0.484	intergenic_variant	RN7SKP19 - LINC01360	3e-34	Tier 4: intronic/intergenic
rs61990288	14	41605523	G>A,T	0.492	non_coding_transcript_exon_variant	LRFN5-DT	2e-31	Tier 4: intronic/intergenic
rs301799	1	8429242	C>A,G,T	0.431	intron_variant	RERE, RERE-AS1	4e-31	Tier 4: intronic/intergenic
rs11135349	5	165096466	A>C	0.471	intron_variant	LINC03000	2e-30	Tier 4: intronic/intergenic
rs7030813	9	36999372	C>T	0.374	intron_variant	PAX5	9e-30	Tier 4: intronic/intergenic
rs9592461	13	66367660	A>G	0.487	intron_variant	PCDH9	1e-28	Tier 4: intronic/intergenic
rs7227069	18	53205432	G>A,T	0.433	intron_variant	DCC	2e-28	Tier 4: intronic/intergenic
rs7200826	16	12972976	C>A,G,T	0.255	intron_variant	SHISA9	3e-28	Tier 4: intronic/intergenic
rs12967143	18	55431781	G>C	0.302	intron_variant	TCF4	2e-27	Tier 4: intronic/intergenic
rs3823624	7	2070711	T>C	0.193	intron_variant	MAD1L1	2e-26	Tier 4: intronic/intergenic
rs1343605	13	53072913	A>C	0.384	intergenic_variant	OLFM4 - LINC01065	2e-25	Tier 4: intronic/intergenic
rs7932640	11	89011257	T>C,G	0.442	intron_variant	GRM5	3e-25	Tier 4: intronic/intergenic
rs1045430	14	74663532	T>C,G	0.479	3_prime_UTR_variant	AREL1	4e-25	Tier 2: splice/UTR
rs12923444	16	21628389	A>C	0.438	intron_variant	METTL9	2e-24	Tier 4: intronic/intergenic
rs2043539	7	12214254	G>A,T	0.418	intron_variant	TMEM106B	8e-24	Tier 4: intronic/intergenic
rs1021363	10	104851081	A>C,G,T	0.355	intron_variant	SORCS3	4e-23	Tier 4: intronic/intergenic
rs7198928	16	7616400	T>A,C	0.384	intron_variant	RBFOX1	4e-23	Tier 4: intronic/intergenic
rs62057061	17	45779273	C>G	0.05	intron_variant	LINC02210-CRHR1	2e-22	Tier 4: intronic/intergenic
rs12052908	2	22280172	A>C,T	0.468	intron_variant	LINC01830	4e-22	Tier 4: intronic/intergenic
rs7807677	7	117862520	C>T	0.45	intron_variant	CTTNBP2	5e-22	Tier 4: intronic/intergenic
rs10061069	5	93735924	G>C	0.221	3_prime_UTR_variant	POU5F2, ARB2A	5e-22	Tier 2: splice/UTR
rs3793577	9	23737629	A>C,G,T	0.467	intron_variant	ELAVL2	6e-22	Tier 4: intronic/intergenic
rs10149470	14	103551616	A>G,T	0.487	regulatory_region_variant	RNU7-160P - BAG5	7e-22	Tier 3: regulatory

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 2 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3164	NM_173353.4(TPH2):c.616C>T (p.Pro206Ser)	TPH2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3575264	NM_173353.4(TPH2):c.710G>A (p.Arg237Gln)	TPH2	Uncertain significance	criteria provided, single submitter
310378	NM_173353.4(TPH2):c.122C>A (p.Ser41Tyr)	TPH2	Likely benign	criteria provided, multiple submitters, no conflicts
88639	NM_000041.4(APOE):c.364C>A (p.Leu122Met)	APOE	not provided	no classification provided
88640	NM_000041.4(APOE):c.451C>A (p.Leu151Met)	APOE	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 68 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RORA	Orphanet:528084	Non-specific syndromic intellectual disability
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
CNNM4	Orphanet:1873	Jalili syndrome
ATXN1	Orphanet:98755	Spinocerebellar ataxia type 1
ATXN7	Orphanet:94147	Spinocerebellar ataxia type 7
BLK	Orphanet:536	Systemic lupus erythematosus
BLK	Orphanet:552	MODY
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome
SGCG	Orphanet:353	Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
SIM1	Orphanet:171829	6q16 microdeletion syndrome
SIM1	Orphanet:369873	Obesity due to SIM1 deficiency
SIM1	Orphanet:398079	SIM1-related Prader-Willi-like syndrome
SLC1A3	Orphanet:209967	Episodic ataxia type 6
SLC1A3	Orphanet:2131	Alternating hemiplegia of childhood
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
SOX5	Orphanet:313884	12p12.1 microdeletion syndrome
SOX5	Orphanet:313892	Developmental and speech delay due to SOX5 deficiency
SOX5	Orphanet:626	Large/giant congenital melanocytic nevus
SPTBN2	Orphanet:352403	Spectrin-associated autosomal recessive cerebellar ataxia
SPTBN2	Orphanet:98766	Spinocerebellar ataxia type 5
TARS1	Orphanet:33364	Trichothiodystrophy
TBX15	Orphanet:93333	Pelviscapular dysplasia
TCF20	Orphanet:528084	Non-specific syndromic intellectual disability
TCF4	Orphanet:171	Primary sclerosing cholangitis
TCF4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TCF4	Orphanet:2896	Pitt-Hopkins syndrome
TCF4	Orphanet:98974	Fuchs endothelial corneal dystrophy
TDO2	Orphanet:2224	Hypertryptophanemia
TFAP2B	Orphanet:46627	Char syndrome
TFAP2B	Orphanet:466729	Familial patent arterial duct
MED12	Orphanet:1415	Hardikar syndrome

Cohort genes → proteins

75 cohort genes, 73 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	74
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RGS6	HGNC:10002	ENSG00000182732	P49758	Regulator of G-protein signaling 6	gwas
RGS7	HGNC:10003	ENSG00000182901	P49802	Regulator of G-protein signaling 7	gwas
RNGTT	HGNC:10073	ENSG00000111880	O60942	mRNA-capping enzyme	gwas
SNORD48	HGNC:10188	ENSG00000201823		small nucleolar RNA, C/D box 48	gwas
SNORD52	HGNC:10202	ENSG00000201754		small nucleolar RNA, C/D box 52	gwas
RORA	HGNC:10258	ENSG00000069667	P35398	Nuclear receptor ROR-alpha	gwas
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	gwas
RPL38	HGNC:10349	ENSG00000172809	P63173	Large ribosomal subunit protein eL38	gwas
RPLP1	HGNC:10372	ENSG00000137818	P05386	Large ribosomal subunit protein P1	gwas
RSU1	HGNC:10464	ENSG00000148484	Q15404	Ras suppressor protein 1	gwas
RTN1	HGNC:10467	ENSG00000139970	Q16799	Reticulon-1	gwas
CNNM4	HGNC:105	ENSG00000158158	Q6P4Q7	Metal transporter CNNM4	gwas
ATXN1	HGNC:10548	ENSG00000124788	P54253	Ataxin-1	gwas
ATXN7	HGNC:10560	ENSG00000163635	O15265	Ataxin-7	gwas
BLK	HGNC:1057	ENSG00000136573	P51451	Tyrosine-protein kinase Blk	gwas
SCG2	HGNC:10575	ENSG00000171951	P13521	Secretogranin-2	gwas
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	gwas
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	gwas
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	gwas
SF3B2	HGNC:10769	ENSG00000087365	Q13435	Splicing factor 3B subunit 2	gwas
SGCG	HGNC:10809	ENSG00000102683	Q13326	Gamma-sarcoglycan	gwas
SH3BP4	HGNC:10826	ENSG00000130147	Q9P0V3	SH3 domain-binding protein 4	gwas
SHMT2	HGNC:10852	ENSG00000182199	P34897	Serine hydroxymethyltransferase, mitochondrial	gwas
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	gwas
SLC18A1	HGNC:10934	ENSG00000036565	P54219	Chromaffin granule amine transporter	gwas
SLC1A3	HGNC:10941	ENSG00000079215	P43003	Excitatory amino acid transporter 1	gwas
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gwas
SLC24A3	HGNC:10977	ENSG00000185052	Q9HC58	Sodium/potassium/calcium exchanger 3	gwas
SLC4A8	HGNC:11034	ENSG00000050438	Q2Y0W8	Electroneutral sodium bicarbonate exchanger 1	gwas
SLC6A6	HGNC:11052	ENSG00000131389	P31641	Sodium- and chloride-dependent taurine transporter	gwas
SLC6A7	HGNC:11054	ENSG00000011083	Q99884	Sodium-dependent proline transporter	gwas
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	gwas
SNX4	HGNC:11175	ENSG00000114520	O95219	Sorting nexin-4	gwas
SOD3	HGNC:11181	ENSG00000109610	P08294	Extracellular superoxide dismutase [Cu-Zn]	gwas
SORT1	HGNC:11186	ENSG00000134243	Q99523	Sortilin	gwas
SOX5	HGNC:11201	ENSG00000134532	P35711	Transcription factor SOX-5	gwas
SP4	HGNC:11209	ENSG00000105866	Q02446	Transcription factor Sp4	gwas
KLF9	HGNC:1123	ENSG00000119138	Q13886	Krueppel-like factor 9	gwas
SPTBN2	HGNC:11276	ENSG00000173898	O15020	Spectrin beta chain, non-erythrocytic 2	gwas
SRPK2	HGNC:11306	ENSG00000135250	P78362	SRSF protein kinase 2	gwas
WHR1	HGNC:11398	ENSG00000204344	P49842	Winged helix repair factor 1	gwas
TAF1B	HGNC:11533	ENSG00000115750	Q53T94	TATA box-binding protein-associated factor RNA polymerase I subunit B	gwas
TARS1	HGNC:11572	ENSG00000113407	P26639	Threonine–tRNA ligase 1, cytoplasmic	gwas
TBX15	HGNC:11594	ENSG00000092607	Q96SF7	T-box transcription factor TBX15	gwas
TCF19	HGNC:11629	ENSG00000137310	Q9Y242	Transcription factor 19	gwas
TCF20	HGNC:11631	ENSG00000100207	Q9UGU0	Transcription factor 20	gwas
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	gwas
TDO2	HGNC:11708	ENSG00000151790	P48775	Tryptophan 2,3-dioxygenase	clinvar
ELP4	HGNC:1171	ENSG00000109911	Q96EB1	Elongator complex protein 4	gwas
TFAP2B	HGNC:11743	ENSG00000008196	Q92481	Transcription factor AP-2-beta	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RGS6	Regulator of G-protein signaling 6	Regulates G protein-coupled receptor signaling cascades.
RGS7	Regulator of G-protein signaling 7	GTPase activator component of the RGS7-GNB5 complex that regulates G protein-coupled receptor signaling cascades.
RNGTT	mRNA-capping enzyme	Bifunctional mRNA-capping enzyme exhibiting RNA 5’-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part.
RORA	Nuclear receptor ROR-alpha	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
RPL38	Large ribosomal subunit protein eL38	Component of the large ribosomal subunit.
RPLP1	Large ribosomal subunit protein P1	Plays an important role in the elongation step of protein synthesis.
RSU1	Ras suppressor protein 1	Potentially plays a role in the Ras signal transduction pathway.
RTN1	Reticulon-1	Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
CNNM4	Metal transporter CNNM4	Probable metal transporter.
ATXN1	Ataxin-1	Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor.
ATXN7	Ataxin-7	Acts as a component of the SAGA (aka STAGA) transcription coactivator-HAT complex.
BLK	Tyrosine-protein kinase Blk	Non-receptor tyrosine kinase involved in B-lymphocyte development, differentiation and signaling.
SCG2	Secretogranin-2	Neuroendocrine protein of the granin family that regulates the biogenesis of secretory granules.
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
BMP2	Bone morphogenetic protein 2	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis.
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.
SF3B2	Splicing factor 3B subunit 2	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
SGCG	Gamma-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SH3BP4	SH3 domain-binding protein 4	May function in transferrin receptor internalization at the plasma membrane through a cargo-specific control of clathrin-mediated endocytosis.
SHMT2	Serine hydroxymethyltransferase, mitochondrial	Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis.
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
SLC18A1	Chromaffin granule amine transporter	Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles.
SLC1A3	Excitatory amino acid transporter 1	Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SLC24A3	Sodium/potassium/calcium exchanger 3	Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+).
SLC4A8	Electroneutral sodium bicarbonate exchanger 1	Mediates electroneutral sodium- and carbonate-dependent chloride-HCO3(-) exchange with a Na(+):HCO3(-) stoichiometry of 2:1.
SLC6A6	Sodium- and chloride-dependent taurine transporter	Mediates sodium- and chloride-dependent transport of taurine.
SLC6A7	Sodium-dependent proline transporter	Brain specific sodium (and chloride)-dependent proline transporter.
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SNX4	Sorting nexin-4	Involved in the regulation of endocytosis and in several stages of intracellular trafficking.
SOD3	Extracellular superoxide dismutase [Cu-Zn]	Protect the extracellular space from toxic effect of reactive oxygen intermediates by converting superoxide radicals into hydrogen peroxide and oxygen.
SORT1	Sortilin	Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface.
SOX5	Transcription factor SOX-5	Transcription factor involved in chondrocytes differentiation and cartilage formation.
SP4	Transcription factor Sp4	Binds to GT and GC boxes promoters elements.
KLF9	Krueppel-like factor 9	Transcription factor that binds to GC box promoter elements.
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.
SRPK2	SRSF protein kinase 2	Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains and is involved in the phosphorylation of SR splici…
WHR1	Winged helix repair factor 1	DNA-binding protein which is required for efficient transcription-coupled nucleotide excision repair (TC-NER).
TAF1B	TATA box-binding protein-associated factor RNA polymerase I subunit B	Component of RNA polymerase I core factor complex that acts as a GTF2B/TFIIB-like factor and plays a key role in multiple steps during transcription initiation such as pre-initiation complex (PIC) assembly and postpolymerase recruitment ev…
TARS1	Threonine–tRNA ligase 1, cytoplasmic	Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr).
TBX15	T-box transcription factor TBX15	Probable transcriptional regulator involved in the development of the skeleton of the limb, vertebral column and head.
TCF19	Transcription factor 19	Potential transcription factor that may play a role in the regulation of genes involved in cell cycle G1/S transition.
TCF20	Transcription factor 20	Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
TDO2	Tryptophan 2,3-dioxygenase	Heme-dependent dioxygenase that catalyzes the oxidative cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-tryptophan to N-formyl-L-kynurenine.
ELP4	Elongator complex protein 4	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
TFAP2B	Transcription factor AP-2-beta	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
TFEC	Transcription factor EC	Transcriptional regulator that acts as a repressor or an activator.
MPPED2	Metallophosphoesterase MPPED2	Displays low metallophosphoesterase activity (in vitro).

Protein-family classification

Druggable: 23 · Difficult: 19 · Unknown: 33 · Druggable fraction: 0.31

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
Nuclear receptor	1	5.2×	0.531
Kinase	5	1.9×	0.531
Enzyme (other)	10	1.6×	0.531
Transcription factor	13	1.4×	0.531
Scaffold/PPI	6	1.4×	0.638
Ion channel	1	1.5×	0.933
Phosphatase	1	1.1×	0.933
Transporter	1	1.0×	0.933
Antibody/Immunoglobulin	2	0.8×	0.977
Other/Unknown	33	0.8×	0.985
Protease	1	0.5×	0.985
GPCR	1	0.3×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RGS6	Other/Unknown	no		DEP_dom, G-protein_gamma-like_dom, RGS
RGS7	Other/Unknown	no		DEP_dom, G-protein_gamma-like_dom, RGS
RNGTT	Phosphatase	yes	2.7.7.50	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, mRNA_cap_enzyme_adenylation
SNORD48	Other/Unknown	no
SNORD52	Other/Unknown	no
RORA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
RPL38	Other/Unknown	no		Ribosomal_eL38, Ribosomal_eL38_sf
RPLP1	Other/Unknown	no		Ribosomal_P1/P2, P1/P2_N_sf
RSU1	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
RTN1	Other/Unknown	no		Reticulon, RTN1-4
CNNM4	Enzyme (other)	yes	7.2.2.14	cNMP-bd_dom, CBS_dom, CNNM
ATXN1	Other/Unknown	no		Ataxin_AXH_dom, Ataxin-1_N, Ataxin_AXH_dom_sf
ATXN7	Other/Unknown	no		SCA7_dom, Ataxin-7-like_regulator
BLK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
SCG2	Other/Unknown	no		Granin, Chromogranin_CS, ScgII
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SF3B2	Other/Unknown	no		SAP_dom, PSP_pro-rich, DUF382
SGCG	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta
SH3BP4	Scaffold/PPI	no		ZU5_dom, SH3_domain, SH3BP4_SH3
SHMT2	Enzyme (other)	yes	2.1.2.1	Ser_HO-MeTrfase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
SIM1	Transcription factor	no		PAS, PAC, SIM_C
SLC18A1	Transporter	yes		Tet-R_TetA/multi-R_MdtG-like, MFS, MFS_dom
SLC1A3	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SLC24A3	Other/Unknown	no		K/Na/Ca-exchanger, NaCa_Exmemb, NCX_ion-bd_dom_sf
SLC4A8	Other/Unknown	no		HCO3_transpt_euk, Na/HCO3_transpt, HCO3_transpt-like_TM_dom
SLC6A6	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_taurine, SNS_sf
SLC6A7	Other/Unknown	no		Na/ntran_symport, SNS_sf
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SNX4	Scaffold/PPI	no		PX_dom, AH/BAR_dom_sf, SNX4
SOD3	Enzyme (other)	yes	1.15.1.1	SOD_Cu_Zn_dom, SOD_Cu/Zn_BS, SOD_Cu/Zn_/chaperone
SORT1	Scaffold/PPI	no		VPS10, WD40/YVTN_repeat-like_dom_sf, Sortilin_C
SOX5	Transcription factor	no		HMG_box_dom, HMG_box_dom_sf, SOX/SOX-like_TF
SP4	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Sp4-like
KLF9	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
SPTBN2	Scaffold/PPI	no		Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom
SRPK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
WHR1	Other/Unknown	no		STK19-like
TAF1B	Transcription factor	no		TF_Rrn7_Zf, TAF1B/Rrn7, Rrn7_cyclin_C
TARS1	Enzyme (other)	yes	6.1.1.3	aa-tRNA-synt_IIb, Thr-tRNA-ligase_IIa, TGS
TBX15	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TCF19	Transcription factor	no		FHA_dom, Znf_PHD, SMAD_FHA_dom_sf
TCF20	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TDO2	Enzyme (other)	yes	1.13.11.11	Trp_2_3_dOase, Trp/Indoleamine_2_3_dOase-like
ELP4	Other/Unknown	no		Elongator_complex_protein_4, P-loop_NTPase
TFAP2B	Transcription factor	no		TF_AP2, TF_AP2_beta, TF_AP2_C

Expression context

Cohort genes with no expression data: 0.

68 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)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	10
calcaneal tendon	10
sural nerve	6
Brodmann (1909) area 23	5
male germ line stem cell (sensu Vertebrata) in testis	5
ventricular zone	5
primordial germ cell in gonad	5
endothelial cell	4
secondary oocyte	4
stromal cell of endometrium	4
buccal mucosa cell	4
adrenal tissue	4
monocyte	4
middle temporal gyrus	3
liver	3
lateral nuclear group of thalamus	3
oocyte	3
right adrenal gland	3
pons	3
skeletal muscle tissue of rectus abdominis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RGS6	185	broad	marker	cortical plate, sural nerve, middle temporal gyrus
RGS7	159	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
RNGTT	262	ubiquitous	marker	cardia of stomach, nipple, pylorus
SNORD48	74	tissue_specific	yes	sural nerve, vermiform appendix, liver
SNORD52	8	tissue_specific	yes	sural nerve, Brodmann (1909) area 9, liver
RORA	284	ubiquitous	marker	upper leg skin, lateral nuclear group of thalamus, skin of hip
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland
RPL38	295	ubiquitous	marker	calcaneal tendon, cortical plate, olfactory bulb
RPLP1	156	ubiquitous	marker	epithelium of bronchus, thymus, trachea
RSU1	290	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery
RTN1	270	broad	marker	Brodmann (1909) area 23, endothelial cell, pons
CNNM4	189	ubiquitous	marker	mucosa of transverse colon, rectum, ileal mucosa
ATXN1	295	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, skeletal muscle tissue of rectus abdominis
ATXN7	290	ubiquitous	marker	mucosa of paranasal sinus, jejunal mucosa, superficial temporal artery
BLK	145	tissue_specific	marker	spleen, male germ line stem cell (sensu Vertebrata) in testis, lymph node
SCG2	216	broad	marker	type B pancreatic cell, islet of Langerhans, lateral nuclear group of thalamus
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium
SF3B2	292	ubiquitous	marker	ventricular zone, left testis, right testis
SGCG	184	broad	marker	skeletal muscle tissue of rectus abdominis, gluteal muscle, triceps brachii
SH3BP4	274	ubiquitous	marker	parotid gland, trachea, mucosa of paranasal sinus
SHMT2	288	ubiquitous	marker	tendon of biceps brachii, cartilage tissue, right lobe of liver
SIM1	76	broad	yes	renal medulla, skeletal muscle tissue of biceps brachii, biceps brachii
SLC18A1	79	tissue_specific	marker	diaphragm, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
SLC1A3	273	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
SLC24A3	272	broad	marker	lateral nuclear group of thalamus, tongue squamous epithelium, saphenous vein
SLC4A8	219	ubiquitous	marker	pons, Brodmann (1909) area 23, superior vestibular nucleus
SLC6A6	265	ubiquitous	marker	mucosa of paranasal sinus, palpebral conjunctiva, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNF	11,116
BRAF	7,394
VARS1	5,848
SHMT2	5,293
ATXN1	4,465
SMARCA2	4,237
TSC2	4,135
DNAJC7	4,096
SF3B2	3,906
SRPK2	3,839

Intra-cohort edges

A	B	Sources
ATXN1	ATXN7	string_interaction
ATXN1	SPTBN2	string_interaction
ATXN1	TBX15	biogrid_interaction, intact
ATXN7	SPTBN2	string_interaction
ELP4	MPPED2	string_interaction
SCG2	TNF	intact
SLC1A3	SLC4A8	string_interaction
TARS1	VARS1	string_interaction
TBX15	TLE3	string_interaction
TBX15	WARS2	string_interaction
VARS1	WARS2	string_interaction

Structural data

PDB: 44 · AlphaFold-only: 29 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL38	P63173	188
BRAF	P15056	131
TNF	P01375	52
SF3B2	Q13435	50
SLC6A6	P31641	45
SMARCA2	P51531	32
SHMT2	P34897	27
TDO2	P48775	22
BMP2	P12643	21
SORT1	Q99523	17
VIPR1	P32241	17
TRAF3	Q13114	10
UBE2E2	Q96LR5	10
RNGTT	O60942	9
SLC1A3	P43003	9
SLC18A1	P54219	8
CNNM2	Q9H8M5	7
ATXN1	P54253	7
SCN8A	Q9UQD0	7
SLC6A7	Q99884	7
RGS7	P49802	5
RSU1	Q15404	5
ATXN7	O15265	5
WHR1	P49842	5
TARS1	P26639	5
TCF4	P15884	5
VRK2	Q86Y07	5
TRIO	O75962	4
RORA	P35398	3
RPLP1	P05386	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPPED2	Q15777	95.43
DNAJC7	Q99615	90.83
WNT11	O96014	90.35
EIPR1	Q53HC9	89.26
VARS1	P26640	88.12
SNX4	O95219	84.73
SEMA3A	Q14563	84.50
TLL2	Q9Y6L7	81.98
BLK	P51451	81.89
SGCG	Q13326	80.24
TAF1B	Q53T94	79.35
UNC5C	O95185	78.72
ELP4	Q96EB1	74.49
SLC24A3	Q9HC58	70.31
SH3BP4	Q9P0V3	70.15
TLE3	Q04726	68.65
TRIP11	Q15643	66.78
TFEC	O14948	63.79
KLF9	Q13886	63.69
TCF19	Q9Y242	63.17
TBX15	Q96SF7	61.41
SIM1	P81133	60.70
TOX3	O15405	60.22
SOX5	P35711	58.95
SCG2	P13521	58.07
TRPS1	Q9UHF7	49.12
RTN1	Q16799	48.88
SP4	Q02446	39.58
TCF20	Q9UGU0	39.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 538. Enrichment computed across 250 evidence-associated genes (155 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 155 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	3	22.1×	0.093	TFAP2B, WWOX, TFAP2D
Activation of the TFAP2 (AP-2) family of transcription factors	3	18.4×	0.093	TFAP2B, WWOX, TFAP2D
SLC-mediated transport of neurotransmitters	4	10.5×	0.093	SLC6A6, SLC6A7, SLC6A15, SLC17A6
Cell junction organization	5	6.0×	0.187	RSU1, CDH13, CDH18, CDH19, CDH8
NCAM signaling for neurite out-growth	4	7.0×	0.263	SPTBN2, CACNA1C, CACNA1I, CACNB2
Adherens junctions interactions	4	6.4×	0.263	CDH13, CDH18, CDH19, CDH8
Cell-cell junction organization	4	6.4×	0.263	CDH13, CDH18, CDH19, CDH8
Transcriptional regulation by RUNX1	5	4.7×	0.277	BLK, SMARCA2, CBX4, CCND2, CCNH
Cell-Cell communication	5	4.4×	0.320	RSU1, CDH13, CDH18, CDH19, CDH8
Generic Transcription Pathway	19	1.9×	0.363	RORA, BLK, BMP2, SMARCA2, TFAP2B, TIGAR, MED12, YWHAQ (+11 more)
SARS-CoV-2 modulates autophagy	2	13.4×	0.396	MAP1LC3B, VPS45
Presynaptic depolarization and calcium channel opening	2	12.3×	0.396	CACNB2, CACNA2D3
Positive Regulation of CDH1 Gene Transcription	2	12.3×	0.396	KLF9, FOXP2
Phase 0 - rapid depolarisation	3	6.7×	0.396	SCN8A, CACNA1C, CACNB2
RNA Polymerase II Transcription	14	2.0×	0.396	RNGTT, RORA, BLK, BMP2, SMARCA2, TFAP2B, TIGAR, MED12 (+6 more)
Defective SLC1A3 causes episodic ataxia 6 (EA6)	1	73.7×	0.406	SLC1A3
Defective B3GALTL causes PpS	3	6.0×	0.406	ADAMTS12, ADAMTSL1, ADAMTS19
Translation	7	2.8×	0.406	TARS1, VARS1, WARS2, MRPL14, MRPL33, MRPS33, MRPL48
O-glycosylation of TSR domain-containing proteins	3	5.8×	0.414	ADAMTS12, ADAMTSL1, ADAMTS19
Phase 2 - plateau phase	2	9.8×	0.439	CACNA1C, CACNB2
tRNA Aminoacylation	3	5.5×	0.439	TARS1, VARS1, WARS2
Regulation of Homotypic Cell-Cell Adhesion	2	8.7×	0.488	CDH19, CDH8
Regulation of Expression and Function of Type II Classical Cadherins	2	8.7×	0.488	CDH19, CDH8
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	2	8.7×	0.488	CACNA2D1, CACNB2
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	2	8.2×	0.503	TFAP2B, TFAP2D
NCAM1 interactions	3	4.8×	0.503	CACNA1C, CACNA1I, CACNB2
Modulation of host responses by IFN-stimulated genes	2	7.8×	0.506	IFI44, IFI44L
Mitochondrial translation	4	3.5×	0.506	MRPL14, MRPL33, MRPS33, MRPL48
Gene expression (Transcription)	15	1.7×	0.506	RNGTT, RORA, BLK, BMP2, SMARCA2, TAF1B, TFAP2B, TIGAR (+7 more)
R-HSA-425393	4	3.4×	0.567	SLC24A3, SLC4A8, SLC6A6, SLC6A15

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 223 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
calcium-dependent cell-cell adhesion	5	10.8×	0.058	NLGN1, CDH13, CDH18, CDH19, CDH8
negative regulation of fat cell differentiation	6	8.4×	0.058	RORA, BMP2, SORT1, TNF, TRIO, ZFPM2
positive regulation of synaptic vesicle exocytosis	2	75.6×	0.074	SLC4A8, NLGN1
negative regulation of mitophagy	3	20.6×	0.088	TIGAR, TSC2, FBXL4
regulation of transcription by RNA polymerase II	35	1.8×	0.088	RORA, ATXN7, SIM1, SMARCA2, SOX5, SP4, KLF9, TBX15 (+27 more)
calcium ion transmembrane transport via high voltage-gated calcium channel	2	50.4×	0.094	CACNA1C, CACNA2D1
membrane depolarization during atrial cardiac muscle cell action potential	2	50.4×	0.094	CACNA1C, CACNB2
positive regulation of synaptic transmission	3	15.1×	0.117	SLC1A3, TNF, SORCS3
adherens junction organization	4	9.2×	0.117	CDH13, CDH18, CDH19, CDH8
sodium ion transmembrane transport	6	5.5×	0.117	SCN8A, SLC24A3, SLC4A8, SLC6A6, SLC6A7, SLC6A15
membrane depolarization during AV node cell action potential	2	30.2×	0.165	CACNA1C, CACNB2
positive regulation of cartilage development	3	12.6×	0.165	BMP2, SOX5, SOX6
cell-cell junction assembly	4	8.0×	0.165	CDH13, CDH18, CDH19, CDH8
neurotransmitter transport	4	7.6×	0.170	SLC1A3, SLC6A6, SLC6A7, SLC6A15
cell-cell adhesion mediated by cadherin	4	7.4×	0.174	CDH13, CDH18, CDH19, CDH8
L-glutamate import	2	25.2×	0.200	SLC1A3, SLC17A6
regulation of odontogenesis of dentin-containing tooth	2	21.6×	0.211	BMP2, DMRT3
positive regulation of muscle contraction	2	21.6×	0.211	CACNA1C, CACNB2
negative regulation of cardiac muscle cell differentiation	2	21.6×	0.211	BMP2, SOX6
positive regulation of mesenchymal stem cell differentiation	2	21.6×	0.211	SOX5, SOX6
synaptic vesicle exocytosis	3	10.3×	0.211	BRAF, PCLO, RIMS1
cardiac muscle cell action potential involved in contraction	3	9.4×	0.217	SCN8A, CACNA1C, CACNA2D1
postsynaptic modulation of chemical synaptic transmission	3	9.1×	0.233	BRAF, TRIO, SORCS3
xylulose catabolic process	1	75.6×	0.236	XYLB
caudate nucleus development	1	75.6×	0.236	FOXP2
putamen development	1	75.6×	0.236	FOXP2
obsolete L-lysine catabolic process to acetyl-CoA via L-pipecolate	1	75.6×	0.236	PIPOX
90S preribosome assembly	1	75.6×	0.236	RPL38
neuromast hair cell development	1	75.6×	0.236	SLC44A4
regulation of pentose-phosphate shunt	1	75.6×	0.236	TIGAR

Therapeutics

Drugs indicated for this disease

14 approved, 36 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Agomelatine	Approved (phase 4)
Aripiprazole	Approved (phase 4)
Brexpiprazole	Approved (phase 4)
Bupropion	Approved (phase 4)
Citalopram	Approved (phase 4)
Desipramine	Approved (phase 4)
Desvenlafaxine	Approved (phase 4)
Escitalopram	Approved (phase 4)
Isocarboxazid	Approved (phase 4)
Mirtazapine	Approved (phase 4)
Olanzapine	Approved (phase 4)
Paroxetine	Approved (phase 4)
Selegiline	Approved (phase 4)
Sertraline	Approved (phase 4)
Amibegron	Phase 3 (in late-stage trials)
Amitriptyline	Phase 3 (in late-stage trials)
Aprepitant	Phase 3 (in late-stage trials)
Aticaprant	Phase 3 (in late-stage trials)
Buprenorphine	Phase 3 (in late-stage trials)
Cariprazine	Phase 3 (in late-stage trials)
Creatine	Phase 3 (in late-stage trials)
Dexmecamylamine	Phase 3 (in late-stage trials)
Doconexent	Phase 3 (in late-stage trials)
Duloxetine	Phase 3 (in late-stage trials)
Edivoxetine	Phase 3 (in late-stage trials)
Esmethadone	Phase 3 (in late-stage trials)
Fluoxetine	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
Idazoxan	Phase 3 (in late-stage trials)
Insulin Human	Phase 3 (in late-stage trials)
Ketamine	Phase 3 (in late-stage trials)
Liothyronine	Phase 3 (in late-stage trials)
Liraglutide	Phase 3 (in late-stage trials)
Lumateperone	Phase 3 (in late-stage trials)
Lurasidone	Phase 3 (in late-stage trials)
Methylphenidate	Phase 3 (in late-stage trials)
Mifepristone	Phase 3 (in late-stage trials)
Modafinil	Phase 3 (in late-stage trials)
Navacaprant	Phase 3 (in late-stage trials)
Pimavanserin	Phase 3 (in late-stage trials)
Pipamperone	Phase 3 (in late-stage trials)
Psilocybin	Phase 3 (in late-stage trials)
Quetiapine	Phase 3 (in late-stage trials)
Rapastinel	Phase 3 (in late-stage trials)
Risperidone	Phase 3 (in late-stage trials)
Saredutant	Phase 3 (in late-stage trials)
Seltorexant	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Toludesvenlafaxine	Phase 3 (in late-stage trials)
Vortioxetine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): AV-101, Ademetionine, Aspirin, Azetukalner, Buspirone, Casopitant, Centanafadine, Chlordiazepoxide, Clavulanic Acid, Corn Oil, Curcumin, Cycloserine, Dasotraline, Dextromethorphan, Empagliflozin, Ezogabine, Fish Oil, Fosfocreatine, Gaboxadol, Ibuprofen, Ixekizumab, Losmapimod, Maltodextrin, Mecamylamine, Melatonin, Metyrapone, Microcrystalline Cellulose, Midazolam, Minocycline, Naltrexone, Naluzotan, Niacin, Nitrous Oxide, OMEGA-3 FATTY ACIDS, OMEGA-3-ACID ETHYL ESTERS, Onabotulinumtoxina, Pentoxifylline, Pindolol, Pioglitazone, Pramipexole, Quinidine, Riluzole, Scopolamine, Semaglutide, Sirukumab, Tasimelteon, Tocilizumab, Tramadol, Ulotaront, Vasopressin, Ziprasidone.

Drug target analysis

Approved (phase 4): 12 · Phase ≥3: 15 · Phased (≥1): 23 · Undrugged: 52

Druggability breadth: 76 of 250 evidence-associated genes (30%) 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
RORA	TRETINOIN
RPL38	GENTAMICIN SULFATE
RPLP1	GENTAMICIN SULFATE
BLK	AFATINIB
SCN8A	IMIPRAMINE
SHMT2	OXAPROZIN
SLC18A1	RESERPINE
BRAF	VEMURAFENIB
SRPK2	FEDRATINIB
TDO2	BERBERINE
TNF	PREDNISOLONE
VRK2	RUXOLITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BLK	62	4
BRAF	48	4
SCN8A	25	4
TNF	12	4
SRPK2	11	4
SHMT2	7	4
VRK2	4	4
TDO2	3	4
RORA	2	4
SLC1A3	2	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TRETINOIN	4	RORA
GENTAMICIN SULFATE	4	RPL38, RPLP1
AFATINIB	4	BLK
FEDRATINIB	4	BLK, BRAF, SRPK2
AXITINIB	4	BLK
SORAFENIB	4	BLK, BRAF
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK, BRAF
BOSUTINIB	4	BLK, VRK2
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK, BRAF
NINTEDANIB	4	BLK, SRPK2
SUNITINIB	4	BLK, SRPK2
DASATINIB	4	BLK, BRAF, VRK2
ERLOTINIB	4	BLK, BRAF
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK, SRPK2
GEFITINIB	4	BLK, BRAF
IMATINIB	4	BLK, BRAF
IMIPRAMINE	4	SCN8A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
BLK	483	Binding:477, ADMET:4, Functional:2
SMARCA2	311	Binding:274, Functional:25, ADMET:12
SRPK2	221	Binding:221
TNF	193	Binding:162, Functional:31
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
TDO2	152	Binding:152
VRK2	146	Binding:146
RORA	115	Binding:111, Functional:3, Unclassified:1
RPL38	90	Binding:90
RPLP1	90	Binding:90
VIPR1	83	Binding:71, Functional:12
TARS1	53	Binding:53
SLC1A3	47	Binding:38, Functional:9
WHR1	36	Binding:36
TCF4	31	Binding:31
BMP2	22	Binding:18, Functional:4
SF3B2	20	Binding:20
SORT1	17	Binding:15, ADMET:2
DNAJC7	7	Binding:7
VARS1	7	Binding:7
RNGTT	6	Binding:6
SHMT2	6	Binding:6
TAF1B	6	Binding:6
MED12	6	Binding:6
ATXN7	5	Binding:5
SLC6A6	5	Binding:4, Functional:1
TLL2	5	Binding:5
SOD3	3	Binding:3
SLC18A1	2	Functional:1, Binding:1
SLC6A7	2	Binding:2
TRIO	2	Binding:2
RSU1	1	Binding:1
TIGAR	1	Binding:1
TSC2	1	Binding:1
UBE2H	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNGTT	2.7.7.50, 3.6.1.74	mRNA guanylyltransferase, mRNA 5’-phosphatase
CNNM4	7.2.2.14	P-type Mg2+ transporter
BLK	2.7.10.2	non-specific protein-tyrosine kinase
SHMT2	2.1.2.1	glycine hydroxymethyltransferase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
SOD3	1.15.1.1	superoxide dismutase
TARS1	6.1.1.3	threonine-tRNA ligase
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
TDO2	1.13.11.11, 1.13.11.52	tryptophan 2,3-dioxygenase, indoleamine 2,3-dioxygenase
UBE2E2	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
UBE2G1	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
UBE2H	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
VARS1	6.1.1.9	valine-tRNA ligase
WARS2	6.1.1.2	tryptophan-tRNA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RORA	115
BLK	483
SCN8A	173
BRAF	1,442
SMARCA2	311
SRPK2	221
TDO2	152
TNF	193
VRK2	146

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; 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)
TRETINOIN	4	RORA
GENTAMICIN SULFATE	4	RPL38, RPLP1
AFATINIB	4	BLK
FEDRATINIB	4	BLK, BRAF, SRPK2
AXITINIB	4	BLK
SORAFENIB	4	BLK, BRAF
NERATINIB	4	BLK
IBRUTINIB	4	BLK
ENTRECTINIB	4	BLK
BELUMOSUDIL	4	BLK
AFATINIB DIMALEATE	4	BLK
VANDETANIB	4	BLK
NILOTINIB	4	BLK, BRAF
BOSUTINIB	4	BLK, VRK2
BRIGATINIB	4	BLK
ACALABRUTINIB	4	BLK
ZANUBRUTINIB	4	BLK
TIRABRUTINIB	4	BLK
RITLECITINIB	4	BLK
PAZOPANIB	4	BLK, BRAF
NINTEDANIB	4	BLK, SRPK2
SUNITINIB	4	BLK, SRPK2
DASATINIB	4	BLK, BRAF, VRK2
ERLOTINIB	4	BLK, BRAF
QUIZARTINIB	4	BLK
CRIZOTINIB	4	BLK
MIDOSTAURIN	4	BLK, SRPK2
GEFITINIB	4	BLK, BRAF
IMATINIB	4	BLK, BRAF
IMIPRAMINE	4	SCN8A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	12	RORA, RPL38, RPLP1, BLK, SCN8A, SHMT2, SLC18A1, BRAF, SRPK2, TDO2 (+2 more)
B	Phased (≥1) drug, not yet approved	11	RNGTT, SF3B2, SLC1A3, SLC6A6, SMARCA2, SORT1, TAF1B, TCF4, MED12, DNAJC7 (+1 more)
C	Druggable family + PDB, no drug	8	CNNM4, SOD3, TARS1, TRIO, UBE2E2, UBE2G1, UBE2H, WARS2
D	Druggable family + AlphaFold only, no drug	4	SEMA3A, TLL2, UNC5C, VARS1
E	Difficult family or no structure, no drug	40	RGS6, RGS7, SNORD48, SNORD52, CNNM2, RSU1, RTN1, ATXN1, ATXN7, SCG2 (+30 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RGS6	0	—
RGS7	0	—
SNORD48	0	—
SNORD52	0	—
CNNM2	0	—
RSU1	1	—
RTN1	0	—
CNNM4	0	—
ATXN1	0	—
ATXN7	5	—
SCG2	0	—
BMP2	22	—
SEMA3A	0	—
SGCG	0	—
SH3BP4	0	—
SIM1	0	—
SLC24A3	0	—
SLC4A8	0	—
SLC6A7	2	—
SNX4	0	—
SOD3	3	—
SOX5	0	—
SP4	0	—
KLF9	0	—
SPTBN2	0	—
WHR1	36	—
TARS1	53	—
TBX15	0	—
TCF19	0	—
TCF20	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2,270.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	298
PHASE3	293
PHASE4	271
PHASE1	119
PHASE1/PHASE2	46
PHASE2/PHASE3	40
EARLY_PHASE1	23
Not specified	10

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02129751	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Bupropion Hydrobromide in Adolescents and Children With Major Depressive Disorder
NCT02752542	PHASE4	RECRUITING	Personalized Indications for CBT and Antidepressants in Treating Depression
NCT05004987	PHASE4	RECRUITING	Aβ Dynamics in LLMD
NCT05017311	PHASE4	RECRUITING	Optimized Predictive Treatment In Medications for Unipolar Major Depression (OPTIMUM-D)
NCT05273996	PHASE4	ACTIVE_NOT_RECRUITING	Predictors of Cognitive Outcomes in Geriatric Depression
NCT05450432	PHASE4	RECRUITING	Long-Term Maintenance With Ketamine and Esketamine for Reduction of Suicide in High-Risk Patients With Depression
NCT05892744	PHASE4	RECRUITING	Establishing Multimodal Brain Biomarkers for Treatment Selection in Depression
NCT05950711	PHASE4	ACTIVE_NOT_RECRUITING	Ketamine-Assisted Mindfulness-Based Cognitive Therapy for Depression: A Pilot Study
NCT06103760	PHASE4	RECRUITING	Positioning of Esketamine Treatment in the Real-world Management of Depression
NCT06213324	PHASE4	RECRUITING	Neural Circuit Effects of Ketamine in Depression
NCT06223880	PHASE4	RECRUITING	A Study to Evaluate the Efficacy of AXS-05 Compared to Bupropion in Preventing the Relapse of Depressive Symptoms
NCT06417437	PHASE4	RECRUITING	Non-invasive BCI and Application Verification for Depressed People
NCT06426485	PHASE4	NOT_YET_RECRUITING	To Evaluate the Long-term Efficacy and Safety of Toludevenlafaxine Hydrochloride Sustained-release Tablets
NCT06580041	PHASE4	ENROLLING_BY_INVITATION	Precision Care for Major Depressive Disorder
NCT06610305	PHASE4	RECRUITING	Ovarian Hormone Withdrawal, Anhedonia, and Reward Sensitivity in Women With Premenstrual Exacerbations of Depression
NCT06644833	PHASE4	NOT_YET_RECRUITING	Effective of Transcranial Magnetic Stimulation (TMS) vs Treatment as Usual for First-Episode Depression in Adults
NCT06675851	PHASE4	RECRUITING	Reward-specific Changes of the Chemical Messenger Dopamine in the Brain of Healthy and Depressed People
NCT06699966	PHASE4	NOT_YET_RECRUITING	Stony Brook Medicine Anti-Inflammatory Trial
NCT06749470	PHASE4	NOT_YET_RECRUITING	A Randomized, Double-blind, Placebo-controlled, Multicenter Clinical Study on the Treatment of Depression with Jieyu Chufan Capsules
NCT07011693	PHASE4	NOT_YET_RECRUITING	Switching Medication and Augmentation Strategies for SSRI-Resistant Adolescent Depression（SMART-I)
NCT07076342	PHASE4	RECRUITING	The Role of mGluR5 in CBT-I
NCT07095205	PHASE4	RECRUITING	PET Imaging Using the Tracer [18F]VAT to Assess the Antidepressant Effect of Nicotine.
NCT07105111	PHASE4	RECRUITING	A Study to Evaluate the Effectiveness of Valbenazine in Adult Participants With Tardive Dyskinesia (TD) Who Remain Symptomatic While Receiving or After Stopping a Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor
NCT07136714	PHASE4	RECRUITING	Does Semaglutide Improve Depressive Symptoms in Patients With Major Depressive Disorder and Overweight or Obesity
NCT07139106	PHASE4	NOT_YET_RECRUITING	Understanding the Role of the Kappa Opioid Receptor in Ketamine’s Attenuation of Suicidal Thoughts
NCT07266545	PHASE4	RECRUITING	RNA Editing as a Biomarker of Antidepressant Response in Unipolar and Bipolar Depression (EDIT-ANDRE)
NCT07555743	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Daridorexant in Patients With Major Depressive Disorder and Insomnia
NCT00000375	PHASE4	COMPLETED	Continuation Electroconvulsive Therapy Vs Medication to Prevent Relapses in Patients With Major Depressive Disorder
NCT00049972	PHASE4	COMPLETED	Major Depressive Disorder Study In Adults
NCT00157547	PHASE4	COMPLETED	Quantitative EEG (QEEG) as a Predictor of Treatment Outcome in Depression
NCT00166114	PHASE4	COMPLETED	Depression, Epinephrine, and Platelet Function
NCT00177996	PHASE4	COMPLETED	Pharmacotherapy in Depression With Panic Spectrum
NCT00178074	PHASE4	COMPLETED	The Effects of Sleep Deprivation on Antidepressant Response
NCT00178100	PHASE4	COMPLETED	Paroxetine and Interpersonal Psychotherapy for Maintaining Health and Well-being in Elderly Individuals With Depression
NCT00182533	PHASE4	TERMINATED	Sertraline in Generalized Social Phobia With Co-Occurring Anxiety and Mood Disorders
NCT00186446	PHASE4	COMPLETED	Treatment of Nicotine Dependence and Acute Depression
NCT00188942	PHASE4	COMPLETED	A Neuroimaging Investigation of Brain Activity in Major Depressive Disorder and Bipolar Disorder
NCT00191932	PHASE4	COMPLETED	Switching to Duloxetine From Other Antidepressants
NCT00203723	PHASE4	TERMINATED	Use of Risperidone in ECT for Treatment Resistant Depression
NCT00208169	PHASE4	COMPLETED	Abilify Therapy for Reducing Comorbid Substance Abuse

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ESCITALOPRAM	4	116
FLUOXETINE	4	84
BUPROPION	4	63
CITALOPRAM	4	62
VENLAFAXINE	4	56
SERTRALINE	4	44
VILAZODONE	4	40
PAROXETINE	4	37
DULOXETINE	4	34
VORTIOXETINE	4	32
DESVENLAFAXINE	4	29
CARIPRAZINE	4	21
KETAMINE	4	20
QUETIAPINE	4	19
BREXPIPRAZOLE	4	18
AMITRIPTYLINE	4	12
AGOMELATINE	4	11
MIRTAZAPINE	4	10
APREPITANT	4	9
CYCLOSERINE	4	8
ARIPIPRAZOLE	4	7
ZURANOLONE	4	6
LEVOMILNACIPRAN	4	5
LUMATEPERONE	4	5
NITROUS OXIDE	4	5
DEXTROMETHORPHAN	4	4
DEXTROMETHORPHAN HYDROBROMIDE	4	4
MIFEPRISTONE	4	4
MODAFINIL	4	4
PRAMIPEXOLE	4	4