Type 2 diabetes mellitus

Summary

Type 2 diabetes mellitus (MONDO:0005148) is a disease (an umbrella term covering 6 Mondo subtypes) caused by GCK (GenCC Strong), with 74 cohort genes (8,831 GWAS associations across 339 studies) and 8,209 clinical trials. The dominant Reactome pathway is IRS activation (4 cohort genes). Top therapeutic interventions include insulin glargine, vildagliptin, and rosiglitazone.

At a glance

• Causal gene: GCK (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 74
• GWAS associations: 8,831
• ClinVar variants: 2,207
• Clinical trials: 8,209

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	type 2 diabetes mellitus
Mondo ID	MONDO:0005148
MeSH	D003924
OMIM	125853
DOID	DOID:9352
ICD-10-CM	E11
ICD-11	119724091
NCIT	C26747
SNOMED CT	44054006
UMLS	C0011860
MedGen	41523
Is cancer (heuristic)	no

Also known as: adult onset diabetes · adult-onset diabetes · diabetes mellitis type 2 · diabetes mellitis type II · diabetes mellitus, noninsulin-dependent · diabetes mellitus, noninsulin-dependent, 2 · diabetes mellitus, noninsulin-dependent, association with · diabetes mellitus, noninsulin-dependent, late onset · diabetes mellitus, type 2 · diabetes mellitus, type II · diabetes, type 2 · insulin resistance, severe, digenic · NIDDM · non-insulin dependent diabetes · non-insulin dependent diabetes mellitus · noninsulin dependent diabetes · noninsulin-dependent diabetes mellitus · T2D · T2DM · T2DM - type 2 diabetes mellitus (+5 more)

Data availability: 2,207 ClinVar variants · 8,831 GWAS associations (339 studies) · 10 GenCC gene-disease records · 4,431 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › pancreas disorder › endocrine pancreas disorder › diabetes mellitus › type 2 diabetes mellitus

Related subtypes (7): type 1 diabetes mellitus, gestational diabetes, maternally-inherited diabetes and deafness, diabetic ketoacidosis, monogenic diabetes, type 5 diabetes mellitus, cystic fibrosis-related diabetes

Subtypes (6): lipoatrophic diabetes, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, diabetes mellitus, noninsulin-dependent, 3, diabetes mellitus, noninsulin-dependent, 4, diabetes mellitus, noninsulin-dependent, 5

Genetics & variants

GWAS landscape

8,831 GWAS associations across 339 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7903146	1e-219	TCF7L2	T	0.3
rs34872471	1e-94	TCF7L2	C	1.42
rs2237896	3e-70	KCNQ1	G	1.33
rs10811661	2e-68	CDKN2B-AS1	C	0.17
rs2237892	2e-63	KCNQ1	T	0.21
rs7756992	6e-62	CDKAL1	G	0.13
rs7651090	4e-57	IGF2BP2	G	0.12
rs7754840	2e-56	CDKAL1	C	0.13
rs3802177	2e-52	SLC30A8	A	0.12
rs7901695	1e-48	TCF7L2	C	1.37
rs7185735	2e-47	FTO	G	0.11
rs1470579	1e-45	IGF2BP2	C	0.13
rs849135	1e-43	JAZF1	G	0.1
rs13266634	4e-42	SLC30A8	T	0.11
rs7923866	9e-40	Y_RNA - EXOC6	T	0.1
rs8050136	3e-39	FTO	A	0.11
rs1111875	6e-39	HHEX - Y_RNA	T	0.1
rs35612982	6e-36	CDKAL1	C	1.21
rs2972144	3e-34	NYAP2 - MIR5702	A	0.09
rs1801214	6e-34	WFS1	C	0.09
rs2383208	5e-33	CDKN2B-AS1	A	1.22
rs76895963	2e-31	CCND2-AS1, CCND2	?
rs10811660	3e-31	CDKN2B-AS1	?
rs10830963	6e-30	MTNR1B	G	0.09
rs11257655	3e-29	CDC123 - RN7SL198P	T	0.09
rs11708067	6e-29	ADCY5	G	0.1
rs17334919	7e-28	THADA	T	0.14
rs1552224	9e-25	ARAP1	C	0.1
rs1899951	2e-24	PPARG	T	0.11
rs4402960	2e-23	IGF2BP2	T	1.13

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002352	Mahajan A	2014	12,171	56,862	Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
GCST002560	Ng MC	2014	8,284	15,543	Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.
GCST000712	Voight BF	2010	8,130	38,987	Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
GCST001351	Cho YS	2011	5,999	9,001	Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.
GCST002128	Hara K	2013	5,976	20,829	Genome-wide association study identifies three novel loci for type 2 diabetes.
GCST001213	Kooner JS	2011	5,561	14,458	Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
GCST000167	Zeggini E	2008	4,549	5,579	Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
GCST001461	Imamura M	2012	4,470	3,071	A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations.
GCST000787	Yamauchi T	2010	4,470	3,071	A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B.
GCST002317	Williams AL	2013	3,848	4,366	Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	44

MAF distribution

Bucket	Variants
common (>=0.05)	50
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	36
intergenic_variant	7
missense_variant	4
3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7903146	10	112998590	C>G,T	0.292	intron_variant	TCF7L2		Tier 4: intronic/intergenic
rs34872471	10	112994312	T>C	0.05	intron_variant	TCF7L2	1e-94	Tier 4: intronic/intergenic
rs2237896	11	2837210	G>A,T	0.05	intron_variant	KCNQ1	3e-70	Tier 4: intronic/intergenic
rs10811661	9	22134095	T>A,C	0.168	intergenic_variant	CDKN2B-AS1	2e-68	Tier 4: intronic/intergenic
rs2237892	11	2818521	C>T	0.063	intron_variant	KCNQ1	2e-63	Tier 4: intronic/intergenic
rs7756992	6	20679478	A>G,T	0.267	intron_variant	CDKAL1	6e-62	Tier 4: intronic/intergenic
rs7651090	3	185795604	A>C,G,T	0.313	intron_variant	IGF2BP2	4e-57	Tier 4: intronic/intergenic
rs7754840	6	20661019	G>A,C,T	0.318	intron_variant	CDKAL1	2e-56	Tier 4: intronic/intergenic
rs3802177	8	117172786	G>A,C,T	0.311	3_prime_UTR_variant	SLC30A8	2e-52	Tier 2: splice/UTR
rs7901695	10	112994329	T>C	0.05	intron_variant	TCF7L2	1e-48	Tier 4: intronic/intergenic
rs7185735	16	53788739	A>G,T	0.397	intron_variant	FTO	2e-47	Tier 4: intronic/intergenic
rs1470579	3	185811292	A>C	0.304	intron_variant	IGF2BP2	1e-45	Tier 4: intronic/intergenic
rs849135	7	28156794	G>A	0.499	intron_variant	JAZF1	1e-43	Tier 4: intronic/intergenic
rs13266634	8	117172544	C>A,T	0.283	missense_variant	SLC30A8	4e-42	Tier 1: coding
rs7923866	10	92722319	C>G,T	0.379	intergenic_variant	Y_RNA - EXOC6	9e-40	Tier 4: intronic/intergenic
rs8050136	16	53782363	C>A	0.413	intron_variant	FTO	3e-39	Tier 4: intronic/intergenic
rs1111875	10	92703125	C>G,T	0.424	intron_variant	HHEX - Y_RNA	6e-39	Tier 4: intronic/intergenic
rs35612982	6	20682391	T>A,C	0.05	intron_variant	CDKAL1	6e-36	Tier 4: intronic/intergenic
rs2972144	2	226236695	A>C,G,T	0.355	intergenic_variant	NYAP2 - MIR5702	3e-34	Tier 4: intronic/intergenic
rs1801214	4	6301295	C>A,G,T	0.4	missense_variant	WFS1	6e-34	Tier 1: coding
rs2383208	9	22132077	A>G,T	0.05	intergenic_variant	CDKN2B-AS1	5e-33	Tier 4: intronic/intergenic
rs76895963	12	4275678	T>C,G	0.05	non_coding_transcript_exon_variant	CCND2-AS1, CCND2	2e-31	Tier 4: intronic/intergenic
rs10811660	9	22134069	G>A,C,T	0.05	intergenic_variant	CDKN2B-AS1	3e-31	Tier 4: intronic/intergenic
rs10830963	11	92975544	C>G,T	0.276	intron_variant	MTNR1B	6e-30	Tier 4: intronic/intergenic
rs11257655	10	12265895	C>A,T	0.227	regulatory_region_variant	CDC123 - RN7SL198P	3e-29	Tier 3: regulatory
rs11708067	3	123346931	A>G	0.239	intron_variant	ADCY5	6e-29	Tier 4: intronic/intergenic
rs17334919	2	43480246	C>T	0.1	intron_variant	THADA	7e-28	Tier 4: intronic/intergenic
rs1552224	11	72722053	A>C,G,T	0.154	intron_variant	ARAP1	9e-25	Tier 4: intronic/intergenic
rs1899951	3	12353341	C>G,T	0.123	intron_variant	PPARG	2e-24	Tier 4: intronic/intergenic
rs4402960	3	185793899	G>C,T	0.325	intron_variant	IGF2BP2	2e-23	Tier 4: intronic/intergenic

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

259 uncertain significance, 105 likely benign, 93 conflicting classifications of pathogenicity, 38 pathogenic/likely pathogenic, 34 benign/likely benign, 31 pathogenic, 20 benign, 10 likely pathogenic, 5 uncertain significance/uncertain risk allele, 2 protective, 1 pathogenic/likely pathogenic/likely risk allele, 1 association not found, 1 likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065990	NM_000352.6(ABCC8):c.4297G>A (p.Gly1433Ser)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069205	NM_000352.6(ABCC8):c.1617T>A (p.Tyr539Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1071311	NM_000352.6(ABCC8):c.1332G>T (p.Gln444His)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071339	NM_000352.6(ABCC8):c.2252_2253dup (p.Ser752fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076249	NM_000352.6(ABCC8):c.1647del (p.Ile550fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098777	NM_000352.6(ABCC8):c.4288del (p.Leu1430fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179142	NM_000352.6(ABCC8):c.1893del (p.Gln632fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1323821	NM_000352.6(ABCC8):c.494C>A (p.Ser165Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338472	NM_000352.6(ABCC8):c.2473C>T (p.Arg825Trp)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1338676	NM_000352.6(ABCC8):c.805del (p.Ala269fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361635	NM_000352.6(ABCC8):c.696G>A (p.Trp232Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1371056	NM_000352.6(ABCC8):c.2266G>T (p.Glu756Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1390642	NM_000352.6(ABCC8):c.45C>G (p.Tyr15Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1396217	NM_000352.6(ABCC8):c.56del (p.Gln19fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453604	NM_000352.6(ABCC8):c.817del (p.Gln273fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457730	NM_000352.6(ABCC8):c.3988+2T>C	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459964	NM_000352.6(ABCC8):c.502C>T (p.Arg168Cys)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1506182	NM_000352.6(ABCC8):c.4544C>T (p.Thr1515Met)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526015	NM_000352.6(ABCC8):c.61del (p.Val21fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
157696	NM_000352.6(ABCC8):c.3509del (p.Leu1170fs)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1705703	NM_000352.6(ABCC8):c.2800C>T (p.Gln934Ter)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1878337	NM_000352.6(ABCC8):c.1630+1G>A	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188836	NM_000352.6(ABCC8):c.4628T>C (p.Leu1543Pro)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188864	NM_000352.6(ABCC8):c.2797C>T (p.Arg933Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188894	NM_000352.6(ABCC8):c.3124_3126delinsCAGCCAGGAACTG (p.Thr1042fs)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188905	NM_000352.6(ABCC8):c.2857C>T (p.Gln953Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188915	NM_000352.6(ABCC8):c.2506C>T (p.Arg836Ter)	ABCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188931	NM_000352.6(ABCC8):c.4411G>A (p.Asp1471Asn)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
196880	NM_000352.6(ABCC8):c.4160_4162del (p.Phe1387del)	ABCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1179191	NM_006208.3(ENPP1):c.2344C>T (p.Arg782Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 85 · Orphanet: 110 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 24

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

Gene	HGNC	Evidence routes
WFS1	WFS1	GWAS, GenCC, Orphanet
SLC30A8	SLC30A8	GWAS, GenCC
GCK	GCK	GWAS, GenCC, Orphanet
ABCC8	ABCC8	GWAS, GenCC, Orphanet
SLC2A2	SLC2A2	GWAS, Orphanet
HNF1A	HNF1A	GWAS, Orphanet
HNF1B	HNF1B	GWAS, Orphanet
TCF7L2	TCF7L2	GWAS, Orphanet
KSR2	KSR2	GWAS
CDKAL1	CDKAL1	GWAS
PDHX	PDHX	GWAS, Orphanet
PTF1A	PTF1A	GWAS, Orphanet
INS-IGF2	INS-IGF2	GWAS
GLP1R	GLP1R	GWAS
HMGA1	HMGA1	GWAS, GenCC
HNF4A	HNF4A	GWAS, Orphanet
INS	INS	GWAS, Orphanet
INSR	INSR	GWAS, Orphanet
IRS1	IRS1	GWAS
IRS2	IRS2	GWAS
KCNJ11	KCNJ11	GWAS, Orphanet
PAX4	PAX4	GWAS, Orphanet
PPARG	PPARG	GWAS, Orphanet
STAT3	STAT3	GWAS, Orphanet

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
ABCC8	Definitive	Semidominant	diabetes mellitus	32
GCK	Definitive	Autosomal dominant	maturity-onset diabetes of the young type 2	18
AKT2	Strong	Autosomal dominant	diabetes mellitus, noninsulin-dependent	8
HMGA1	Limited	Autosomal dominant	type 2 diabetes mellitus
MAPK8IP1	Limited	Autosomal dominant	diabetes mellitus, noninsulin-dependent	2
PPP1R3A	Limited	Unknown	diabetes mellitus, noninsulin-dependent	3
SLC30A8	Limited	Autosomal dominant	type 2 diabetes mellitus
TGM2	Limited	Autosomal dominant	type 2 diabetes mellitus
WFS1	Limited	Unknown	type 2 diabetes mellitus	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
GCK	Orphanet:552	MODY
GCK	Orphanet:79299	Congenital glucokinase-related hyperinsulinism
GCK	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus
SLC2A2	Orphanet:2088	Fanconi-Bickel syndrome
HNF1A	Orphanet:319303	Chromophobe renal cell carcinoma
HNF1A	Orphanet:324575	Hyperinsulinism due to HNF1A deficiency
HNF1A	Orphanet:404511	Clear cell papillary renal cell carcinoma
HNF1A	Orphanet:552	MODY
HNF1B	Orphanet:1309	Medullary sponge kidney
HNF1B	Orphanet:1331	Familial prostate cancer
HNF1B	Orphanet:2578	Mayer-Rokitansky-Küster-Hauser syndrome type 2
HNF1B	Orphanet:261265	17q12 microdeletion syndrome
HNF1B	Orphanet:93111	HNF1B-related autosomal dominant tubulointerstitial kidney disease
HNF1B	Orphanet:93172	Renal dysplasia, unilateral
HNF1B	Orphanet:93173	Renal dysplasia, bilateral
HNF1B	Orphanet:97363	Unilateral multicystic dysplastic kidney
HNF1B	Orphanet:97364	Bilateral multicystic dysplastic kidney
TCF7L2	Orphanet:528084	Non-specific syndromic intellectual disability
PDHX	Orphanet:255182	Pyruvate dehydrogenase E3-binding protein deficiency
PTF1A	Orphanet:2805	Partial pancreatic agenesis
PTF1A	Orphanet:65288	Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
AKT2	Orphanet:293964	Hypoinsulinemic hypoglycemia and body hemihypertrophy
AKT2	Orphanet:79085	AKT2-related familial partial lipodystrophy
HNF4A	Orphanet:263455	Congenital hyperinsulinism due to HNF4A deficiency
HNF4A	Orphanet:544628	Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome
HNF4A	Orphanet:552	MODY
INS	Orphanet:552	MODY
INS	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
INSR	Orphanet:2297	Insulin-resistance syndrome type A
INSR	Orphanet:263458	Hyperinsulinism due to INSR deficiency
INSR	Orphanet:508	Donohue syndrome
INSR	Orphanet:769	Rabson-Mendenhall syndrome
KCNJ11	Orphanet:276580	Autosomal dominant hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:276603	Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:552	MODY
KCNJ11	Orphanet:79134	DEND syndrome
KCNJ11	Orphanet:79644	Autosomal recessive hyperinsulinism due to Kir6.2 deficiency
KCNJ11	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
KCNJ11	Orphanet:99886	Transient neonatal diabetes mellitus

Cohort genes → proteins

74 cohort genes, 74 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	44
gwas_and_gencc	1
gwas_and_clinvar	18
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	gwas,gencc,clinvar
SLC30A8	HGNC:20303	ENSG00000164756	Q8IWU4	Proton-coupled zinc antiporter SLC30A8	gwas,gencc,clinvar
GCK	HGNC:4195	ENSG00000106633	P35557	Hexokinase-4	gwas,gencc,clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gwas,gencc,clinvar
SLC2A2	HGNC:11006	ENSG00000163581	P11168	Solute carrier family 2, facilitated glucose transporter member 2	gwas,clinvar
HNF1A	HGNC:11621	ENSG00000135100	P20823	Hepatocyte nuclear factor 1-alpha	gwas,clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gwas,clinvar
TCF7L2	HGNC:11641	ENSG00000148737	Q9NQB0	Transcription factor 7-like 2	gwas,clinvar
KSR2	HGNC:18610	ENSG00000171435	Q6VAB6	Kinase suppressor of Ras 2	gwas,clinvar
CDKAL1	HGNC:21050	ENSG00000145996	Q5VV42	Threonylcarbamoyladenosine tRNA methylthiotransferase	gwas,clinvar
PDHX	HGNC:21350	ENSG00000110435	O00330	Pyruvate dehydrogenase protein X component, mitochondrial	gwas,clinvar
PTF1A	HGNC:23734	ENSG00000168267	Q7RTS3	Pancreas transcription factor 1 subunit alpha	gwas,clinvar
INS-IGF2	HGNC:33527	ENSG00000129965	F8WCM5	Insulin, isoform 2	gwas,clinvar
AKT2	HGNC:392	ENSG00000105221	P31751	RAC-beta serine/threonine-protein kinase	gencc,clinvar
GLP1R	HGNC:4324	ENSG00000112164	P43220	Glucagon-like peptide 1 receptor	gwas,clinvar
HMGA1	HGNC:5010	ENSG00000137309	P17096	High mobility group protein HMG-I/HMG-Y	gwas,gencc
HNF4A	HGNC:5024	ENSG00000101076	P41235	Hepatocyte nuclear factor 4-alpha	gwas,clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	gwas,clinvar
INSR	HGNC:6091	ENSG00000171105	P06213	Insulin receptor	gwas,clinvar
IRS1	HGNC:6125	ENSG00000169047	P35568	Insulin receptor substrate 1	gwas,clinvar
IRS2	HGNC:6126	ENSG00000185950	Q9Y4H2	Insulin receptor substrate 2	gwas,clinvar
KCNJ11	HGNC:6257	ENSG00000187486	Q14654	ATP-sensitive inward rectifier potassium channel 11	gwas,clinvar
MAPK8IP1	HGNC:6882	ENSG00000121653	Q9UQF2	C-Jun-amino-terminal kinase-interacting protein 1	gencc,clinvar
PAX4	HGNC:8618	ENSG00000106331	O43316	Paired box protein Pax-4	gwas,clinvar
PPARG	HGNC:9236	ENSG00000132170	P37231	Peroxisome proliferator-activated receptor gamma	gwas,clinvar
PPP1R3A	HGNC:9291	ENSG00000154415	Q16821	Protein phosphatase 1 regulatory subunit 3A	gencc,clinvar
TGM2	HGNC:11778	ENSG00000198959	P21980	Protein-glutamine gamma-glutamyltransferase 2	gencc
BCL6	HGNC:1001	ENSG00000113916	P41182	B-cell lymphoma 6 protein	gwas
PCGF3	HGNC:10066	ENSG00000185619	Q3KNV8	Polycomb group RING finger protein 3	gwas
RNF6	HGNC:10069	ENSG00000127870	Q9Y252	E3 ubiquitin-protein ligase RNF6	gwas
RNF7	HGNC:10070	ENSG00000114125	Q9UBF6	RING-box protein 2	gwas
BCL9	HGNC:1008	ENSG00000116128	O00512	B-cell CLL/lymphoma 9 protein	gwas
ROBO2	HGNC:10250	ENSG00000185008	Q9HCK4	Roundabout homolog 2	gwas
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	gwas
BDNF	HGNC:1033	ENSG00000176697	P23560	Neurotrophic factor BDNF precursor form	gwas
BECN1	HGNC:1034	ENSG00000126581	Q14457	Beclin-1	gwas
RREB1	HGNC:10449	ENSG00000124782	Q92766	Ras-responsive element-binding protein 1	gwas
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	gwas
ATXN7	HGNC:10560	ENSG00000163635	O15265	Ataxin-7	gwas
SCTR	HGNC:10608	ENSG00000080293	P47872	Secretin receptor	gwas
SDC4	HGNC:10661	ENSG00000124145	P31431	Syndecan-4	clinvar
SFRP2	HGNC:10777	ENSG00000145423	Q96HF1	Secreted frizzled-related protein 2	gwas
ACHE	HGNC:108	ENSG00000087085	P22303	Acetylcholinesterase	gwas
SGCG	HGNC:10809	ENSG00000102683	Q13326	Gamma-sarcoglycan	gwas
SHB	HGNC:10838	ENSG00000107338	Q15464	SH2 domain-containing adapter protein B	gwas
ST6GAL1	HGNC:10860	ENSG00000073849	P15907	Beta-galactoside alpha-2,6-sialyltransferase 1	gwas
SIX3	HGNC:10889	ENSG00000138083	O95343	Homeobox protein SIX3	gwas
SLC18A2	HGNC:10935	ENSG00000165646	Q05940	Synaptic vesicular amine transporter	gwas
SLC1A2	HGNC:10940	ENSG00000110436	P43004	Excitatory amino acid transporter 2	gwas
SLC22A2	HGNC:10966	ENSG00000112499	O15244	Solute carrier family 22 member 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
SLC30A8	Proton-coupled zinc antiporter SLC30A8	Proton-coupled zinc ion antiporter mediating the entry of zinc into the lumen of pancreatic beta cell secretory granules, thereby regulating insulin secretion.
GCK	Hexokinase-4	Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively).
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
SLC2A2	Solute carrier family 2, facilitated glucose transporter member 2	Facilitative hexose transporter that mediates the transport of glucose, fructose and galactose.
HNF1A	Hepatocyte nuclear factor 1-alpha	Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
TCF7L2	Transcription factor 7-like 2	Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.
KSR2	Kinase suppressor of Ras 2	Location-regulated scaffold connecting MEK to RAF.
CDKAL1	Threonylcarbamoyladenosine tRNA methylthiotransferase	Catalyzes the methylthiolation of N6-threonylcarbamoyladenosine (t(6)A), leading to the formation of 2-methylthio-N6-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 in tRNAs that read codons beginning with adenine.
PDHX	Pyruvate dehydrogenase protein X component, mitochondrial	Required for anchoring dihydrolipoamide dehydrogenase (E3) to the dihydrolipoamide transacetylase (E2) core of the pyruvate dehydrogenase complexes of eukaryotes.
PTF1A	Pancreas transcription factor 1 subunit alpha	Transcription factor implicated in the cell fate determination in various organs.
AKT2	RAC-beta serine/threonine-protein kinase	Serine/threonine kinase closely related to AKT1 and AKT3.
GLP1R	Glucagon-like peptide 1 receptor	G-protein coupled receptor for glucagon-like peptide 1 (GLP-1).
HMGA1	High mobility group protein HMG-I/HMG-Y	HMG-I/Y bind preferentially to the minor groove of A+T rich regions in double-stranded DNA.
HNF4A	Hepatocyte nuclear factor 4-alpha	Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes.
INS	Insulin	Insulin decreases blood glucose concentration.
INSR	Insulin receptor	Receptor tyrosine kinase which mediates the pleiotropic actions of insulin.
IRS1	Insulin receptor substrate 1	Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R.
IRS2	Insulin receptor substrate 2	Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R.
KCNJ11	ATP-sensitive inward rectifier potassium channel 11	Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells.
MAPK8IP1	C-Jun-amino-terminal kinase-interacting protein 1	The JNK-interacting protein (JIP) group of scaffold proteins selectively mediates JNK signaling by aggregating specific components of the MAPK cascade to form a functional JNK signaling module.
PAX4	Paired box protein Pax-4	Plays an important role in the differentiation and development of pancreatic islet beta cells.
PPARG	Peroxisome proliferator-activated receptor gamma	Ligand-activated transcription factor that forms obligate heterodimers with the retinoic acid receptor and acts as a key regulator of biological processes, such as adipocyte differentiation, lipid metabolism, glucose homeostasis and beta-o…
PPP1R3A	Protein phosphatase 1 regulatory subunit 3A	Seems to act as a glycogen-targeting subunit for PP1.
TGM2	Protein-glutamine gamma-glutamyltransferase 2	Calcium-dependent acyltransferase that catalyzes the formation of covalent bonds between peptide-bound glutamine and various primary amines, such as gamma-amino group of peptide-bound lysine, or mono- and polyamines, thereby producing cros…
BCL6	B-cell lymphoma 6 protein	Transcriptional repressor mainly required for germinal center (GC) formation and antibody affinity maturation which has different mechanisms of action specific to the lineage and biological functions.
PCGF3	Polycomb group RING finger protein 3	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
RNF6	E3 ubiquitin-protein ligase RNF6	E3 ubiquitin-protein ligase mediating ‘Lys-48’-linked polyubiquitination of LIMK1 and its subsequent targeting to the proteasome for degradation.
RNF7	RING-box protein 2	Catalytic component of multiple cullin-5-RING E3 ubiquitin-protein ligase complexes (ECS complexes), which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
BCL9	B-cell CLL/lymphoma 9 protein	Involved in signal transduction through the Wnt pathway.
ROBO2	Roundabout homolog 2	Receptor for SLIT2, and probably SLIT1, which are thought to act as molecular guidance cue in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neu…
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
BDNF	Neurotrophic factor BDNF precursor form	Important signaling molecule that activates signaling cascades downstream of NTRK2.
BECN1	Beclin-1	Plays a central role in autophagy.
RREB1	Ras-responsive element-binding protein 1	Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
ATXN7	Ataxin-7	Acts as a component of the SAGA (aka STAGA) transcription coactivator-HAT complex.
SCTR	Secretin receptor	G protein-coupled receptor activated by secretin (SCT), which is involved in different processes such as regulation of the pH of the duodenal content, food intake and water homeostasis.
SDC4	Syndecan-4	Cell surface proteoglycan which regulates exosome biogenesis in concert with SDCBP and PDCD6IP.
SFRP2	Secreted frizzled-related protein 2	Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts.
ACHE	Acetylcholinesterase	Hydrolyzes rapidly the acetylcholine neurotransmitter released into the synaptic cleft allowing to terminate the signal transduction at the neuromuscular junction.
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.
SHB	SH2 domain-containing adapter protein B	Adapter protein which regulates several signal transduction cascades by linking activated receptors to downstream signaling components.
ST6GAL1	Beta-galactoside alpha-2,6-sialyltransferase 1	Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substrates.
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.
SLC18A2	Synaptic vesicular amine transporter	Electrogenic antiporter that exchanges one cationic monoamine with two intravesicular protons across the membrane of secretory and synaptic vesicles.
SLC1A2	Excitatory amino acid transporter 2	Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate.
SLC22A2	Solute carrier family 22 member 2	Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics.
SLC22A3	Solute carrier family 22 member 3	Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics.

Protein-family classification

Druggable: 26 · Difficult: 23 · Unknown: 25 · Druggable fraction: 0.35

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
Transporter	7	7.4×	5e-04
Transcription factor	18	2.0×	0.015
Nuclear receptor	2	10.4×	0.047
Kinase	7	2.6×	0.047
Ion channel	1	1.5×	0.893
Scaffold/PPI	5	1.2×	0.893
Antibody/Immunoglobulin	2	0.8×	0.962
Enzyme (other)	4	0.7×	0.962
GPCR	2	0.7×	0.962
Protease	1	0.5×	0.962
Other/Unknown	25	0.6×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
SLC30A8	Other/Unknown	no		Cation_efflux, Cation_efflux_TMD_sf, Cation_efflux_CTD
GCK	Kinase	yes	2.7.1.1	Hexokinase, Hexokinase_BS, Hexokinase_N
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
SLC2A2	Transporter	yes		Glc_transpt_2, Sugar/inositol_transpt, MFS_sugar_transport-like
HNF1A	Transcription factor	no		HD, HNF1b_C, HNF1a_C
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
TCF7L2	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
KSR2	Kinase	yes	2.7.11.25	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
CDKAL1	Other/Unknown	no		TRAM_dom, Methylthiotransferase, MiaB-like_arc_euk
PDHX	Enzyme (other)	yes	1.2.1.104	Biotin_lipoyl, 2-oxoacid_DH_actylTfrase, 2-oxoA_DH_lipoyl-BS
PTF1A	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
INS-IGF2	Other/Unknown	no		Insulin, Insulin-like, Insulin-like_sf
AKT2	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
GLP1R	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_GLP1/glucagon_rcpt
HMGA1	Other/Unknown	no		HMGA, HMGI/Y_DNA-bd_CS, AT_hook_DNA-bd_motif
HNF4A	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
INSR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
IRS1	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
IRS2	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
KCNJ11	Ion channel	yes		K_chnl_inward-rec_Kir6.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
MAPK8IP1	Scaffold/PPI	no		SH3_domain, PTB/PI_dom, PH-like_dom_sf
PAX4	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
PPARG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PPP1R3A	Other/Unknown	no		CBM21_dom, CBM21_dom_sf, PP1_regulatory_subunit_3
TGM2	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
BCL6	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
PCGF3	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RNF6	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, RING_finger_E3_ligase
RNF7	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_H2
BCL9	Transcription factor	no		Znf_RING/FYVE/PHD, Bcl-9/Bcl-9l, BCL9_beta-catenin-bd_dom
ROBO2	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
BDNF	Other/Unknown	no		Nerve_growth_factor-rel, Nerve_growth_factor_CS, Nerve_growth_factor-like
BECN1	Other/Unknown	no		Atg6/Beclin, BH3_dom, Atg6/Beclin_C_sf
RREB1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, RREB1
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
ATXN7	Other/Unknown	no		SCA7_dom, Ataxin-7-like_regulator
SCTR	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_secretin_rcpt
SDC4	Other/Unknown	no		Syndecan, Neurexin-like, Syndecan/Neurexin_dom
SFRP2	Other/Unknown	no		Netrin_domain, TIMP-like_OB-fold, Frizzled/SFRP
ACHE	Enzyme (other)	yes	3.1.1.7	Cholinesterase, CarbesteraseB, AChE_tetra
SGCG	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta
SHB	Scaffold/PPI	no		SH2, SHB_SH2, SH2_dom_sf
ST6GAL1	Enzyme (other)	yes	2.4.99.1	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SIX3	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
SLC18A2	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
SLC1A2	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
SLC22A2	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS

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)	73
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	7
ganglionic eminence	6
hindlimb stylopod muscle	6
right hemisphere of cerebellum	5
gastrocnemius	5
ventricular zone	5
pancreas	4
jejunal mucosa	4
right lobe of liver	4
Brodmann (1909) area 23	4
buccal mucosa cell	4
body of pancreas	4
type B pancreatic cell	4
cartilage tissue	4
cortical plate	4
monocyte	4
cerebellar hemisphere	3
liver	3
endothelial cell	3
skeletal muscle tissue of rectus abdominis	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
SLC30A8	117	tissue_specific	marker	islet of Langerhans, pancreas, epithelial cell of pancreas
GCK	155	tissue_specific	marker	pituitary gland, adenohypophysis, islet of Langerhans
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
SLC2A2	80	tissue_specific	marker	right lobe of liver, liver, jejunal mucosa
HNF1A	81	tissue_specific	yes	right lobe of liver, mucosa of transverse colon, liver
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
TCF7L2	291	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pancreatic ductal cell
KSR2	114	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
CDKAL1	201	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, ganglionic eminence
PDHX	296	ubiquitous	marker	biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii
PTF1A	96	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
INS-IGF2	20	broad	marker	islet of Langerhans, pancreas, body of pancreas
AKT2	272	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, right lobe of thyroid gland
GLP1R	117	tissue_specific	marker	islet of Langerhans, type B pancreatic cell, pancreatic ductal cell
HMGA1	286	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, cartilage tissue
HNF4A	110	tissue_specific	marker	right lobe of liver, mucosa of transverse colon, duodenum
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
INSR	296	ubiquitous	marker	buccal mucosa cell, palpebral conjunctiva, visceral pleura
IRS1	293	ubiquitous	marker	endometrium epithelium, skeletal muscle tissue of rectus abdominis, tibia
IRS2	290	ubiquitous	marker	decidua, CA1 field of hippocampus, postcentral gyrus
KCNJ11	161	broad	yes	gastrocnemius, hindlimb stylopod muscle, muscle of leg
MAPK8IP1	179	broad	marker	C1 segment of cervical spinal cord, right frontal lobe, adenohypophysis
PAX4	32	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, cerebellar vermis, Brodmann (1909) area 10
PPARG	194	ubiquitous	marker	omental fat pad, peritoneum, adipose tissue of abdominal region
PPP1R3A	79	tissue_specific	yes	skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii
TGM2	255	ubiquitous	marker	type B pancreatic cell, right coronary artery, left coronary artery
BCL6	300	ubiquitous	marker	gastrocnemius, mucosa of stomach, blood
PCGF3	286	ubiquitous	marker	sural nerve, left ovary, lower esophagus mucosa
RNF6	294	ubiquitous	marker	bronchial epithelial cell, epithelium of nasopharynx, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 87.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
STAT3	10,108
PPARG	7,747
BRAF	7,394
BDNF	5,587
SYK	5,172
BECN1	4,924
HNF4A	4,731
INSR	4,446
IRS1	4,337

Intra-cohort edges

A	B	Sources
ABCC8	GCK	string_interaction
ABCC8	HMGA1	intact
ABCC8	HNF1A	string_interaction
ABCC8	INS	string_interaction
ABCC8	KCNJ11	biogrid_interaction, intact, string_interaction
ABCC8	PAX4	string_interaction
ABCC8	SLC2A2	string_interaction
ABCC8	SLC30A8	string_interaction
ABCC8	WFS1	string_interaction
AKT2	INS	string_interaction
AKT2	IRS1	string_interaction
AKT2	SLC2A4	string_interaction
ATXN7	SUMO2	biogrid_interaction
ATXN7	TAF12	intact
BCL6	HNF1A	intact
BCL9	HNF1B	intact
BCL9	HNF4A	string_interaction
BCL9	TCF7L2	intact
BDNF	SLC6A4	string_interaction
BDNF	SORT1	biogrid_interaction, intact, string_interaction
BECN1	IRS1	string_interaction
BRAF	GCK	intact
BRAF	KSR2	intact, string_interaction
BRAF	SPRY2	string_interaction
CDKAL1	HNF1B	string_interaction
CDKAL1	KCNJ11	string_interaction
CDKAL1	SLC1A2	biogrid_interaction
CDKAL1	SLC30A8	string_interaction
CDKAL1	TCF7L2	string_interaction
CDKAL1	WFS1	intact, string_interaction
GCK	HNF1A	string_interaction
GCK	HNF1B	string_interaction
GCK	INS	string_interaction
GCK	KCNJ11	string_interaction
GCK	SLC2A2	string_interaction
GLP1R	INS	string_interaction
GLP1R	TCF7L2	string_interaction
HMGA1	PPARG	biogrid_interaction
HNF1A	HNF1B	biogrid_interaction, intact, string_interaction
HNF1A	HNF4A	string_interaction
HNF1A	INS	string_interaction
HNF1A	KCNJ11	string_interaction
HNF1A	PAX4	string_interaction
HNF1A	PTF1A	string_interaction
HNF1A	STAT3	biogrid_interaction
HNF1B	HNF4A	string_interaction
HNF1B	PAX4	string_interaction
HNF4A	SREBF1	biogrid_interaction
HNF4A	TCF7L2	string_interaction
INS	INSR	intact, string_interaction

Structural data

PDB: 59 · AlphaFold-only: 15 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
PPARG	P37231	380
BCL6	P41182	246
BRAF	P15056	131
SYK	P43405	93
INSR	P06213	88
ACHE	P22303	79
GLP1R	P43220	70
GCK	P35557	35
TAF12	Q16514	34
SLC18A2	Q05940	32
BECN1	Q14457	31
SLC6A4	P31645	30
MAPK8IP1	Q9UQF2	27
SUMO2	P61956	25
AKT2	P31751	19
SORT1	Q99523	17
TGM2	P21980	13
KSR2	Q6VAB6	9
KCNJ11	Q14654	9
ABCC8	Q09428	8
HNF4A	P41235	8
IRS1	P35568	8
BCL9	O00512	8
RNF7	Q9UBF6	7
SACS	Q9NZJ4	7
SLC1A2	P43004	7
HNF1A	P20823	6
ROBO2	Q9HCK4	6
ROR2	Q01974	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC2A2	P11168	86.56
PCGF3	Q3KNV8	85.76
CDKAL1	Q5VV42	82.72
SFRP2	Q96HF1	82.34
SGCG	Q13326	80.24
SYN2	Q92777	75.24
TCEA3	O75764	74.57
WFS1	O76024	73.85
SIX3	O95343	70.38
PAX4	O43316	70.35
TCF19	Q9Y242	63.17
PTF1A	Q7RTS3	61.81
SHB	Q15464	60.27
RNF6	Q9Y252	49.92
RREB1	Q92766	48.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 880. Enrichment computed across 250 evidence-associated genes (172 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 172 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
IRS activation	4	53.1×	2e-04	INS, INSR, IRS1, IRS2
Signaling by Insulin receptor	5	25.5×	3e-04	AKT2, INS, INSR, IRS1, IRS2
Regulation of gene expression in beta cells	6	18.1×	3e-04	GCK, SLC2A2, HNF1A, AKT2, HNF4A, INS
Signaling by Receptor Tyrosine Kinases	15	4.5×	3e-04	AKT2, INS, INSR, IRS1, IRS2, BDNF, SHB, BRAF (+7 more)
Negative regulation of the PI3K/AKT network	7	11.3×	3e-04	AKT2, INS, INSR, IRS1, IRS2, BDNF, CD86
Diseases of signal transduction by growth factor receptors and second messengers	14	4.6×	3e-04	TCF7L2, KSR2, AKT2, IRS1, IRS2, BDNF, BRAF, STAT3 (+6 more)
Insulin receptor signalling cascade	5	19.5×	5e-04	AKT2, INS, INSR, IRS1, IRS2
PI3K/AKT Signaling in Cancer	6	12.8×	6e-04	AKT2, IRS1, IRS2, BDNF, CD86, CDKN1B
Disease	31	2.4×	6e-04	ABCC8, TCF7L2, KSR2, AKT2, IRS1, IRS2, KCNJ11, BDNF (+23 more)
Signal Transduction	36	2.1×	8e-04	TCF7L2, KSR2, AKT2, INS, INSR, IRS1, IRS2, BCL9 (+28 more)
Signal attenuation	4	24.1×	0.001	INS, INSR, IRS1, IRS2
Intracellular signaling by second messengers	10	5.3×	0.001	AKT2, INS, INSR, IRS1, IRS2, BDNF, CAMK2G, CAMKK2 (+2 more)
Cytokine Signaling in Immune system	15	3.6×	0.001	AKT2, IRS1, IRS2, BCL6, BECN1, STAT3, SYK, TGFB1 (+7 more)
Signaling by FGFR1	4	19.0×	0.003	BRAF, SPRY2, TGFBR3, SPRED2
FOXO-mediated transcription	5	9.8×	0.008	AKT2, INS, BCL6, SREBF1, CDKN1B
IGF1R signaling cascade	3	24.9×	0.010	AKT2, IRS1, IRS2
Defective ABCC8 can cause hypo- and hyper-glycemias	2	66.4×	0.011	ABCC8, KCNJ11
Neurotransmitter clearance	3	22.1×	0.011	ACHE, SLC22A2, SLC6A4
Signaling by PTK6	4	12.7×	0.011	STAT3, CCND1, ARAP1, CDKN1B
Signaling by Non-Receptor Tyrosine Kinases	4	12.7×	0.011	STAT3, CCND1, ARAP1, CDKN1B
Interleukin-4 and Interleukin-13 signaling	8	4.8×	0.011	BCL6, STAT3, TGFB1, TWIST1, VEGFA, CCND1, CD36, RHOU
MAPK1/MAPK3 signaling	7	5.3×	0.013	KSR2, IRS1, IRS2, BRAF, SPTB, CAMK2G, SPRED2
IRS-mediated signalling	3	18.1×	0.017	AKT2, IRS1, IRS2
IRS-related events triggered by IGF1R	3	18.1×	0.017	AKT2, IRS1, IRS2
Signaling by Leptin	3	18.1×	0.017	IRS1, IRS2, STAT3
TGFBR3 expression	4	10.6×	0.017	TCF12, TCF4, TGFBR3, TNRC6A
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	3	16.6×	0.022	AKT2, IRS1, IRS2
Deactivation of the beta-catenin transactivating complex	5	6.8×	0.026	TCF7L2, AKT2, BCL9, TLE1, TLE4
Aberrant regulation of mitotic G1/S transition in cancer due to RB1 defects	3	15.3×	0.026	CCND1, CCND2, CDKN1B
Regulation of insulin secretion	5	6.4×	0.031	ABCC8, SLC2A2, INS, KCNJ11, CD36

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 232 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of gene expression	25	4.2×	3e-06	HNF1B, INS, PPARG, BRAF, SLC6A4, SOX11, SPRY2, STAT3 (+17 more)
glucose homeostasis	13	7.3×	3e-05	WFS1, GCK, HNF1A, TCF7L2, HNF4A, INS, INSR, IRS1 (+5 more)
positive regulation of glycogen biosynthetic process	6	25.6×	5e-05	GCK, AKT2, INS, INSR, IRS1, IRS2
cellular response to insulin stimulus	10	7.3×	5e-04	GCK, AKT2, INSR, IRS1, IRS2, PPARG, SLC2A4, LPIN1 (+2 more)
cellular response to low-density lipoprotein particle stimulus	5	19.1×	0.002	PPARG, SYK, TGFB1, CASR, CD36
histamine uptake	3	54.5×	0.002	SLC18A2, SLC22A2, SLC22A3
positive regulation of fatty acid beta-oxidation	4	26.4×	0.002	AKT2, IRS1, IRS2, TWIST1
serotonin uptake	4	26.4×	0.002	SLC18A2, SLC22A2, SLC22A3, SLC6A4
positive regulation of D-glucose import across plasma membrane	6	11.8×	0.002	AKT2, INS, INSR, IRS1, IRS2, SLC1A2
insulin receptor signaling pathway	8	7.7×	0.002	AKT2, INS, INSR, IRS1, IRS2, SREBF1, PHIP, SH2B2
negative regulation of transcription by RNA polymerase II	31	2.4×	0.002	WFS1, HNF1B, TCF7L2, PPARG, BCL6, RREB1, SOX11, SREBF1 (+23 more)
positive regulation of transcription by RNA polymerase II	34	2.2×	0.002	HNF1A, TCF7L2, HMGA1, HNF4A, PPARG, BCL9, RREB1, SFRP2 (+26 more)
regulation of transcription by RNA polymerase II	40	2.0×	0.002	HNF1A, HNF1B, TCF7L2, PTF1A, HNF4A, PAX4, PPARG, PCGF3 (+32 more)
pancreas development	5	14.5×	0.003	WFS1, HNF1A, HNF1B, TCF7L2, PTF1A
response to glucose	7	7.7×	0.004	SLC30A8, GCK, HNF1B, TCF7L2, HNF4A, IRS2, SREBF1
fat cell differentiation	8	6.2×	0.005	TCF7L2, AKT2, PPARG, SREBF1, TFAP2B, CCND1, FITM2, ARID5B
transport across blood-brain barrier	8	6.2×	0.005	INSR, SLC1A2, SLC22A2, SLC22A3, SLC2A4, TFRC, ATP8A1, SLC13A3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	4.0×	0.005	TCF7L2, INS, INSR, IRS1, IRS2, BECN1, SPRY2, TGFB1 (+4 more)
lipid homeostasis	6	8.7×	0.006	HNF4A, IRS2, PPARG, TM6SF2, ZBTB20, FITM2
positive regulation of glucose metabolic process	3	31.1×	0.008	AKT2, IRS1, IRS2
positive regulation of DNA-templated transcription	21	2.5×	0.009	HNF1A, HNF1B, HMGA1, HNF4A, INSR, PPARG, RNF6, RREB1 (+13 more)
Wnt signaling pathway	10	4.3×	0.011	ROR2, TLE1, TLE4, TNKS, CCN4, WNT5A, WNT7B, WWOX (+2 more)
obsolete D-glucose import	4	14.5×	0.012	SLC2A2, HNF1A, SLC2A4, SORT1
positive regulation of tumor necrosis factor production	8	5.3×	0.012	ABCC8, STAT3, SYK, TGFB1, TWIST1, WNT5A, ZBTB20, CD36
response to xenobiotic stimulus	12	3.6×	0.012	ABCC8, KCNJ11, BECN1, SFRP2, SLC1A2, SLC6A4, SREBF1, TFAP2B (+4 more)
negative regulation of DNA-templated transcription	19	2.6×	0.012	TCF7L2, HMGA1, HNF4A, PPARG, BCL6, SFRP2, SIX3, MLX (+11 more)
positive regulation of brain-derived neurotrophic factor receptor signaling pathway	2	72.6×	0.013	BDNF, SLC2A4
regulation of growth rate	2	72.6×	0.013	WRN, BNIPL
insulin secretion	5	9.3×	0.013	SLC30A8, HNF1A, HNF1B, SREBF1, CAMK2G
neurotransmitter transport	5	9.1×	0.014	SLC18A2, SLC1A2, SLC22A2, SLC22A3, SLC6A4

Therapeutics

Drugs indicated for this disease

39 approved, 107 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acarbose	Approved (phase 4)
Albiglutide	Approved (phase 4)
Bexagliflozin	Approved (phase 4)
Biotin	Approved (phase 4)
Chlorpropamide	Approved (phase 4)
Cyanocobalamin	Approved (phase 4)
Dapagliflozin	Approved (phase 4)
Dulaglutide	Approved (phase 4)
Empagliflozin	Approved (phase 4)
Exenatide	Approved (phase 4)
Fenofibrate	Approved (phase 4)
Fenofibric Acid	Approved (phase 4)
Finerenone	Approved (phase 4)
Folic Acid	Approved (phase 4)
Glimepiride	Approved (phase 4)
Glipizide	Approved (phase 4)
Glyburide	Approved (phase 4)
Insulin Detemir	Approved (phase 4)
Insulin Glargine	Approved (phase 4)
Insulin Human	Approved (phase 4)
Insulin Icodec	Approved (phase 4)
Irbesartan	Approved (phase 4)
Linagliptin	Approved (phase 4)
Liraglutide	Approved (phase 4)
Lixisenatide	Approved (phase 4)
Miglitol	Approved (phase 4)
Nateglinide	Approved (phase 4)
OMEGA-3-ACID ETHYL ESTERS	Approved (phase 4)
Pyridoxine	Approved (phase 4)
Repaglinide	Approved (phase 4)
Rosiglitazone	Approved (phase 4)
Semaglutide	Approved (phase 4)
Sotagliflozin	Approved (phase 4)
Ticagrelor	Approved (phase 4)
Tirzepatide	Approved (phase 4)
Tolazamide	Approved (phase 4)
Tolbutamide	Approved (phase 4)
Tyrosine	Approved (phase 4)
Vildagliptin	Approved (phase 4)
Aleglitazar	Phase 3 (in late-stage trials)
Allopurinol	Phase 3 (in late-stage trials)
Alogliptin	Phase 3 (in late-stage trials)
Amlodipine	Phase 3 (in late-stage trials)
Anagliptin	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Atorvastatin	Phase 3 (in late-stage trials)
Avexitide	Phase 3 (in late-stage trials)
Azilsartan	Phase 3 (in late-stage trials)
Balaglitazone	Phase 3 (in late-stage trials)
Benazepril	Phase 3 (in late-stage trials)
Berberine	Phase 3 (in late-stage trials)
Biguanide	Phase 3 (in late-stage trials)
Bosentan	Phase 3 (in late-stage trials)
Cagrilintide	Phase 3 (in late-stage trials)
Candesartan	Phase 3 (in late-stage trials)
Candesartan Cilexetil	Phase 3 (in late-stage trials)
Carvedilol	Phase 3 (in late-stage trials)
Chiglitazar	Phase 3 (in late-stage trials)
Chlorothiazide	Phase 3 (in late-stage trials)
Chlorthalidone	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Choline Alfoscerate	Phase 3 (in late-stage trials)
DBPR-108	Phase 3 (in late-stage trials)
Diltiazem	Phase 3 (in late-stage trials)
Dorzagliatin	Phase 3 (in late-stage trials)
Dutogliptin	Phase 3 (in late-stage trials)
Ecnoglutide	Phase 3 (in late-stage trials)
Efpeglenatide	Phase 3 (in late-stage trials)
Enavogliflozin	Phase 3 (in late-stage trials)
Ertugliflozin	Phase 3 (in late-stage trials)
Evogliptin	Phase 3 (in late-stage trials)
Ezetimibe	Phase 3 (in late-stage trials)
Fasiglifam	Phase 3 (in late-stage trials)
Felodipine	Phase 3 (in late-stage trials)
Furosemide	Phase 3 (in late-stage trials)
Gemigliptin	Phase 3 (in late-stage trials)
Gliclazide	Phase 3 (in late-stage trials)
Gosogliptin	Phase 3 (in late-stage trials)
Henagliflozin	Phase 3 (in late-stage trials)
Heparin	Phase 3 (in late-stage trials)
Heparin Sodium	Phase 3 (in late-stage trials)
Hydralazine	Phase 3 (in late-stage trials)
Hydrochlorothiazide	Phase 3 (in late-stage trials)
Indapamide	Phase 3 (in late-stage trials)
Insulin Aspart	Phase 3 (in late-stage trials)
Insulin Degludec	Phase 3 (in late-stage trials)
Insulin Efsitora Alfa	Phase 3 (in late-stage trials)
Insulin Glulisine	Phase 3 (in late-stage trials)
Insulin Lispro	Phase 3 (in late-stage trials)
Insulin Peglispro	Phase 3 (in late-stage trials)
Insulin Pork	Phase 3 (in late-stage trials)
Insulin Susp Isophane Beef	Phase 3 (in late-stage trials)
Insulin Susp Isophane Recombinant Human	Phase 3 (in late-stage trials)
Insulin Susp Isophane Semisynthetic Purified Human	Phase 3 (in late-stage trials)
Ipragliflozin	Phase 3 (in late-stage trials)
Ipragliflozin L-Proline	Phase 3 (in late-stage trials)
JT-001	Phase 3 (in late-stage trials)
Lactose, Anhydrous	Phase 3 (in late-stage trials)
Lapaquistat Acetate	Phase 3 (in late-stage trials)
Laropiprant	Phase 3 (in late-stage trials)
Lisinopril Anhydrous	Phase 3 (in late-stage trials)
MK-0767	Phase 3 (in late-stage trials)
Magnesium Oxide	Phase 3 (in late-stage trials)
Mazdutide	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Metformin Glycinate	Phase 3 (in late-stage trials)
Metoprolol	Phase 3 (in late-stage trials)
Mitiglinide	Phase 3 (in late-stage trials)
Mitiglinide Calcium Dihydrate	Phase 3 (in late-stage trials)
Muraglitazar	Phase 3 (in late-stage trials)
Niacin	Phase 3 (in late-stage trials)
Omarigliptin	Phase 3 (in late-stage trials)
Orforglipron	Phase 3 (in late-stage trials)
Paroxetine	Phase 3 (in late-stage trials)
Perindopril	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Pitavastatin	Phase 3 (in late-stage trials)
Pramlintide	Phase 3 (in late-stage trials)
Ramipril	Phase 3 (in late-stage trials)
Ranolazine	Phase 3 (in late-stage trials)
Reserpine	Phase 3 (in late-stage trials)
Retagliptin	Phase 3 (in late-stage trials)
Retatrutide	Phase 3 (in late-stage trials)
Rimonabant	Phase 3 (in late-stage trials)
Rivaroxaban	Phase 3 (in late-stage trials)
Rivoglitazone	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)
Sitagliptin	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Soybean Oil	Phase 3 (in late-stage trials)
Sucralose	Phase 3 (in late-stage trials)
Tagatose	Phase 3 (in late-stage trials)
Taranabant	Phase 3 (in late-stage trials)
Taspoglutide	Phase 3 (in late-stage trials)
Telmisartan	Phase 3 (in late-stage trials)
Teneligliptin	Phase 3 (in late-stage trials)
Terazosin	Phase 3 (in late-stage trials)
Tesaglitazar	Phase 3 (in late-stage trials)
Thiazolidinedione	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)
Trelagliptin	Phase 3 (in late-stage trials)
Triamterene	Phase 3 (in late-stage trials)
Urea	Phase 3 (in late-stage trials)
Ursodiol	Phase 3 (in late-stage trials)
Valsartan	Phase 3 (in late-stage trials)
Voglibose	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcarnitine, Acetylcholine, Acipimox, Alcohol, Amantadine, Ascorbic Acid, Bempedoic Acid, Benfluorex, Benfotiamine, Bermekimab, Bezafibrate, Bezisterim, Bifidobacterium Spp., Bimagrumab, Canakinumab, Cinnamon, Colestilan Chloride, Dextromethorphan, Diacerein, Diazoxide, Diflunisal, Donepezil, Ebselen, Elafibranor, Epigalocatechin Gallate, Gevokizumab, Ginseng, American, Hyaluronidase (Human Recombinant), Hydroxychloroquine, Levocarnitine, Levoketoconazole, Linerixibat, Lipoic Acid, Alpha, Mecobalamin, Microcrystalline Cellulose, Nitazoxanide, Pantoprazole, Paricalcitol, Prednisolone, Propolis Wax, Quercetin, Resveratrol, Roflumilast, Ruboxistaurin, Silybin A, Sulforaphane, Tadalafil, Taurine, Tesamorelin, Vitamin E, Yohimbine, Zanamivir, Zinc Gluconate.

Drug target analysis

Approved (phase 4): 17 · Phase ≥3: 21 · Phased (≥1): 26 · Undrugged: 48

Druggability breadth: 100 of 250 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ABCC8	REPAGLINIDE
AKT2	CAPIVASERTIB
GLP1R	DIHYDROERGOTAMINE MESYLATE
INSR	FEDRATINIB
KCNJ11	PINACIDIL ANHYDROUS
PPARG	METHYLENE BLUE ANHYDROUS
SCTR	SECRETIN
SDC4	BRIGATINIB
ACHE	ISOFLUROPHATE
SLC18A2	TETRABENAZINE
SLC22A2	PROGESTERONE
SLC22A3	PROGESTERONE
BRAF	VEMURAFENIB
SLC6A4	CETIRIZINE
SREBF1	CALCIFEDIOL ANHYDROUS
STAT3	MOMELOTINIB
SYK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A4	422	4
ACHE	153	4
PPARG	83	4
SYK	54	4
BRAF	48	4
SLC22A2	47	4
INSR	36	4
SLC22A3	20	4
GLP1R	18	4
STAT3	18	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8, KCNJ11
GLYBURIDE	4	ABCC8, KCNJ11, PPARG
CAPIVASERTIB	4	AKT2
SUNITINIB	4	ACHE, AKT2, INSR, SLC6A4
MIDOSTAURIN	4	AKT2, SYK
DIHYDROERGOTAMINE MESYLATE	4	GLP1R
LOPERAMIDE HYDROCHLORIDE	4	GLP1R, SLC6A4
SEMAGLUTIDE	4	GLP1R
TOLVAPTAN	4	GLP1R
LIRAGLUTIDE	4	GLP1R
EXENATIDE	4	GLP1R
TIRZEPATIDE	4	GLP1R
ELAGOLIX SODIUM	4	GLP1R
GLUCAGON	4	GLP1R
PERPHENAZINE	4	GLP1R, SLC6A4
SECRETIN	4	GLP1R, SCTR
FEDRATINIB	4	BRAF, INSR, SLC6A4, SYK
SORAFENIB	4	BRAF, INSR
NERATINIB	4	INSR, SYK
INFIGRATINIB PHOSPHATE	4	BRAF, INSR, SYK
INFIGRATINIB	4	BRAF, INSR, SYK
ENTRECTINIB	4	INSR, SYK
CERITINIB	4	INSR, SYK
OSIMERTINIB	4	INSR, SLC6A4
BRIGATINIB	4	INSR, SDC4
NINTEDANIB	4	INSR, PPARG
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR, SDC4, SLC6A4, SYK
PINACIDIL ANHYDROUS	4	KCNJ11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 13.

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

Symbol	Assays	Type breakdown
ACHE	2,563	Binding:2513, ADMET:27, Functional:22, Toxicity:1
PPARG	2,033	Binding:1593, Functional:380, ADMET:56, Toxicity:3, Unclassified:1
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
STAT3	1,319	Binding:1304, Functional:12, Unclassified:2, ADMET:1
SLC6A4	1,055	Binding:1021, Functional:18, ADMET:9, Toxicity:6, Unclassified:1
INSR	954	Binding:900, Functional:49, ADMET:4, Toxicity:1
SYK	873	Binding:863, Functional:10
AKT2	822	Binding:802, Functional:19, Toxicity:1
GLP1R	314	Functional:230, Binding:84
GCK	228	Binding:226, ADMET:1, Functional:1
BCL6	209	Binding:202, Functional:7
TGM2	127	Binding:127
BCL9	125	Binding:125
HNF4A	106	Binding:97, Functional:9
KCNJ11	102	Functional:59, Binding:43
SLC22A2	101	Functional:62, ADMET:21, Binding:18
SLC1A2	90	Binding:84, Functional:6
ABCC8	84	Functional:52, Binding:32
SLC22A3	33	Binding:17, Functional:11, ADMET:5
KSR2	28	Binding:28
SLC18A2	28	Binding:26, ADMET:1, Functional:1
ST6GAL1	27	Binding:27
SLC2A4	24	Binding:23, Functional:1
TCF7L2	22	Binding:22
SCTR	20	Functional:16, Binding:4
SORT1	17	Binding:15, ADMET:2
SREBF1	17	Binding:17
SLC2A2	12	Binding:11, Functional:1
INS	8	Binding:7, ADMET:1
BECN1	7	Binding:7
SUMO2	7	Binding:5, Functional:2
SSR1	7	Binding:7
HMGA1	6	Binding:6
ATXN7	5	Binding:5
ROR2	4	Binding:4
IRS1	2	Binding:2
BDNF	2	Binding:2
WFS1	1	Binding:1
HNF1A	1	Binding:1
CDKAL1	1	Binding:1
PDHX	1	Binding:1
SDC4	1	Binding:1
EPCAM	1	Binding:1
TCF12	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCK	2.7.1.1	hexokinase
KSR2	2.7.11.25	mitogen-activated protein kinase kinase kinase
PDHX	1.2.1.104	pyruvate dehydrogenase system
AKT2	2.7.11.1	non-specific serine/threonine protein kinase
INSR	2.7.10.1	receptor protein-tyrosine kinase
TGM2	2.3.2.13	protein-glutamine gamma-glutamyltransferase
ROR2	2.7.10.1	receptor protein-tyrosine kinase
ACHE	3.1.1.7, 3.5.1.13	acetylcholinesterase, aryl-acylamidase
ST6GAL1	2.4.99.1	beta-galactoside alpha-(2,6)-sialyltransferase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
SPG7	3.4.24.B18
SYK	2.7.10.2, 2.7.12.1	non-specific protein-tyrosine kinase, dual-specificity kinase
EPCAM	2.4.1.37, 2.4.1.40	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GCK	228
AKT2	822
GLP1R	314
HNF4A	106
INSR	954
KCNJ11	102
PPARG	2,033
TGM2	127
BCL6	209
BCL9	125
ACHE	2,563
SLC22A2	101
BRAF	1,442
SLC6A4	1,055
STAT3	1,319
SYK	873

Pharmacogenomics

Cohort genes with a PharmGKB record: 74; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
SLC6A4	1

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)
DIAZOXIDE	4	ABCC8, KCNJ11
CAPIVASERTIB	4	AKT2
SUNITINIB	4	ACHE, AKT2, INSR, SLC6A4
MIDOSTAURIN	4	AKT2, SYK
DIHYDROERGOTAMINE MESYLATE	4	GLP1R
LOPERAMIDE HYDROCHLORIDE	4	GLP1R, SLC6A4
SEMAGLUTIDE	4	GLP1R
TOLVAPTAN	4	GLP1R
LIRAGLUTIDE	4	GLP1R
TIRZEPATIDE	4	GLP1R
ELAGOLIX SODIUM	4	GLP1R
GLUCAGON	4	GLP1R
PERPHENAZINE	4	GLP1R, SLC6A4
SECRETIN	4	GLP1R, SCTR
FEDRATINIB	4	BRAF, INSR, SLC6A4, SYK
SORAFENIB	4	BRAF, INSR
NERATINIB	4	INSR, SYK
INFIGRATINIB PHOSPHATE	4	BRAF, INSR, SYK
INFIGRATINIB	4	BRAF, INSR, SYK
ENTRECTINIB	4	INSR, SYK
CERITINIB	4	INSR, SYK
OSIMERTINIB	4	INSR, SLC6A4
BRIGATINIB	4	INSR, SDC4
NINTEDANIB	4	INSR, PPARG
LAPATINIB	4	INSR
CRIZOTINIB	4	INSR, SDC4, SLC6A4, SYK
PINACIDIL ANHYDROUS	4	KCNJ11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	17	ABCC8, AKT2, GLP1R, INSR, KCNJ11, PPARG, SCTR, SDC4, ACHE, SLC18A2 (+7 more)
B	Phased (≥1) drug, not yet approved	9	GCK, SLC2A2, TGM2, BCL6, BCL9, BECN1, SLC1A2, SORT1, SSR1
C	Druggable family + PDB, no drug	10	KSR2, PDHX, HNF4A, ROBO2, ROR2, ST6GAL1, SLC2A4, SLC7A7, SPG7, EPCAM
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	38	WFS1, SLC30A8, HNF1A, HNF1B, TCF7L2, CDKAL1, PTF1A, INS-IGF2, HMGA1, INS (+28 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HNF4A	106	BCL9
WFS1	1	ABCC8
HNF1A	1	GCK
KSR2	28	BRAF
INS	8	INSR
BDNF	2	SORT1
SLC30A8	0	—
HNF1B	0	—
TCF7L2	22	—
CDKAL1	1	—
PDHX	1	—
PTF1A	0	—
INS-IGF2	0	—
HMGA1	6	—
IRS1	2	—
IRS2	0	—
MAPK8IP1	0	—
PAX4	0	—
PPP1R3A	0	—
PCGF3	0	—
RNF6	0	—
RNF7	0	—
ROBO2	0	—
ROR2	4	—
RREB1	0	—
SACS	0	—
ATXN7	5	—
SFRP2	0	—
SGCG	0	—
SHB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8,209.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1,003
PHASE3	95
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00725127	PHASE4	ACTIVE_NOT_RECRUITING	Chronotherapy with Low-dose Aspirin for Primary Prevention
NCT02817360	PHASE4	RECRUITING	NT-proBNP Selected Prevention of Cardiac Events in Diabetic Patients
NCT03264352	PHASE4	RECRUITING	Intervention for High-normal Blood Pressure in Adults With Type 2 Diabetes
NCT04128995	PHASE4	ACTIVE_NOT_RECRUITING	Surgical or Medical Treatment
NCT04639414	PHASE4	ACTIVE_NOT_RECRUITING	Combined Active Treatment in Type 2 Diabetes with NASH
NCT04892199	PHASE4	ACTIVE_NOT_RECRUITING	Does GLP-1RA Prevent Deterioration of Metabolic State in Prediabetic and Diabetic Patients Treated With Antipsychotic Medication?
NCT05164263	PHASE4	RECRUITING	Real World Safety & Efficacy Experience of Empagliflozin With or Without Metformin in T2DM Patients - EASE Study
NCT05264727	PHASE4	ACTIVE_NOT_RECRUITING	Glucagon Suppression by Hyperglycemia in the Presence and Absence of Amino Acid Infusion
NCT05305287	PHASE4	RECRUITING	Quantifying Hepatic Mitochondrial Fluxes in Humans
NCT05307731	PHASE4	RECRUITING	Fingolimod for Type 2 Diabetes Mellitus
NCT05365425	PHASE4	RECRUITING	Choline Fenofibrate and Carotid Atherosclerosis in Patients With Type 2 Diabetes and Combined Dyslipidemia
NCT05365438	PHASE4	RECRUITING	Atmeg (Atorvastatin and Omega-3 Combination) and Carotid Atherosclerosis in Patients With Type 2 Diabetes and Combined Dyslipidemia
NCT05366868	PHASE4	ACTIVE_NOT_RECRUITING	Durable Effect of Imeglimin on the Glycemic Control in Patients With Type 2 Diabetes Mellitus
NCT05433584	PHASE4	ACTIVE_NOT_RECRUITING	A Study of Tirzepatide Compared With Intensified Conventional Care in Adult Participants With Type 2 Diabetes
NCT05441267	PHASE4	RECRUITING	A Study of Cardiovascular Events iN Diabetes Plus
NCT05553093	PHASE4	RECRUITING	Effects of Tirzepatide and Insulin Glargine on Glucolipid Metabolism and Brain Function in Patients With Type 2 Diabetes
NCT05700877	PHASE4	RECRUITING	Screening and Intervention for Subclinical Coronary Artery Disease in Patients With Type 2 Diabetes
NCT05708859	PHASE4	RECRUITING	Effect of Tirzepatide on Progression of Coronary Atherosclerosis Using MDCT
NCT05780905	PHASE4	RECRUITING	Effects of Semaglutide on Intracranial Blood Flow and Brain-Barrier Permeability in Type-2 Diabetes
NCT05836350	PHASE4	NOT_YET_RECRUITING	Role of BCAA in Glucose Homeostasis
NCT05887817	PHASE4	ACTIVE_NOT_RECRUITING	Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in T2D and CKD (FIVE-STAR)
NCT05949008	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Metformin, a Drug Used to Treat Diabetes, vs Placebo
NCT06003153	PHASE4	RECRUITING	GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH
NCT06042153	PHASE4	ACTIVE_NOT_RECRUITING	DIALYSIS-TIR Study
NCT06205030	PHASE4	NOT_YET_RECRUITING	Efficacy of NOSHINtrial in Diabetic Patients
NCT06291155	PHASE4	RECRUITING	Mechanism of SGLT2 Inhibition in the Kidney
NCT06296836	PHASE4	RECRUITING	Effect of Continuing Versus Holding Metformin During Hospitalizations.
NCT06399835	PHASE4	RECRUITING	Enavogliflozin vs. Pioglitazone on Glucose and Atherosclerosis
NCT06402747	PHASE4	RECRUITING	Clopidogrel Versus Cilostazol on Vessels
NCT06408532	PHASE4	NOT_YET_RECRUITING	The Efficacy and Safety of Insulin Degludec/Liraglutide Combination (IDegLira) in Patients With Type 2 Diabetes
NCT06417489	PHASE4	NOT_YET_RECRUITING	Evaluation of Efficacy and Safety of Combination Therapy of Henagliflozin Proline, Retagliptin and Metformin in New Diagnosed Type 2 Diabetes Patients
NCT06448130	PHASE4	NOT_YET_RECRUITING	Henagliflozin’s Impact on Prediabetes Remission
NCT06461377	PHASE4	RECRUITING	The Ameliorative Effects of GLP-1RA on Diabetic Cardiac Autonomatic Neuropathy
NCT06478186	PHASE4	RECRUITING	Knee Osteoarthritis Treatment With Zilretta vs. Kenalog in the Context of Type II Diabetes
NCT06501651	PHASE4	NOT_YET_RECRUITING	Sacubitril/Valsartan Treats Patients With Essential Hypertension and Type 2 Diabetic Nephropathy
NCT06613854	PHASE4	RECRUITING	Effect of Early Combination Antihyperglycemic Treatment on Metabolic Control in Individuals With Type 2 Diabetes
NCT06642272	PHASE4	RECRUITING	A Pragmatic Trial Comparing Empagliflozin and Dapagliflozin Through Cluster Randomization Embedded in the Electronic Health Record
NCT06642623	PHASE4	RECRUITING	A Prospective Trial of Enavogliflozin to Evaluate Cardio-renal Outcome in Type 2 Diabetes Mellitus Patients
NCT06657209	PHASE4	RECRUITING	Normal-weight Diabetes: Adipocyte-directed Therapy With Pioglitazone or Tirzepatide
NCT06671587	PHASE4	RECRUITING	iGlarLixi CGM Study in Chinese T2D Individuals After OADs

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INSULIN GLARGINE	4	71
VILDAGLIPTIN	4	60
ROSIGLITAZONE	4	58
METFORMIN	4	57
SITAGLIPTIN	4	56
GLIMEPIRIDE	4	48
EXENATIDE	4	46
PIOGLITAZONE	4	46
INSULIN HUMAN	4	39
INSULIN ASPART	4	33
INSULIN DETEMIR	4	31
ACARBOSE	4	21
INSULIN GLULISINE	4	19
REPAGLINIDE	4	18
GLICLAZIDE	4	13
INSULIN LISPRO	4	11
GLIPIZIDE	4	9
CILOSTAZOL	4	8
GLYBURIDE	4	8
NATEGLINIDE	4	8
ASPIRIN	4	7
AMLODIPINE	4	6
ATORVASTATIN	4	6
HYDROCHLOROTHIAZIDE	4	6
ROSUVASTATIN	4	6
CHOLECALCIFEROL	4	5
ERGOCALCIFEROL	4	5
EZETIMIBE	4	5
SIMVASTATIN	4	5
VALSARTAN	4	5