Hyperthyroidism

Summary

Hyperthyroidism (MONDO:0004425) is a disease (an umbrella term covering 10 Mondo subtypes) whose subtypes are caused by variants in TSHR, ALB, and THRB. Overactivity of the thyroid gland resulting in overproduction of thyroid hormone and increased metabolic rate. Causes include diffuse hyperplasia of the thyroid gland (Graves’ disease), single nodule in the thyroid gland, and thyroiditis (Mondo). This page aggregates 14 associated genes (92 GWAS associations across 17 studies) and 78 registered clinical trials. The dominant Reactome pathway is Hemostasis (4 associated genes). Top therapeutic interventions include propranolol, methimazole, and doxycycline anhydrous.

At a glance

• Umbrella term: 10 Mondo subtypes
• Cohort genes: 14
• GWAS associations: 92 (top 1% of diseases corpus-wide)
• ClinVar variants: 22
• Clinical trials: 78 (top 5% of diseases corpus-wide)
• Approved drugs (ChEMBL indications): 2 — Methimazole, Propylthiouracil
• Druggability snapshot: 1 of 14 cohort genes is drug-illuminated (an approved/clinical drug with curated evidence); 7 functionally characterized but not yet drugged (SOX9, TG, PRDM11, CAPZB). Atlas-derived.

Clinical features

Clinical description

Mondo: Overactivity of the thyroid gland resulting in overproduction of thyroid hormone and increased metabolic rate. Causes include diffuse hyperplasia of the thyroid gland (Graves’ disease), single nodule in the thyroid gland, and thyroiditis. The symptoms are related to the increased metabolic rate and include weight loss, fatigue, heat intolerance, excessive sweating, diarrhea, tachycardia, insomnia, muscle weakness, and tremor.

MeSH: Hypersecretion of THYROID HORMONES from the THYROID GLAND. Elevated levels of thyroid hormones increase BASAL METABOLIC RATE.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperthyroidism
Mondo ID	MONDO:0004425
EFO	EFO:0009189
MeSH	D006980
DOID	DOID:7998
NCIT	C3123
SNOMED CT	34486009
UMLS	C0020550
MedGen	6972
Is cancer (heuristic)	no

Also known as: overactive thyroid

Data availability: 22 ClinVar variants · 92 GWAS associations (17 studies).

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › hyperthyroidism

Sibling subtypes (11): thyroiditis, thyroid malformation, goiter, hypothyroidism, C-cell hyperplasia, euthyroid sick syndrome, thyroid tumor, … (+4 more under thyroid gland disorder)

Subtypes (10): toxic diffuse goiter, thyroid crisis, selective pituitary resistance to thyroid hormone, generalized resistance to thyroid hormone, thyrotoxicosis, familial gestational hyperthyroidism, familial hyperthyroidism due to mutations in TSH receptor, hyperthyroxinemia, familial dysalbuminemic, … (+2 more)

Genetics & variants

GWAS landscape

92 GWAS associations across 17 studies. Top hits map to 21 distinct genes (as reported by GWAS).

Top associations by p-value

showing 30 of 92 associations by p-value:

rsID	p-value	Gene	Risk allele	Odds ratio
chr6:32633960	5e-147		AG	0.51
rs7747236	8e-117	HLA-DRB5 - RNU1-61P	T	0.67
rs12148331	2e-66	LINC01586	T	1.68
chr14:80990913	5e-54		C	0.25
rs1794280	2e-44	HLA-DQB1 - MTCO3P1	T	0.55
rs2160215	2e-37	TSHR	C	1.29
chr2:203874196	3e-35		A	0.2
rs2300519	8e-34	TSHR	A	0.3
rs28687418	5e-32	LINC01586	A	1.78
rs41269265	8e-32	ZNF184	C	0.39
rs58722186	7e-30	MAFTRR, LINC01229	T	1.43
rs28366272	6e-29	HLA-DRB1 - HLA-DQA1	A	0.4
rs6754506	3e-28	TESHL	A	0.63
chr1:113761186	1e-23		A	0.25
rs3087243	1e-22	CTLA4 - ICOS	A	0.24
rs11571297	2e-22	CTLA4 - ICOS	T	1.2
rs2046045	4e-22	PDE8B	T	0.33
rs1033701	2e-21	PDE10A	A	1.5
rs2476601	6e-21	AP4B1-AS1, PTPN22	A	1.28
rs714862	4e-20	DIRC3	G	1.41
rs334706	1e-18	NFIA	G	1.59
rs147828653	6e-18	HCG27 - HLA-C	C	0.37
rs7873463	4e-17	GLIS3	A	0.76
rs12515498	6e-17	PDE8B	T	1.37
rs6679677	6e-17	PHTF1 - RSBN1	A	0.32
chr10:6056861	2e-16		C	0.13
rs34038921	3e-16	ZNF70P1 - HTATSF1P1	C	1.41
rs2215981	3e-16	TSHR	A	0.8
chr11:95578258	8e-16		C	0.17
rs3118358	1e-15	NOP56P1 - LINC01623	G	1.82

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90473161	UK Biobank Whole-Genome Sequencing Consortium	2025	7,956	450,484	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90667836	UK Biobank Whole-Genome Sequencing Consortium	2025	7,956	450,484	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90319319	Figueredo J	2024	6,442	736,566	Uncovering the Shared Genetic Components of Thyroid Disorders and Reproductive Health.
GCST90435199	Wei Y	2024	4,491	68,140	Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies.
GCST90038636	Donertas HM	2021	3,731	480,867	Common genetic associations between age-related diseases.
GCST90018860	Sakaue S	2021	3,557	456,942	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST90077728	Backman JD	2021	3,510	328,244	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90081714	Backman JD	2021	3,510	328,244	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90103389	Fitzgerald T	2022	2,581	168,176	CNest: A novel copy number association discovery method uncovers 862 new associations from 200,629 whole-exome sequence datasets in the UK Biobank.
GCST006897	Teumer A	2018	1,840	49,983	Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	48

MAF distribution

Bucket	Variants
common (>=0.05)	33
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	15

Functional consequences

5 consequence types:

Consequence	Count
intron_variant	22
unknown	15
intergenic_variant	9
non_coding_transcript_exon_variant	2
missense_variant	2

Top variants

showing 30 of 50 variants:

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr6:32633960							5e-147	Tier 4: intronic/intergenic
rs7747236	6	32534622	C>T	0.138	intergenic_variant	HLA-DRB5 - RNU1-61P	8e-117	Tier 4: intronic/intergenic
rs12148331	15	88566850	C>G,T	0.249	intron_variant	LINC01586	2e-66	Tier 4: intronic/intergenic
chr14:80990913							5e-54	Tier 4: intronic/intergenic
rs1794280	6	32699394	A>T	0.05	intergenic_variant	HLA-DQB1 - MTCO3P1	2e-44	Tier 4: intronic/intergenic
rs2160215	14	80995128	T>A,C	0.05	intron_variant	TSHR	2e-37	Tier 4: intronic/intergenic
chr2:203874196							3e-35	Tier 4: intronic/intergenic
rs2300519	14	80992418	T>A,G	0.383	intron_variant	TSHR	8e-34	Tier 4: intronic/intergenic
rs28687418	15	88572631	G>A	0.26	intron_variant	LINC01586	5e-32	Tier 4: intronic/intergenic
rs41269265	6	27457570	T>C,G	0.114	non_coding_transcript_exon_variant	ZNF184	8e-32	Tier 4: intronic/intergenic
rs58722186	16	79717694	C>A,T	0.229	intron_variant	MAFTRR, LINC01229	7e-30	Tier 4: intronic/intergenic
rs28366272	6	32592198	C>A	0.162	intergenic_variant	HLA-DRB1 - HLA-DQA1	6e-29	Tier 4: intronic/intergenic
rs6754506	2	216749927	G>A	0.497	intron_variant	TESHL	3e-28	Tier 4: intronic/intergenic
chr1:113761186							1e-23	Tier 4: intronic/intergenic
rs3087243	2	203874196	G>A,T	0.451	intergenic_variant	CTLA4 - ICOS	1e-22	Tier 4: intronic/intergenic
rs11571297	2	203880280	T>C	0.05	intergenic_variant	CTLA4 - ICOS	2e-22	Tier 4: intronic/intergenic
rs2046045	5	77239986	T>A,C,G	0.4	intron_variant	PDE8B	4e-22	Tier 4: intronic/intergenic
rs1033701	6	165627371	G>A	0.149	intron_variant	PDE10A	2e-21	Tier 4: intronic/intergenic
rs2476601	1	113834946	A>G,T	0.05	missense_variant	AP4B1-AS1, PTPN22	6e-21	Tier 1: coding
rs714862	2	217374703	A>C,G,T	0.472	intron_variant	DIRC3	4e-20	Tier 4: intronic/intergenic
rs334706	1	61150575	G>A,C	0.039	intron_variant	NFIA	1e-18	Tier 4: intronic/intergenic
rs147828653	6	31257783	G>C	0.097	intergenic_variant	HCG27 - HLA-C	6e-18	Tier 4: intronic/intergenic
rs7873463	9	4221298	A>C,T	0.321	intron_variant	GLIS3	4e-17	Tier 4: intronic/intergenic
rs12515498	5	77244147	T>A,C,G	0.166	intron_variant	PDE8B	6e-17	Tier 4: intronic/intergenic
rs6679677	1	113761186	C>A,T	0.102	intergenic_variant	PHTF1 - RSBN1	6e-17	Tier 4: intronic/intergenic
chr10:6056861							2e-16	Tier 4: intronic/intergenic
rs34038921	6	33227606	G>A,C	0.05	intergenic_variant	ZNF70P1 - HTATSF1P1	3e-16	Tier 4: intronic/intergenic
rs2215981	14	80978623	G>A,T	0.323	intron_variant	TSHR	3e-16	Tier 4: intronic/intergenic
chr11:95578258							8e-16	Tier 4: intronic/intergenic
rs3118358	6	28831611	T>C,G	0.05	intergenic_variant	NOP56P1 - LINC01623	1e-15	Tier 4: intronic/intergenic

ClinVar germline variants

22 retrieved; paginated sample, class counts are floors:

10 pathogenic, 6 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12542	NM_001354712.2(THRB):c.949G>A (p.Ala317Thr)	THRB	Pathogenic	criteria provided, multiple submitters, no conflicts
12550	NM_001354712.2(THRB):c.1357C>A (p.Pro453Thr)	THRB	Pathogenic	criteria provided, multiple submitters, no conflicts
12553	NM_001354712.2(THRB):c.959G>A (p.Arg320His)	THRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12554	NM_001354712.2(THRB):c.700G>A (p.Ala234Thr)	LOC126806630	Pathogenic	criteria provided, multiple submitters, no conflicts
12559	NM_001354712.2(THRB):c.1313G>A (p.Arg438His)	THRB	Pathogenic	criteria provided, multiple submitters, no conflicts
12567	NM_001354712.2(THRB):c.727C>T (p.Arg243Trp)	LOC126806630	Pathogenic	criteria provided, multiple submitters, no conflicts
439310	NM_001354712.2(THRB):c.1357C>T (p.Pro453Ser)	THRB	Pathogenic	criteria provided, multiple submitters, no conflicts
548123	NM_001354712.2(THRB):c.1286G>A (p.Arg429Gln)	THRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2630860	NM_001354712.2(THRB):c.1304A>G (p.His435Arg)	THRB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
268009	46;X;t(X;3)(p21.3;p25.1)dn		Pathogenic	criteria provided, single submitter
492920	NM_001354712.2(THRB):c.1293A>G (p.Ile431Met)	THRB	Pathogenic	criteria provided, single submitter
4682120	NM_000477.7(ALB):c.724C>A (p.Arg242Ser)	ALB	Pathogenic	criteria provided, single submitter
4890880	NM_001354712.2(THRB):c.989T>C (p.Leu330Ser)	THRB	Pathogenic	criteria provided, single submitter
4682108	NM_001354712.2(THRB):c.959G>C (p.Arg320Pro)	THRB	Likely pathogenic	criteria provided, single submitter
4820253	NM_000369.5(TSHR):c.1454C>T (p.Ala485Val)	TSHR	Likely pathogenic	criteria provided, single submitter
4820259	NM_001354712.2(THRB):c.964G>A (p.Asp322Asn)	THRB	Likely pathogenic	criteria provided, single submitter
13434	NM_000371.4(TTR):c.416C>T (p.Thr139Met)	TTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18225	NM_000477.7(ALB):c.725G>A (p.Arg242His)	ALB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43454	NM_000371.4(TTR):c.385G>A (p.Ala129Thr)	TTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619915	NM_001354712.2(THRB):c.1147C>T (p.Arg383Cys)	THRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2237467	NM_000369.5(TSHR):c.2170G>T (p.Val724Phe)	TSHR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2636515	NM_001354712.2(THRB):c.1052A>G (p.Asp351Gly)	THRB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Pathogenic / likely-pathogenic variants link to their full per-variant reference — ACMG evidence, calibrated predictors, gnomAD frequency — on Sugi Variant.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 25 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Genes curated across subtypes (GenCC)

Genes with a Definitive or Strong GenCC gene–disease validity classification for this term’s subtypes (up to three levels down), ranked by the number of subtypes they are curated for.

3 genes:

Gene	Subtypes	Example subtypes
TSHR	2	familial gestational hyperthyroidism; familial hyperthyroidism due to mutations in TSH receptor
ALB	1	hyperthyroxinemia, familial dysalbuminemic
THRB	1	thyroid hormone resistance, generalized, autosomal dominant

Orphanet rare-disease linkage (cohort genes)

25 cohort genes:

Gene	Orphanet ID	Rare disease
SOX9	Orphanet:140	Campomelic dysplasia
SOX9	Orphanet:2138	46,XX ovotesticular difference of sex development
SOX9	Orphanet:242	46,XY complete gonadal dysgenesis
SOX9	Orphanet:251510	46,XY partial gonadal dysgenesis
SOX9	Orphanet:393	46,XX testicular difference of sex development
SOX9	Orphanet:718	Isolated Pierre Robin sequence
TG	Orphanet:95716	Familial thyroid dyshormonogenesis
THRB	Orphanet:566243	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
TTR	Orphanet:597939	Euthyroid dysprealbuminemic hyperthyroxinemia
TTR	Orphanet:85447	ATTRV30M amyloidosis
TTR	Orphanet:85451	ATTRV122I amyloidosis
FOXE1	Orphanet:1226	Bamforth-Lazarus syndrome
FOXE1	Orphanet:146	Differentiated thyroid carcinoma
FOXE1	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
FOXE1	Orphanet:95713	Athyreosis
ALB	Orphanet:86816	Congenital analbuminemia
PDE10A	Orphanet:494526	Infantile-onset generalized dyskinesia with orofacial involvement
PDE10A	Orphanet:494541	Childhood-onset benign chorea with striatal involvement
PDE8B	Orphanet:228169	Autosomal dominant striatal neurodegeneration
PDE8B	Orphanet:647782	Isolated micronodular adrenocortical disease

Cohort genes → proteins

14 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9
multi_evidence	5

Cohort genes

14 cohort genes:

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX9	HGNC:11204	ENSG00000125398	P48436	Transcription factor SOX-9	gwas
TG	HGNC:11764	ENSG00000042832	P01266	Thyroglobulin	gwas
THRB	HGNC:11799	ENSG00000151090	P10828	Thyroid hormone receptor beta	clinvar
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	clinvar
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar
VEGFA	HGNC:12680	ENSG00000112715	P15692	Vascular endothelial growth factor A, long form	gwas
PRDM11	HGNC:13996	ENSG00000019485	Q9NQV5	PR domain-containing protein 11	gwas
CAPZB	HGNC:1491	ENSG00000077549	P47756	F-actin-capping protein subunit beta	gwas
FBF1	HGNC:24674	ENSG00000188878	Q8TES7	Fas-binding factor 1	clinvar
FOXE1	HGNC:3806	ENSG00000178919	O00358	Forkhead box protein E1	gwas
ALB	HGNC:399	ENSG00000163631	P02768	Albumin	clinvar
LINC01512	HGNC:51201	ENSG00000289313		long independently transcribed non-coding RNA 1512	gwas
PDE10A	HGNC:8772	ENSG00000112541	Q9Y233	cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A	gwas
PDE8B	HGNC:8794	ENSG00000113231	O95263	High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

13 cohort genes:

Symbol	Protein name	Function (lead sentence)
SOX9	Transcription factor SOX-9	Transcription factor that plays a key role in chondrocytes differentiation and skeletal development.
TG	Thyroglobulin	Acts as a substrate for the production of iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3).
THRB	Thyroid hormone receptor beta	Nuclear hormone receptor that can act as a repressor or activator of transcription.
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
TTR	Transthyretin	Thyroid hormone-binding protein.
VEGFA	Vascular endothelial growth factor A, long form	Participates in the induction of key genes involved in the response to hypoxia and in the induction of angiogenesis such as HIF1A.
PRDM11	PR domain-containing protein 11	May be involved in transcription regulation.
CAPZB	F-actin-capping protein subunit beta	F-actin-capping proteins bind in a Ca(2+)-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends.
FBF1	Fas-binding factor 1	Keratin-binding protein required for epithelial cell polarization.
FOXE1	Forkhead box protein E1	Transcription factor that binds consensus sites on a variety of gene promoters and activate their transcription.
ALB	Albumin	Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs.
PDE10A	cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A	Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides.
PDE8B	High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Protein-family classification

Druggable: 2 · Difficult: 5 · Unknown: 7 · Druggable fraction: 0.14

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	27.6×	0.071
Transcription factor	5	3.0×	0.071
GPCR	1	1.7×	0.600
Other/Unknown	7	0.9×	0.761

Per-gene assignment

14 cohort genes:

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX9	Transcription factor	no		HMG_box_dom, Sox_N, HMG_box_dom_sf
TG	Other/Unknown	no		Thyroglobulin_1, CarbesteraseB, Tyr-kin_ephrin_A/B_rcpt-like
THRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
TTR	Other/Unknown	no		Transthyretin/HIU_hydrolase, Transthyretin/HIU_hydrolase_d, Thyroxine_BS
VEGFA	Other/Unknown	no		PDGF/VEGF_dom, PD_growth_factor_CS, VEGF_C
PRDM11	Transcription factor	no		SET_dom, PRDM11_PR/SET, SET_dom_sf
CAPZB	Other/Unknown	no		CAPZB, F-actin_capping_bsu_CS, CapZ_alpha/beta
FBF1	Other/Unknown	no		FBF1, FBF1_C
FOXE1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
ALB	Other/Unknown	no		ALB/AFP/VDB, Serum_albumin_N, Serum_albumin_CS
LINC01512	Other/Unknown	no
PDE10A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, GAF, HD/PDEase_dom
PDE8B	Transcription factor	no	3.1.4.53	PAS, PDEase_catalytic_dom, HD/PDEase_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	13
unknown	1

Top tissues across cohort

20 tissues:

Tissue	Cohort genes
right lobe of thyroid gland	6
left lobe of thyroid gland	5
thyroid gland	5
right lobe of liver	2
cranial nerve II	1
hair follicle	1
ventricular zone	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
tibia	1
choroid plexus epithelium	1
type B pancreatic cell	1
descending thoracic aorta	1
epithelial cell of pancreas	1
thoracic aorta	1
monocyte	1
muscle layer of sigmoid colon	1
smooth muscle tissue	1
left testis	1
right testis	1

Per-gene tissue summary

14 cohort genes:

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX9	274	ubiquitous	marker	ventricular zone, cranial nerve II, hair follicle
TG	169	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
THRB	267	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, tibia
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TTR	185	broad	marker	choroid plexus epithelium, type B pancreatic cell, right lobe of liver
VEGFA	297	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
PRDM11	214	ubiquitous	yes	epithelial cell of pancreas, descending thoracic aorta, thoracic aorta
CAPZB	303	ubiquitous	marker	muscle layer of sigmoid colon, monocyte, smooth muscle tissue
FBF1	163	ubiquitous	yes	right testis, left testis, right lobe of thyroid gland
FOXE1	94	tissue_specific	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
ALB	178	tissue_specific	marker	right lobe of liver, liver, body of pancreas
LINC01512		tissue_specific
PDE10A	219	broad	marker	adrenal tissue, left uterine tube, cartilage tissue
PDE8B	170	broad	marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALB	11,260
CAPZB	4,870
SOX9	4,539
TTR	3,734
THRB	1,684
TSHR	1,438
TG	1,260
PDE10A	1,185
FBF1	1,130
FOXE1	1,048

Intra-cohort edges

8 intra-cohort edges:

A	B	Sources
ALB	TTR	biogrid_interaction, string_interaction
CAPZB	PDE8B	string_interaction
FOXE1	PDE8B	string_interaction
FOXE1	TG	string_interaction
FOXE1	TSHR	string_interaction
PDE8B	PRDM11	string_interaction
TG	TSHR	string_interaction
THRB	TSHR	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures

10 cohort genes:

Symbol	UniProt	PDB entries
TTR	P02766	493
PDE10A	Q9Y233	359
ALB	P02768	189
VEGFA	P15692	57
THRB	P10828	34
TSHR	P16473	9
CAPZB	P47756	8
TG	P01266	3
SOX9	P48436	1
PRDM11	Q9NQV5	1

AlphaFold-only cohort genes (by pLDDT)

3 cohort genes:

Symbol	UniProt	pLDDT
PDE8B	O95263	74.88
FBF1	Q8TES7	64.11
FOXE1	O00358	62.02

Alliance gene associations

Curated gene–disease associations from the Alliance of Genome Resources (Disease Ontology) — distinct from the cohort above: implicated (causal/mechanistic) vs biomarker (a marker for the disease).

Implicated genes (1): HLA-DQB1

Biomarker genes (1): SERPINE1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 116. Enrichment computed across 14 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth.

30 pathways by enrichment:

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Hemostasis	4	14.4×	0.007	VEGFA, CAPZB, ALB, PDE10A
Signal Transduction	6	6.1×	0.007	SOX9, TSHR, VEGFA, CAPZB, PDE10A, PDE8B
G alpha (s) signalling events	3	22.0×	0.011	TSHR, PDE10A, PDE8B
Response to elevated platelet cytosolic Ca2+	2	32.6×	0.031	VEGFA, ALB
GPCR downstream signalling	3	13.0×	0.031	TSHR, PDE10A, PDE8B
Signaling by GPCR	3	12.0×	0.031	TSHR, PDE10A, PDE8B
Defective visual phototransduction due to STRA6 loss of function	1	380.7×	0.033	TTR
Retinoid cycle disease events	1	285.5×	0.033	TTR
Diseases associated with visual transduction	1	285.5×	0.033	TTR
Diseases of the neuronal system	1	285.5×	0.033	TTR
Cellular responses to stress	3	11.1×	0.033	VEGFA, CAPZB, ALB
Cellular responses to stimuli	3	9.4×	0.033	VEGFA, CAPZB, ALB
Platelet activation, signaling and aggregation	2	21.1×	0.033	VEGFA, ALB
Ciprofloxacin ADME	1	228.4×	0.035	ALB
Sensory Perception	2	19.0×	0.035	TTR, CAPZB
VEGF ligand-receptor interactions	1	190.3×	0.036	VEGFA
Platelet degranulation	2	17.6×	0.036	VEGFA, ALB
Metabolism of proteins	4	5.0×	0.038	THRB, TTR, CAPZB, ALB
Metabolism of porphyrins	1	142.8×	0.042	ALB
VEGF binds to VEGFR leading to receptor dimerization	1	126.9×	0.042	VEGFA
Prednisone ADME	1	126.9×	0.042	ALB
RNA Polymerase II Transcription	3	6.8×	0.042	SOX9, THRB, VEGFA
HDL remodeling	1	114.2×	0.043	ALB
Regulation of gene expression by Hypoxia-inducible Factor	1	95.2×	0.046	VEGFA
Hormone ligand-binding receptors	1	95.2×	0.046	TSHR
Cellular response to hypoxia	1	87.8×	0.046	VEGFA
Scavenging of heme from plasma	1	87.8×	0.046	ALB
Heme degradation	1	81.6×	0.046	ALB
Nitric oxide stimulates guanylate cyclase	1	81.6×	0.046	PDE10A
Heme biosynthesis	1	76.1×	0.046	ALB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth.

30 GO terms by enrichment:

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA-templated transcription	4	69.1×	6e-05	SOX9, THRB, PRDM11, FOXE1
cAMP catabolic process	2	288.1×	0.002	PDE10A, PDE8B
thyroid hormone generation	2	152.5×	0.006	TG, FOXE1
positive regulation of branching involved in ureteric bud morphogenesis	2	123.5×	0.007	SOX9, VEGFA
negative regulation of miRNA transcription	2	96.0×	0.008	SOX9, VEGFA
negative regulation of cAMP/PKA signal transduction	2	92.6×	0.008	PDE10A, PDE8B
thyroid gland development	2	83.6×	0.009	TG, FOXE1
basophil chemotaxis	1	1296.3×	0.017	VEGFA
positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway	1	1296.3×	0.017	VEGFA
thyroid-stimulating hormone signaling pathway	1	1296.3×	0.017	TSHR
cellular response to thyrotropin-releasing hormone	1	1296.3×	0.017	TSHR
negative regulation of immune system process	1	648.1×	0.017	SOX9
coronary vein morphogenesis	1	648.1×	0.017	VEGFA
obsolete regulation of nitric oxide mediated signal transduction	1	648.1×	0.017	VEGFA
bilirubin transport	1	648.1×	0.017	ALB
VEGF-activated neuropilin signaling pathway	1	648.1×	0.017	VEGFA
epithelial cell proliferation involved in prostatic bud elongation	1	648.1×	0.017	SOX9
regulation of cell proliferation involved in tissue homeostasis	1	648.1×	0.017	SOX9
cellular stress response to acid chemical	1	648.1×	0.017	VEGFA
negative regulation of establishment of endothelial barrier	1	648.1×	0.017	VEGFA
negative regulation of adherens junction organization	1	648.1×	0.017	VEGFA
positive regulation of epithelial cell proliferation	2	37.6×	0.017	SOX9, VEGFA
neural crest cell fate specification	1	432.1×	0.017	SOX9
male germ-line sex determination	1	432.1×	0.017	SOX9
lymph vessel morphogenesis	1	432.1×	0.017	VEGFA
positive regulation of cell proliferation by VEGF-activated platelet derived growth factor receptor signaling pathway	1	432.1×	0.017	VEGFA
cardiac vascular smooth muscle cell development	1	432.1×	0.017	VEGFA
ureter urothelium development	1	432.1×	0.017	SOX9
chordate pharynx development	1	432.1×	0.017	FOXE1
cellular response to glycoprotein	1	432.1×	0.017	TSHR

Therapeutics

Drugs indicated or in trials for this disease

2 approved drugs — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Methimazole	Approved (phase 4)
Propylthiouracil	Approved (phase 4)

4 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Cholestyramine	Phase 3
Levocarnitine	Phase 3
Potassium Iodide	Phase 3
Prednisolone	Phase 3

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 6 · Undrugged: 8

Druggability breadth: 10 of 14 evidence-associated genes (71%) 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
THRB	Resmetirom
TSHR	Acetaminophen
TTR	Acoramidis
VEGFA	Belzutifan
ALB	Abacavir
PDE10A	Cinchophen

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
THRB	117	4
ALB	36	4
TTR	29	4
PDE10A	16	4
VEGFA	5	4
SOX9	0	0
TG	0	0
PRDM11	0	0
CAPZB	0	0

Drugs targeting cohort genes

30 drugs:

Molecule	Max phase	Targets in cohort
Resmetirom	4	THRB
Acetazolamide	4	THRB
Acetohexamide	4	THRB, TSHR
Acetylcysteine	4	THRB
Altretamine	4	THRB
Amantadine Hydrochloride	4	THRB
Amiloride Hydrochloride	4	THRB
Aminocaproic Acid	4	THRB
Aminopyrine	4	THRB, TSHR
Amiodarone	4	THRB, TSHR
Amoxapine	4	THRB, TSHR
Atorvastatin	4	THRB
Azaribine	4	THRB
Benzbromarone	4	ALB, THRB, TSHR, TTR
Bisoprolol Fumarate	4	THRB
Bithionol	4	THRB, TSHR, TTR
Carbetapentane	4	THRB, TSHR
Chlormadinone Acetate	4	THRB
Chlormezanone	4	THRB
Chlorpropamide	4	THRB, TSHR
Clomipramine Hydrochloride	4	THRB
Cyclothiazide	4	THRB
Cytarabine	4	THRB
Daunorubicin	4	THRB
Daunorubicin Hydrochloride	4	THRB, TSHR
Debrisoquin Sulfate	4	THRB, TSHR
Dextrothyroxine	4	THRB, TTR
Diazoxide	4	THRB, TSHR
Diltiazem Hydrochloride	4	THRB
Dipyridamole	4	PDE10A, THRB, TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity

10 cohort genes by assay count:

Symbol	Assays	Type breakdown
ALB	953	ADMET:767, Binding:168, Functional:18
TTR	423	Binding:391, Functional:32
PDE10A	357	Binding:345, ADMET:9, Functional:3
THRB	169	Binding:129, Functional:40
VEGFA	64	Binding:64
PDE8B	35	Binding:33, ADMET:1, Functional:1
TSHR	33	Functional:24, Binding:9
CAPZB	9	Binding:9
SOX9	3	Binding:3
PRDM11	1	Binding:1

Cohort enzymes (BRENDA EC)

2 cohort enzymes:

Symbol	EC numbers	Names
PDE10A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
PDE8B	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

Cohort genes with high screening signal

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

4 cohort genes:

Symbol	ChEMBL assays
THRB	169
TTR	423
ALB	953
PDE10A	357

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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.

30 compounds:

Compound	Max phase	Cohort target (bioactivity)
Resmetirom	4	THRB
Acetazolamide	4	THRB
Acetohexamide	4	THRB, TSHR
Acetylcysteine	4	THRB
Altretamine	4	THRB
Amantadine Hydrochloride	4	THRB
Amiloride Hydrochloride	4	THRB
Aminocaproic Acid	4	THRB
Aminopyrine	4	THRB, TSHR
Amiodarone	4	THRB, TSHR
Amoxapine	4	THRB, TSHR
Atorvastatin	4	THRB
Azaribine	4	THRB
Benzbromarone	4	ALB, THRB, TSHR, TTR
Bisoprolol Fumarate	4	THRB
Bithionol	4	THRB, TSHR, TTR
Carbetapentane	4	THRB, TSHR
Chlormadinone Acetate	4	THRB
Chlormezanone	4	THRB
Chlorpropamide	4	THRB, TSHR
Clomipramine Hydrochloride	4	THRB
Cyclothiazide	4	THRB
Cytarabine	4	THRB
Daunorubicin	4	THRB
Daunorubicin Hydrochloride	4	THRB, TSHR
Debrisoquin Sulfate	4	THRB, TSHR
Dextrothyroxine	4	THRB, TTR
Diazoxide	4	THRB, TSHR
Diltiazem Hydrochloride	4	THRB
Dipyridamole	4	PDE10A, THRB, TSHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	THRB, TSHR, TTR, VEGFA, ALB, PDE10A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	SOX9, TG, PRDM11, CAPZB, FBF1, FOXE1, LINC01512, PDE8B

Undrugged target profiles

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

8 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
TG	0	TSHR
FOXE1	0	TSHR
SOX9	3	—
PRDM11	1	—
CAPZB	9	—
FBF1	0	—
LINC01512	0	—
PDE8B	35	—

Clinical trials & evidence

Clinical trials

Clinical trials: 78.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	67
Phase 4	4
Phase 3	3
Phase 2	2
Phase 1/2	1
Phase 1	1

Top trials by phase / activity

showing 40 of 78 trials:

NCT	Phase	Status	Sponsor	Title
NCT00946296	Phase 4	COMPLETED	University of Massachusetts, Worcester	Impact of SSKI Pre-Treatment on Blood Loss in Thyroidectomy for Graves Disease
NCT03379181	Phase 4	COMPLETED	University Hospital, Basel, Switzerland	Thermogenesis in Hyperthyroidism and Effect of Anti-Adrenergic Therapy
NCT03393728	Phase 4	COMPLETED	Yaounde Central Hospital	Heart Rate Variability and Hyperthyroidism: Evaluation of the Short-term Effects of Propanolol
NCT05512715	Phase 4	COMPLETED	Universiti Kebangsaan Malaysia Medical Centre	LIthium as Bridging thErapy Prior to Radioactiveiodine in hyperThYroidism
NCT04856488	Phase 3	RECRUITING	Jan Calissendorff	Preoperative Lugol’s Solution in Graves’ Disease and Toxic Nodular Goiter
NCT03303053	Phase 3	UNKNOWN	Clinical Research Centre, Malaysia	Efficacy and Safety of Cholestyramine and Prednisolone as Adjunctive Therapy in Treatment of Overt Hyperthyroidism
NCT05118542	Phase 3	COMPLETED	Universitas Indonesia	Effect of Hyperthyroidism and Its Treatment in Graves’ Disease to Early Marker of Atherosclerosis
NCT07369063	Phase 2	RECRUITING	Northwell Health	Impact of Vitamin D Therapy on Thyroid Function and Antibody Levels in Pediatric Graves’ Disease
NCT01727973	Phase 1/2	COMPLETED	Sun Yat-sen University	Efficacy of Subantimicrobial Dose Doxycycline for Moderate to Severe and Active Graves’ Orbitopathy
NCT02203682	Phase 2	UNKNOWN	Sun Yat-sen University	Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy
NCT04346901	Phase 1	COMPLETED	Dr.dr.Irma Bernadette, SpKK (K)	Comparative Study of mMASI Before and After Hyperthyroid Therapy in Hyperthyroid Subjects With Melasma
NCT00001159	Not specified	RECRUITING	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	Natural History of Thyroid Function Disorders
NCT06540469	Not specified	NOT_YET_RECRUITING	Shandong Provincial Hospital	Iodine Supplementation in Graves’ Hyperthyroidism
NCT06570967	Not specified	RECRUITING	Shengjing Hospital	A Clinical Study of Hyperthyroidism in Children
NCT06583395	Not specified	ENROLLING_BY_INVITATION	Tobias Moeller-Bertram	Quest to Analyze One Thousand Humans Meditating
NCT06591858	Not specified	NOT_YET_RECRUITING	Assiut University	Evaluation of Renal Function in Patients With Hyperthyroidism
NCT06779747	Not specified	RECRUITING	IRCCS Azienda Ospedaliero-Universitaria di Bologna	Evaluation of Different Diagnostic Therapeutic Strategies in Patients with Thyroid Pathology
NCT06794203	Not specified	RECRUITING	IRCCS Azienda Ospedaliero-Universitaria di Bologna	Hyperthyroidism as a Potential Predictive of Worse Outcome of Renal Graft
NCT06868459	Not specified	ENROLLING_BY_INVITATION	Sarasota Memorial Health Care System	Pressure-enabled Retrograde Occlusive Therapy With Embolization for Control of Thyroid Disease (PROTECT Registry): A Multicenter Registry
NCT07017907	Not specified	RECRUITING	THYROSCOPE INC.	Evaluating an AI Tool for Detecting Thyrotoxic States
NCT07048548	Not specified	ACTIVE_NOT_RECRUITING	Superior University	Assessment of THL and Potential Risk of Hypothyroidism in Healthcare Workers Exposed to Low-dose Ionizing Radiation
NCT07405320	Not specified	NOT_YET_RECRUITING	University of Auckland, New Zealand	A Brief Video Intervention to Improve Patient Outcomes Following Radioiodine Treatment
NCT07472062	Not specified	ACTIVE_NOT_RECRUITING	University Hospital, Ghent	Development of a Non-Invasive Prognostic Test for Graves Orbitopathy
NCT07557810	Not specified	RECRUITING	Chinese PLA General Hospital	Efficacy of Thermal Ablation Combined With Antithyroid Drugs in the Treatment of Primary Hyperthyroidism
NCT07733375	Not specified	RECRUITING	Yeditepe University Hospital	Evaluation of Levothyroxine Replacement Therapy After Total Thyroidectomy Using a Smart Wristband
NCT00151723	Not specified	UNKNOWN	Radboud University Medical Center	Does Radioiodine Treatment Prevent Atrial Fibrillation and Bone Loss in Endogenous Subclinical Hyperthyroidism?
NCT00437931	Not specified	COMPLETED	HaEmek Medical Center, Israel	Color Flow Doppler Ultrasound in Subclinical Thyroid Dysfunction
NCT00471458	Not specified	COMPLETED	Tampere University	Follow-up Study of the RAI-Treated Hyperthyroid Patients
NCT00525122	Not specified	UNKNOWN	Medisch Centrum Rijnmond-Zuid, Netherlands	Treatment of M.Graves With Radioactive Iodine: Follow-up Study
NCT00796913	Not specified	COMPLETED	Aalborg University Hospital	Remission Induction and Sustenance in Graves’ Disease 2
NCT00822289	Not specified	UNKNOWN	Rabin Medical Center	The Effect of Radioactive Iodine Administration for Thyroid Diseases on H.Pylori Eradication
NCT01095341	Not specified	COMPLETED	Heidelberg University	Postoperative Hyperthyroidism
NCT01105923	Not specified	UNKNOWN	Brigham and Women’s Hospital	Study of an Intervention to Improve Problem List Accuracy and Use
NCT01145040	Not specified	UNKNOWN	Ruhr University of Bochum	NOMOTHETICOS: Nonlinear Modelling of Thyroid Hormones’ Effect on Thyrotropin Incretion in Confirmed Open-loop Situation
NCT01306916	Not specified	COMPLETED	Walter Reed Army Medical Center	Coexisting Thyroid Disease and Hyperparathyroidism
NCT01376648	Not specified	UNKNOWN	Huashan Hospital	Thyroid Hormones Effect on Brown Adipose Tissue
NCT01945229	Not specified	TERMINATED	Karolinska Institutet	Thumb-ECG Ambulant Screening for Atrial Fibrillation in Patients Treated for Hyperthyroidism (TAMBOURINE)
NCT02005250	Not specified	COMPLETED	Steen Bonnema	Bone Structure and Strength Evaluated by Extreme-CT Scan Before and After Treatment of Hyper- and Hypothyroidism
NCT02107794	Not specified	COMPLETED	Mayo Clinic	Shared Decision Making in Graves Disease - Graves Disease (GD) Choice
NCT02133040	Not specified	UNKNOWN	Aarhus University Hospital	Effects of Hyperthyroidism on Amount and Activity of Brown Adipose Tissue

Drugs tested across these trials

13 drugs:

Molecule	Max phase	Trials referencing
Propranolol	4	5
Methimazole	4	3
Doxycycline Anhydrous	4	2
Potassium Iodide	4	1
Propylthiouracil	4	1
Iodine	3	1
Selenium	3	1
Dexpropranolol	2	1
Levopropranolol	2	1
CHEMBL50241	0	1
CHEMBL4778520	0	1
Potassium Ion	0	1
Thyroxine	0	1

Other drugs named in trials

Drugs named in these trials’ interventions but not in the ChEMBL table above — includes investigational drugs not yet in ChEMBL. Linked where an Atlas drug page exists.

19 drugs named in trials:

Drug	Max trial phase
Propanolol	Phase 4
Cholestyramine Powder 4g	Phase 3
Iodine-Potassium Iodide 5%-10% Oral and Topical Solution	Phase 3
Prednisolone	Phase 3
Standard treatment	Phase 3
Doxycycline	Phase 1/2
Doxycycline hyclate	Phase 2
Ergocalciferol 50,000 IU	Phase 2
Thiamazol	Phase 1
Anti-Thyroid Drugs	Not specified
Bupivacain	Not specified
Carbimazole (CMZ) or thiamazole (TMZ)	Not specified
Cyclotron-produced 99mTc	Not specified
Dexmedetomidine & Bupivacaine.	Not specified
Generator-produced 99mTc	Not specified
Methimazole(MMI)	Not specified
Prophylactic administration of antithyroid drugs before iodinated contrast media exposure	Not specified
Routine postoperative calcium and calcitriol	Not specified
Thionamide treatment for 3 months	Not specified