Frontotemporal dementia

Summary

Frontotemporal dementia (MONDO:0017276) is a disease with 56 cohort genes (55 GWAS associations across 13 studies) and 144 clinical trials. The dominant Reactome pathway is Regulation of PLK1 Activity at G2/M Transition (5 cohort genes). Top therapeutic interventions include citalopram, florbetapir, and memantine.

At a glance

• Prevalence: 1-9 / 100 000 (Italy) [Orphanet-validated]
• Cohort genes: 56
• GWAS associations: 55
• ClinVar variants: 585
• Clinical trials: 144

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	3.05	Italy	Validated
Point prevalence	1-9 / 100 000	3	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia
Mondo ID	MONDO:0017276
MeSH	D057180
Orphanet	282
DOID	DOID:9255
ICD-10-CM	G31.0
ICD-11	831337417
NCIT	C84719
UMLS	C0338451
MedGen	83266
GARD	0008436
MedDRA	10068968
Is cancer (heuristic)	no

Also known as: frontotemporal lobe dementia (FLDEM) · FTD · MSTD

Data availability: 585 ClinVar variants · 55 GWAS associations (13 studies) · 143 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › frontotemporal dementia

Related subtypes (14): neuronal intranuclear inclusion disease, hereditary sensory neuropathy-deafness-dementia syndrome, Alzheimer disease 17, Alzheimer disease 18, Huntington disease-like syndrome, frontotemporal dementia with motor neuron disease, neurodegeneration with brain iron accumulation, PRKAR1B-related neurodegenerative dementia with intermediate filaments, adrenoleukodystrophy, corticobasal syndrome, metachromatic leukodystrophy, posterior cortical atrophy, autosomal dominant cerebellar ataxia, familial Alzheimer disease

Subtypes (4): inclusion body myopathy with Paget disease of bone and frontotemporal dementia, Pick disease, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, behavioral variant of frontotemporal dementia

Genetics & variants

GWAS landscape

55 GWAS associations across 13 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs12554036	8e-40	MOB3B	T	0.09
rs429358	8e-37	APOE	T	0.5
rs12608932	7e-26	UNC13A	C	0.06
rs7791726	4e-16	TMEM106B - VWDE	G	1.85
rs553913507	4e-11	BRD7P6 - TGFA	C	2.58
rs903914982	4e-11	SYNE1	G	3.52
rs147211831	5e-11	MOB3B	?	4.62
rs229243	5e-11	G2E3	A	6.56
rs117204439	6e-11	C9orf72 - CTAGE12P	?	4.22
rs4676496	9e-10	RPSA - MOBP	G	0.03
rs4810992	4e-09	RNF114	A	0.04
rs9268856	6e-09	HLA-DRB9	C	1.24
rs517339	1e-08	ERGIC1	C	0.03
rs36196656	2e-08	GFRA2	A	1.49
rs12546767	1e-07	WASHC5	?	1.22
rs906175	1e-07	CEP131	T	1.58
rs302668	2e-07	RAB38	T	1.23
rs17042852	2e-07	LINC01867, NRXN1-DT	C	2.82
rs6108746	3e-07	LINC01752 - LINC02871	C	3.19
rs1048775	8e-07	TEPSIN; NDUFAF8; CEP131; CEP131; CEP131; CEP131; CEP131	?	1.49
rs6962939	8e-07	COL28A1	A	6.04
rs9792144	8e-07	ST18	G	3.78
rs6809184	1e-06	TNIK	T	5.46
rs6111609	1e-06	RRBP1 - BANF2	A	2.86
rs7240419	1e-06	ATP9B	A	1.52
rs13393316	1e-06	NDUFS1	A	1.89
rs10101195	1e-06	GATA4 - NEIL2	C	1.61
rs13072484	1e-06	DLG1-AS1 - LINC02012	A	1.51
rs10860097	2e-06	CFAP54	T	3.04
rs2922921	2e-06	SEM1 - MARK2P10	A	9.5

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002510	Diekstra FP	2014	4,377	14,431	C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.
GCST90428108	Chen K	2023	3,526	9,402	Identifying risk loci for FTD and shared genetic component with ALS: A large-scale multitrait association analysis.
GCST005319	Broce I	2018	2,154	4,308	Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.
GCST90476500	Verma A	2024	1,830	448,078	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST002516	Ferrari R	2014	1,377	4,308	Frontotemporal dementia and its subtypes: a genome-wide association study.
GCST002960	Ferrari R	2015	530	0	A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.
GCST002508	Diekstra FP	2014	435	1,414	C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.
GCST006148	Pottier C	2018	382	1,146	Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.
GCST006150	Pottier C	2018	382	1,146	Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.
GCST006154	Pottier C	2018	382	1,146	Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	39

MAF distribution

Bucket	Variants
common (>=0.05)	35
low_freq (0.01-0.05)	4
rare (<0.01)	2
unknown	1

Functional consequences

Consequence	Count
intron_variant	30
intergenic_variant	6
missense_variant	1
non_coding_transcript_exon_variant	1
3_prime_UTR_variant; intron_variant; non_coding_transcript_exon_variant; intron_variant; intron_variant; intron_variant; intron_variant	1
regulatory_region_variant	1
intron_variant; 3_prime_UTR_variant; 3_prime_UTR_variant; intron_variant; intron_variant; non_coding_transcript_exon_variant; intron_variant; intron_variant; intron_variant; intron_variant; intron_variant; intron_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12554036	9	27509213	G>T	0.23	intron_variant	MOB3B	8e-40	Tier 4: intronic/intergenic
rs429358	19	44908684	T>C	0.156	missense_variant	APOE	8e-37	Tier 1: coding
rs12608932	19	17641880	A>C,T	0.349	intron_variant	UNC13A	7e-26	Tier 4: intronic/intergenic
rs7791726	7	12243703	G>A,C,T	0.42	intergenic_variant	TMEM106B - VWDE	4e-16	Tier 4: intronic/intergenic
rs553913507	2	70361745	C>A	0.001	intron_variant	BRD7P6 - TGFA	4e-11	Tier 4: intronic/intergenic
rs903914982	6	152211182	G>A,T	0	intron_variant	SYNE1	4e-11	Tier 4: intronic/intergenic
rs147211831	9	27436086	C>A,T		intron_variant	MOB3B	5e-11	Tier 4: intronic/intergenic
rs229243	14	30614542	C>A,G,T	0.363	intron_variant	G2E3	5e-11	Tier 4: intronic/intergenic
rs117204439	9	27607975	T>C	0.05	intron_variant	C9orf72 - CTAGE12P	6e-11	Tier 4: intronic/intergenic
rs4676496	3	39456514	A>C,G	0.48	intergenic_variant	RPSA - MOBP	9e-10	Tier 4: intronic/intergenic
rs4810992	20	49944619	G>A	0.32	intron_variant	RNF114	4e-09	Tier 4: intronic/intergenic
rs9268856	6	32461942	C>A,T	0.252	intron_variant	HLA-DRB9	6e-09	Tier 4: intronic/intergenic
rs517339	5	172927728	T>A,C	0.387	intron_variant	ERGIC1	1e-08	Tier 4: intronic/intergenic
rs36196656	8	21763735	C>A,G,T	0.37	intron_variant	GFRA2	2e-08	Tier 4: intronic/intergenic
rs12546767	8	125070323	T>C,G	0.1	intron_variant	WASHC5	1e-07	Tier 4: intronic/intergenic
rs906175	17	81199662	C>T	0.48	non_coding_transcript_exon_variant	CEP131	1e-07	Tier 4: intronic/intergenic
rs302668	11	88143743	T>A,C,G	0.292	intron_variant	RAB38	2e-07	Tier 4: intronic/intergenic
rs17042852	2	52372929	T>C	0.04	intron_variant	LINC01867, NRXN1-DT	2e-07	Tier 4: intronic/intergenic
rs6108746	20	10922123	T>C	0.25	intron_variant	LINC01752 - LINC02871	3e-07	Tier 4: intronic/intergenic
rs1048775	17;17;17;17;17;17;17	81228529	G>A,C,T	0.05	3_prime_UTR_variant; intron_variant; non_coding_transcript_exon_variant; intron_variant; intron_variant; intron_variant; intron_variant	TEPSIN; NDUFAF8; CEP131; CEP131; CEP131; CEP131; CEP131	8e-07	Tier 4: intronic/intergenic
rs6962939	7	7484595	T>A,C	0.06	intron_variant	COL28A1	8e-07	Tier 4: intronic/intergenic
rs9792144	8	52168991	C>G,T	0.18	intron_variant	ST18	8e-07	Tier 4: intronic/intergenic
rs6809184	3	171170409	C>T	0.09	intron_variant	TNIK	1e-06	Tier 4: intronic/intergenic
rs6111609	20	17683901	C>A	0.22	intergenic_variant	RRBP1 - BANF2	1e-06	Tier 4: intronic/intergenic
rs7240419	18	79168989	G>A	0.23	intron_variant	ATP9B	1e-06	Tier 4: intronic/intergenic
rs13393316	2	206134615	A>G	0.14	intron_variant	NDUFS1	1e-06	Tier 4: intronic/intergenic
rs10101195	8	11765703	C>A	0.23	regulatory_region_variant	GATA4 - NEIL2	1e-06	Tier 3: regulatory
rs13072484	3	197409951	G>A	0.22	intron_variant	DLG1-AS1 - LINC02012	1e-06	Tier 4: intronic/intergenic
rs10860097	12	96805878	A>T	0.02	intron_variant	CFAP54	2e-06	Tier 4: intronic/intergenic
rs2922921	7	96768767	A>C,G,T	0.03	intergenic_variant	SEM1 - MARK2P10	2e-06	Tier 4: intronic/intergenic

ClinVar germline variants

585 retrieved; paginated sample, class counts are floors:

199 uncertain significance, 144 likely benign, 81 pathogenic, 64 conflicting classifications of pathogenicity, 28 benign, 25 likely pathogenic, 22 pathogenic/likely pathogenic, 21 benign/likely benign, 1 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
68126	NM_000487.6(ARSA):c.256C>T (p.Arg86Trp)	ARSA	Pathogenic	criteria provided, multiple submitters, no conflicts
16011	NM_002087.4(GRN):c.388_391del (p.Gln130fs)	GRN	Pathogenic	criteria provided, multiple submitters, no conflicts
203455	NM_002087.4(GRN):c.462+1G>C	GRN	Pathogenic	no assertion criteria provided
203456	NM_002087.4(GRN):c.882T>G (p.Tyr294Ter)	GRN	Pathogenic	criteria provided, single submitter
203457	NM_002087.4(GRN):c.1212C>A (p.Cys404Ter)	GRN	Pathogenic	no assertion criteria provided
203458	NM_002087.4(GRN):c.1246dup (p.Cys416fs)	GRN	Pathogenic	criteria provided, single submitter
203459	NM_002087.4(GRN):c.87dup (p.Cys30fs)	GRN	Pathogenic	criteria provided, single submitter
203460	NM_002087.4(GRN):c.708+1G>A	GRN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3778832	NM_002087.4(GRN):c.464_465insGGAA (p.Ser156fs)	GRN	Pathogenic	criteria provided, single submitter
599609	NM_002087.4(GRN):c.522_523insTGTGAAGACAGGGTGCACTGCTGTC (p.His175fs)	GRN	Pathogenic	criteria provided, single submitter
599610	NM_002087.4(GRN):c.759_760dup (p.Asp254fs)	GRN	Pathogenic	criteria provided, single submitter
599612	NM_002087.4(GRN):c.776dup (p.Cys260fs)	GRN	Pathogenic	criteria provided, multiple submitters, no conflicts
599613	NM_002087.4(GRN):c.1446C>A (p.Cys482Ter)	GRN	Pathogenic	criteria provided, single submitter
599615	NM_002087.4(GRN):c.560del (p.Leu187fs)	GRN	Pathogenic	criteria provided, single submitter
599617	NM_002087.4(GRN):c.385dup (p.Ser129fs)	GRN	Pathogenic	criteria provided, single submitter
599618	NM_002087.4(GRN):c.232dup (p.Ser78fs)	GRN	Pathogenic	criteria provided, single submitter
98152	NM_002087.4(GRN):c.759_760del (p.Cys253_Asp254delinsTer)	GRN	Pathogenic	criteria provided, multiple submitters, no conflicts
14245	NM_001377265.1(MAPT):c.2078C>T (p.Pro693Leu)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14246	NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val)	MAPT	Pathogenic	no assertion criteria provided
14247	NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14248	NM_001377265.1(MAPT):c.2091+14C>T	MAPT	Pathogenic	no assertion criteria provided
14251	NM_001377265.1(MAPT):c.2091+1G>A	MAPT	Pathogenic	no assertion criteria provided
14252	NM_001377265.1(MAPT):c.2185G>A (p.Val729Met)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14253	NM_001377265.1(MAPT):c.2013T>G (p.Asn671Lys)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14254	NM_001377265.1(MAPT):c.2090G>A (p.Ser697Asn)	MAPT	Pathogenic	criteria provided, single submitter
14255	NM_001377265.1(MAPT):c.2341G>A (p.Gly781Arg)	MAPT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14257	NM_001377265.1(MAPT):c.2064T>C (p.Asn688=)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14258	NM_001377265.1(MAPT):c.2201A>T (p.Glu734Val)	MAPT	Pathogenic	no assertion criteria provided
14262	NM_001377265.1(MAPT):c.2135C>T (p.Ser712Phe)	MAPT	Pathogenic	criteria provided, single submitter
14266	NM_001377265.1(MAPT):c.1972C>G (p.Leu658Val)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 81 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
TMEM106B	TMEM106B	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEM1	Orphanet:2440	Isolated split hand-split foot malformation
BTNL2	Orphanet:797	Sarcoidosis
TARDBP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
TARDBP	Orphanet:700154	TARDBP-related predominantly upper-limb distal myopathy
TARDBP	Orphanet:803	Amyotrophic lateral sclerosis
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
CCNF	Orphanet:803	Amyotrophic lateral sclerosis
OPTN	Orphanet:803	Amyotrophic lateral sclerosis
TREM2	Orphanet:100069	Semantic dementia
TREM2	Orphanet:100070	Progressive non-fluent aphasia
TREM2	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
TREM2	Orphanet:275864	Behavioral variant of frontotemporal dementia
TREM2	Orphanet:2770	Nasu-Hakola disease
TREM2	Orphanet:803	Amyotrophic lateral sclerosis
LRRK2	Orphanet:2828	Young-onset Parkinson disease
LRRK2	Orphanet:411602	Hereditary late-onset Parkinson disease
CHRNA4	Orphanet:98784	Sleep-related hypermotor epilepsy
TUBB4A	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum
TUBB4A	Orphanet:98805	Primary dystonia, DYT4 type
TMEM106B	Orphanet:100069	Semantic dementia
TMEM106B	Orphanet:100070	Progressive non-fluent aphasia
TMEM106B	Orphanet:275864	Behavioral variant of frontotemporal dementia
UNC13A	Orphanet:803	Amyotrophic lateral sclerosis
CSF1R	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
CSF1R	Orphanet:556985	Early-onset calcifying leukoencephalopathy-skeletal dysplasia
GLT8D1	Orphanet:803	Amyotrophic lateral sclerosis
NSMCE2	Orphanet:436182	Microcephalic primordial dwarfism-insulin resistance syndrome
NSMCE2	Orphanet:808	Seckel syndrome
DCTN1	Orphanet:139589	Distal hereditary motor neuropathy type 7
DCTN1	Orphanet:178509	Perry syndrome
DCTN1	Orphanet:803	Amyotrophic lateral sclerosis
WASHC5	Orphanet:100989	Autosomal dominant spastic paraplegia type 8
WASHC5	Orphanet:7	3C syndrome
TNIK	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
NDUFAF8	Orphanet:2609	Isolated complex I deficiency
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma

Cohort genes → proteins

56 cohort genes, 55 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	33
multi_evidence	23

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNASE4	HGNC:10047	ENSG00000258818	P34096	Ribonuclease 4	clinvar
BDH1	HGNC:1027	ENSG00000161267	Q02338	D-beta-hydroxybutyrate dehydrogenase, mitochondrial	gwas
RRBP1	HGNC:10448	ENSG00000125844	Q9P2E9	Ribosome-binding protein 1	gwas
STMN2	HGNC:10577	ENSG00000104435	Q93045	Stathmin-2	gwas
SEM1	HGNC:10845	ENSG00000127922	P60896	26S proteasome complex subunit SEM1	gwas
SQLE	HGNC:11279	ENSG00000104549	Q14534	Squalene monooxygenase	gwas
BTNL2	HGNC:1142	ENSG00000204290	Q9UIR0	Butyrophilin-like protein 2	gwas
TARDBP	HGNC:11571	ENSG00000120948	Q13148	TAR DNA-binding protein 43	clinvar
HNF1B	HGNC:11630	ENSG00000275410	P35680	Hepatocyte nuclear factor 1-beta	gwas
ATP9B	HGNC:13541	ENSG00000166377	O43861	Probable phospholipid-transporting ATPase IIB	gwas
PALM2	HGNC:15845			paralemmin 2	gwas
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	clinvar
ACTN3	HGNC:165	ENSG00000248746	Q08043	Alpha-actinin-3	gwas
OPTN	HGNC:17142	ENSG00000123240	Q96CV9	Optineurin	clinvar
PJA2	HGNC:17481	ENSG00000198961	O43164	E3 ubiquitin-protein ligase Praja-2	gwas
TREM2	HGNC:17761	ENSG00000095970	Q9NZC2	Triggering receptor expressed on myeloid cells 2	clinvar
LRRK2	HGNC:18618	ENSG00000188906	Q5S007	Leucine-rich repeat serine/threonine-protein kinase 2	clinvar
ST18	HGNC:18695	ENSG00000147488	O60284	Suppression of tumorigenicity 18 protein	gwas
NEIL2	HGNC:18956	ENSG00000154328	Q969S2	Endonuclease 8-like 2	gwas
STARD3NL	HGNC:19169	ENSG00000010270	O95772	STARD3 N-terminal-like protein	gwas
CHRNA4	HGNC:1958	ENSG00000101204	P43681	Neuronal acetylcholine receptor subunit alpha-4	clinvar
CHRNB4	HGNC:1964	ENSG00000117971	P30926	Neuronal acetylcholine receptor subunit beta-4	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
TMEM106B	HGNC:22407	ENSG00000106460	Q9NUM4	Transmembrane protein 106B	gwas
COL28A1	HGNC:22442	ENSG00000215018	Q2UY09	Collagen alpha-1(XXVIII) chain	gwas
UNC13A	HGNC:23150	ENSG00000130477	Q9UPW8	Protein unc-13 homolog A	gwas
CRHR1	HGNC:2357	ENSG00000120088	P34998	Corticotropin-releasing factor receptor 1	clinvar
CSF1R	HGNC:2433	ENSG00000182578	P07333	Macrophage colony-stimulating factor 1 receptor	clinvar
GLT8D1	HGNC:24870	ENSG00000016864	Q68CQ7	Glycosyltransferase 8 domain-containing protein 1	clinvar
TMEM184C	HGNC:25587	ENSG00000164168	Q9NVA4	Transmembrane protein 184C	gwas
TEPSIN	HGNC:26458	ENSG00000167302	Q96N21	AP-4 complex accessory subunit Tepsin	gwas
NSMCE2	HGNC:26513	ENSG00000156831	Q96MF7	E3 SUMO-protein ligase NSE2	gwas
ZCCHC24	HGNC:26911	ENSG00000165424	Q8N2G6	Zinc finger CCHC domain-containing protein 24	gwas
DCTN1	HGNC:2711	ENSG00000204843	Q14203	Dynactin subunit 1	clinvar
WASHC5	HGNC:28984	ENSG00000164961	Q12768	WASH complex subunit 5	gwas
MARCHF4	HGNC:29269	ENSG00000144583	Q9P2E8	E3 ubiquitin-protein ligase MARCHF4	clinvar
CEP131	HGNC:29511	ENSG00000141577	Q9UPN4	Centrosomal protein of 131 kDa	gwas
TNIK	HGNC:30765	ENSG00000154310	Q9UKE5	TRAF2 and NCK-interacting protein kinase	gwas
NDUFAF8	HGNC:33551	ENSG00000224877	A1L188	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	gwas
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	clinvar
GFRA2	HGNC:4244	ENSG00000168546	O00451	GDNF family receptor alpha-2	gwas
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
GRN	HGNC:4601	ENSG00000030582	P28799	Progranulin	clinvar
HLA-DRA	HGNC:4947	ENSG00000204287	P01903	HLA class II histocompatibility antigen, DR alpha chain	gwas
HLA-DRB5	HGNC:4953	ENSG00000198502	Q30154	HLA class II histocompatibility antigen, DR beta 5 chain	gwas
HNRNPA2B1	HGNC:5033	ENSG00000122566	P22626	Heterogeneous nuclear ribonucleoproteins A2/B1	clinvar
JAG1	HGNC:6188	ENSG00000101384	P78504	Protein jagged-1	gwas
MAPT	HGNC:6893	ENSG00000186868	P10636	Microtubule-associated protein tau	clinvar
MEF2C	HGNC:6996	ENSG00000081189	Q06413	Myocyte-specific enhancer factor 2C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNASE4	Ribonuclease 4	Cleaves preferentially after uridine bases.
RRBP1	Ribosome-binding protein 1	Acts as a ribosome receptor and mediates interaction between the ribosome and the endoplasmic reticulum membrane.
STMN2	Stathmin-2	Regulator of microtubule stability.
SEM1	26S proteasome complex subunit SEM1	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
SQLE	Squalene monooxygenase	Catalyzes the stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, and is considered to be a rate-limiting enzyme in steroid biosynthesis.
BTNL2	Butyrophilin-like protein 2	Negative regulator of T-cell proliferation.
TARDBP	TAR DNA-binding protein 43	RNA-binding protein that is involved in various steps of RNA biogenesis and processing.
HNF1B	Hepatocyte nuclear factor 1-beta	Transcription factor that binds to the inverted palindrome 5’-GTTAATNATTAAC-3'.
CCNF	Cyclin-F	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
ACTN3	Alpha-actinin-3	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
OPTN	Optineurin	Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8.
PJA2	E3 ubiquitin-protein ligase Praja-2	Has E2-dependent E3 ubiquitin-protein ligase activity.
TREM2	Triggering receptor expressed on myeloid cells 2	Forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding.
LRRK2	Leucine-rich repeat serine/threonine-protein kinase 2	Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking.
ST18	Suppression of tumorigenicity 18 protein	Repressor that binds to DNA sequences containing a bipartite element consisting of a direct repeat of the sequence 5’-AAAGTTT-3’ separated by 2-9 nucleotides.
NEIL2	Endonuclease 8-like 2	Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents.
STARD3NL	STARD3 N-terminal-like protein	Tethering protein that creates contact site between the endoplasmic reticulum and late endosomes: localizes to late endosome membranes and contacts the endoplasmic reticulum via interaction with VAPA and VAPB.
CHRNA4	Neuronal acetylcholine receptor subunit alpha-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
CHRNB4	Neuronal acetylcholine receptor subunit beta-4	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
TMEM106B	Transmembrane protein 106B	In neurons, involved in the transport of late endosomes/lysosomes.
COL28A1	Collagen alpha-1(XXVIII) chain	May act as a cell-binding protein.
UNC13A	Protein unc-13 homolog A	Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
CRHR1	Corticotropin-releasing factor receptor 1	G-protein coupled receptor for CRH (corticotropin-releasing factor) and UCN (urocortin).
CSF1R	Macrophage colony-stimulating factor 1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes…
GLT8D1	Glycosyltransferase 8 domain-containing protein 1	In vitro, catalyzes the transfer of a galactose residue from UDP-galactose onto GalNAc and GlcNAc structures.
TMEM184C	Transmembrane protein 184C	Possible tumor suppressor which may play a role in cell growth.
TEPSIN	AP-4 complex accessory subunit Tepsin	Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.
NSMCE2	E3 SUMO-protein ligase NSE2	E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination.
DCTN1	Dynactin subunit 1	Part of the dynactin complex that activates the molecular motor dynein for ultra-processive transport along microtubules.
WASHC5	WASH complex subunit 5	Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fi…
MARCHF4	E3 ubiquitin-protein ligase MARCHF4	E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I and CD4, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies.
CEP131	Centrosomal protein of 131 kDa	Component of centriolar satellites contributing to the building of a complex and dynamic network required to regulate cilia/flagellum formation.
TNIK	TRAF2 and NCK-interacting protein kinase	Serine/threonine kinase that acts as an essential activator of the Wnt signaling pathway.
NDUFAF8	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 8	Involved in the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I, MT-ND1).
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
GFRA2	GDNF family receptor alpha-2	Receptor for neurturin (NRTN), a growth factor that supports the survival of sympathetic neurons.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
GRN	Progranulin	Secreted protein that acts as a key regulator of lysosomal function and as a growth factor involved in inflammation, wound healing and cell proliferation.
HLA-DRA	HLA class II histocompatibility antigen, DR alpha chain	An alpha chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
HLA-DRB5	HLA class II histocompatibility antigen, DR beta 5 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HNRNPA2B1	Heterogeneous nuclear ribonucleoproteins A2/B1	Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles.
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.
MAPT	Microtubule-associated protein tau	Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.
MEF2C	Myocyte-specific enhancer factor 2C	Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes.
ARSA	Arylsulfatase A	Hydrolyzes cerebroside sulfate.
NDUFS1	NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
NEDD1	Protein NEDD1	Required for mitosis progression.
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

Protein-family classification

Druggable: 13 · Difficult: 11 · Unknown: 32 · Druggable fraction: 0.23

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
Antibody/Immunoglobulin	5	2.6×	0.381
Kinase	4	2.0×	0.429
Transcription factor	10	1.5×	0.429
Phosphatase	1	1.5×	0.881
Other/Unknown	32	1.0×	0.881
Protease	1	0.7×	0.992
GPCR	1	0.4×	0.992
Scaffold/PPI	1	0.3×	0.992
Enzyme (other)	1	0.2×	0.992

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNASE4	Other/Unknown	no		RNaseA, RNaseA_AS, RNaseA_domain
BDH1	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
RRBP1	Other/Unknown	no		Rib_rcpt_KP, RRBP1
STMN2	Other/Unknown	no		Stathmin_fam, Stathmin_CS, Stathmin_sf
SEM1	Other/Unknown	no		DSS1_SEM1, DUF5543
SQLE	Enzyme (other)	yes	1.14.14.17	Squalene_epoxidase, FAD/NAD-bd_sf, Squalene_monox
BTNL2	Antibody/Immunoglobulin	yes		Ig_C1-set, Ig_sub, Ig-like_dom
TARDBP	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
HNF1B	Transcription factor	no		HD, HNF1b_C, HNF-1_N
ATP9B	Transcription factor	no		P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
PALM2	Other/Unknown	no
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N
ACTN3	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
OPTN	Other/Unknown	no		NEMO_N, CC2-LZ_dom, NEMO_ZF
PJA2	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD
TREM2	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Ig-like_dom_sf
LRRK2	Kinase	yes		Prot_kinase_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
ST18	Transcription factor	no		Znf_C2H2C, Myelin_TF, Znf_C2H2C_sf
NEIL2	Transcription factor	no	3.2.2.23	Znf_DNA_glyclase/AP_lyase, Ribosomal_uS13-like_H2TH, FPG_cat
STARD3NL	Other/Unknown	no		MENTAL, STARD3
CHRNA4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRNB4	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
TMEM106B	Other/Unknown	no		TMEM106, TMEM106_C, TMEM106_N
COL28A1	Other/Unknown	no		VWF_A, Kunitz_BPTI, Collagen
UNC13A	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
CRHR1	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_CRF_rcpt
CSF1R	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
GLT8D1	Other/Unknown	no		Glyco_trans_8, Nucleotide-diphossugar_trans, Glycosyltrans_8_dom-fam
TMEM184C	Other/Unknown	no		Ostalpha/TMEM184C
TEPSIN	Other/Unknown	no		ENTH_VHS, ENTH, ENTH/VHS_tepsin
NSMCE2	Transcription factor	no		Znf_MIZ, Znf_RING/FYVE/PHD, Nse2(Mms21)
ZCCHC24	Transcription factor	no		Znf_CCHC, Zn_knuckle_CX2CX3GHX4C, ZAR1/RTP1-5-like_Znf-3CxxC
DCTN1	Other/Unknown	no		CAP-Gly_domain, Dynactin, CAP-Gly_dom_sf
WASHC5	Other/Unknown	no		WASH_strumpellin
MARCHF4	Transcription factor	no		Znf_RING-CH, Znf_RING/FYVE/PHD, MARCHF4/9/11
CEP131	Other/Unknown	no		CEP131
TNIK	Kinase	yes		Prot_kinase_dom, CNH_dom, Ser/Thr_kinase_AS
NDUFAF8	Other/Unknown	no		NDUFAF8
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
GFRA2	Other/Unknown	no		GDNF_rcpt, GDNF_rcpt_a2, GDNF/GAS1
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
GRN	Other/Unknown	no		Granulin, Granulin_sf, Granulin_fam
HLA-DRA	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DRB5	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HNRNPA2B1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C
JAG1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom
MAPT	Other/Unknown	no		MAP_tubulin-bd_rpt, Tau, MAP2/MAP4/Tau
MEF2C	Transcription factor	no		TF_MADSbox, HJURP_C, MEF2-like_N

Expression context

Cohort genes with no expression data: 1.

50 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)	55
unknown	1

Top tissues across cohort

Tissue	Cohort genes
cortical plate	6
secondary oocyte	6
ventricular zone	5
right hemisphere of cerebellum	5
granulocyte	5
calcaneal tendon	4
tendon of biceps brachii	4
sural nerve	4
monocyte	4
corpus callosum	4
oocyte	4
right testis	4
right lobe of liver	3
primordial germ cell in gonad	3
male germ line stem cell (sensu Vertebrata) in testis	3
C1 segment of cervical spinal cord	3
leukocyte	3
cerebellar cortex	3
cerebellar hemisphere	3
prefrontal cortex	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNASE4	134	ubiquitous	marker	right lobe of liver, liver, calcaneal tendon
BDH1	134	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon
RRBP1	298	ubiquitous	marker	body of pancreas, parotid gland, tendon of biceps brachii
STMN2	222	broad	marker	cortical plate, pons, cerebellar vermis
SEM1	285	ubiquitous	marker	calcaneal tendon, tendon, tendon of biceps brachii
SQLE	287	ubiquitous	marker	adrenal tissue, ventricular zone, ganglionic eminence
BTNL2	106		yes	sural nerve, ventricular zone, primordial germ cell in gonad
TARDBP	301	ubiquitous	marker	secondary oocyte, ventricular zone, ganglionic eminence
HNF1B	74	broad	marker	metanephros cortex, adult mammalian kidney, kidney
ATP9B	263	ubiquitous	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
PALM2
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle
ACTN3	146	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, diaphragm
OPTN	302	ubiquitous	marker	amniotic fluid, gastrocnemius, muscle of leg
PJA2	294	ubiquitous	marker	cortical plate, cauda epididymis, postcentral gyrus
TREM2	186	broad	marker	C1 segment of cervical spinal cord, spinal cord, amniotic fluid
LRRK2	220	broad	marker	buccal mucosa cell, monocyte, leukocyte
ST18	192	broad	marker	corpus callosum, C1 segment of cervical spinal cord, spinal cord
NEIL2	224	ubiquitous	marker	oviduct epithelium, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis
STARD3NL	258	ubiquitous	marker	secondary oocyte, oocyte, epithelial cell of pancreas
CHRNA4	138	tissue_specific	yes	right lobe of liver, cortical plate, cingulate cortex
CHRNB4	125	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, right testis
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TMEM106B	286	ubiquitous	marker	caput epididymis, corpus epididymis, cauda epididymis
COL28A1	182	tissue_specific	marker	sural nerve, trigeminal ganglion, tibial nerve
UNC13A	193	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CRHR1	113	tissue_specific	yes	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
CSF1R	245	broad	marker	granulocyte, monocyte, leukocyte
GLT8D1	296	ubiquitous	marker	pituitary gland, bronchial epithelial cell, adenohypophysis
TMEM184C	259	ubiquitous	marker	parotid gland, endothelial cell, hair follicle

Protein interactions among cohort

Intra-cohort edges: 26.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRRK2	7,628
MAPT	7,289
TARDBP	7,245
CCNF	6,626
HNRNPA2B1	5,996
FUS	5,250
TUBB4A	5,138
JAG1	4,405
CSF1R	4,392
ERBB4	4,325

Intra-cohort edges

A	B	Sources
BTNL2	HLA-DRA	string_interaction
BTNL2	HLA-DRB5	string_interaction
CSF1R	TREM2	string_interaction
DCTN1	MAPT	biogrid_interaction
DCTN1	SETX	string_interaction
FUS	HNRNPA2B1	string_interaction
FUS	MAPT	string_interaction
FUS	OPTN	string_interaction
FUS	SEM1	intact
FUS	SETX	string_interaction
FUS	TARDBP	intact, string_interaction
GRN	SEM1	intact
HLA-DRA	HLA-DRB5	biogrid_interaction, intact, string_interaction
HNRNPA2B1	TARDBP	string_interaction
LRRK2	MAPT	string_interaction
LRRK2	RAB38	intact, string_interaction
LRRK2	SEM1	intact
MAPT	PSEN1	string_interaction
MAPT	TARDBP	string_interaction
MAPT	TMEM106B	string_interaction
MAPT	TUBB4A	intact
OPTN	TARDBP	string_interaction
PSEN1	TREM2	intact, string_interaction
SETX	TARDBP	string_interaction
STARD3NL	TMEM106B	intact
TARDBP	TMEM106B	string_interaction

Structural data

PDB: 35 · AlphaFold-only: 20 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPT	P10636	293
HLA-DRA	P01903	140
SEM1	P60896	129
TARDBP	Q13148	44
LRRK2	Q5S007	44
TMEM106B	Q9NUM4	29
PSEN1	P49768	27
CSF1R	P07333	26
FUS	P35637	23
TREM2	Q9NZC2	15
OPTN	Q96CV9	14
ERBB4	Q15303	14
DCTN1	Q14203	13
HNRNPA2B1	P22626	13
CHRNA4	P43681	12
CRHR1	P34998	11
TNIK	Q9UKE5	11
ARSA	P15289	10
GRN	P28799	8
JAG1	P78504	7
NDUFS1	P28331	7
NECTIN2	Q92692	7
GFRA2	O00451	5
CHRNB4	P30926	4
HLA-DRB5	Q30154	4
SQLE	Q14534	3
HNF1B	P35680	3
ACTN3	Q08043	3
NSMCE2	Q96MF7	3
RNASE4	P34096	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB4A	P04350	92.25
NDUFAF8	A1L188	91.12
WASHC5	Q12768	90.27
BDH1	Q02338	87.23
BTNL2	Q9UIR0	85.97
STMN2	Q93045	85.95
GLT8D1	Q68CQ7	85.35
NEIL2	Q969S2	81.95
ATP9B	O43861	79.49
UNC13A	Q9UPW8	73.58
TMEM184C	Q9NVA4	72.08
RRBP1	Q9P2E9	70.52
ZCCHC24	Q8N2G6	69.49
CEP131	Q9UPN4	67.20
STARD3NL	O95772	62.78
MARCHF4	Q9P2E8	62.42
COL28A1	Q2UY09	61.81
MEF2C	Q06413	56.80
SETX	Q7Z333	52.93
PJA2	O43164	48.16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 427. Enrichment computed across 56 evidence-associated genes (43 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 43 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of PLK1 Activity at G2/M Transition	5	14.8×	0.009	OPTN, TUBB4A, DCTN1, CEP131, NEDD1
Loss of Nlp from mitotic centrosomes	4	14.8×	0.019	TUBB4A, DCTN1, CEP131, NEDD1
Loss of proteins required for interphase microtubule organization from the centrosome	4	14.8×	0.019	TUBB4A, DCTN1, CEP131, NEDD1
AURKA Activation by TPX2	4	14.2×	0.019	TUBB4A, DCTN1, CEP131, NEDD1
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	2	75.9×	0.020	CHRNA4, CHRNB4
Recruitment of mitotic centrosome proteins and complexes	4	12.7×	0.020	TUBB4A, DCTN1, CEP131, NEDD1
Highly calcium permeable nicotinic acetylcholine receptors	2	59.0×	0.026	CHRNA4, CHRNB4
Recruitment of NuMA to mitotic centrosomes	4	10.8×	0.026	TUBB4A, DCTN1, CEP131, NEDD1
Anchoring of the basal body to the plasma membrane	4	10.5×	0.026	TUBB4A, DCTN1, CEP131, NEDD1
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	2	48.3×	0.029	CHRNA4, CHRNB4
NOTCH4 Activation and Transmission of Signal to the Nucleus	2	48.3×	0.029	JAG1, PSEN1
Presynaptic nicotinic acetylcholine receptors	2	44.3×	0.032	CHRNA4, CHRNB4
Nephron development	2	40.9×	0.035	HNF1B, JAG1
Acetylcholine binding and downstream events	2	37.9×	0.035	CHRNA4, CHRNB4
Postsynaptic nicotinic acetylcholine receptors	2	37.9×	0.035	CHRNA4, CHRNB4
MHC class II antigen presentation	4	8.3×	0.035	TUBB4A, DCTN1, HLA-DRA, HLA-DRB5
Translocation of ZAP-70 to Immunological synapse	2	29.5×	0.051	HLA-DRA, HLA-DRB5
Phosphorylation of CD3 and TCR zeta chains	2	25.3×	0.066	HLA-DRA, HLA-DRB5
Co-inhibition by PD-1	2	24.1×	0.069	HLA-DRA, HLA-DRB5
Signaling by NOTCH4	2	23.1×	0.071	SEM1, JAG1
NOTCH3 Activation and Transmission of Signal to the Nucleus	2	22.1×	0.074	JAG1, PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	2	20.4×	0.079	JAG1, PSEN1
Downstream TCR signaling	3	8.9×	0.079	SEM1, HLA-DRA, HLA-DRB5
Mitotic G2-G2/M phases	3	8.8×	0.079	SEM1, TUBB4A, NEDD1
G2/M Transition	3	8.8×	0.079	SEM1, TUBB4A, NEDD1
Immune System	9	2.7×	0.079	SEM1, BTNL2, CCNF, CHRNB4, TUBB4A, HNRNPA2B1, MEF2C, ARSA (+1 more)
Activation of AMPK downstream of NMDARs	2	17.7×	0.089	TUBB4A, MAPT
Activated NOTCH1 Transmits Signal to the Nucleus	2	16.6×	0.097	JAG1, PSEN1
Nuclear signaling by ERBB4	2	16.1×	0.097	ERBB4, PSEN1
Generation of second messenger molecules	2	16.1×	0.097	HLA-DRA, HLA-DRB5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 51 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of synaptic transmission, glutamatergic	4	40.0×	0.002	LRRK2, UNC13A, MEF2C, PSEN1
astrocyte activation	3	58.3×	0.006	TREM2, MAPT, PSEN1
lysosome organization	4	24.0×	0.006	LRRK2, TMEM106B, WASHC5, GRN
astrocyte activation involved in immune response	2	165.2×	0.010	GRN, PSEN1
microglial cell activation involved in immune response	2	132.2×	0.011	TREM2, GRN
amyloid fibril formation	3	35.4×	0.011	TARDBP, FUS, MAPT
intracellular distribution of mitochondria	2	94.4×	0.018	LRRK2, MAPT
neuron cellular homeostasis	3	26.8×	0.018	TMEM106B, DCTN1, PSEN1
regulation of mitochondrial fission	2	82.6×	0.019	LRRK2, MAPT
positive regulation of microglial cell activation	2	82.6×	0.019	TREM2, LRRK2
behavioral response to nicotine	2	73.4×	0.020	CHRNA4, CHRNB4
microglial cell proliferation	2	73.4×	0.020	TREM2, CSF1R
protein autophosphorylation	4	11.4×	0.025	LRRK2, CSF1R, TNIK, ERBB4
maintenance of synapse structure	2	60.1×	0.027	DCTN1, GRN
epithelial cell proliferation	3	18.4×	0.030	HNF1B, GRN, PSEN1
negative regulation of microtubule polymerization	2	50.8×	0.031	STMN2, TUBB4A
regulation of resting membrane potential	2	50.8×	0.031	TREM2, PSEN1
nervous system development	6	5.4×	0.034	DCTN1, ERBB4, GFRA2, SETX, JAG1, MEF2C
neuron projection maintenance	2	44.1×	0.035	DCTN1, PSEN1
peptide antigen assembly with MHC class II protein complex	2	41.3×	0.035	HLA-DRA, HLA-DRB5
regulation of microtubule polymerization or depolymerization	2	41.3×	0.035	STMN2, MAPT
lysosomal protein catabolic process	2	41.3×	0.035	TMEM106B, GRN
regulation of synaptic plasticity	3	15.2×	0.035	MAPT, MEF2C, PSEN1
response to ischemia	3	14.8×	0.035	TREM2, CSF1R, MEF2C
antigen processing and presentation of peptide or polysaccharide antigen via MHC class II	1	330.4×	0.035	HLA-DRA
sinoatrial valve morphogenesis	1	330.4×	0.035	MEF2C
detection of peptidoglycan	1	330.4×	0.035	TREM2
regulation of toll-like receptor 6 signaling pathway	1	330.4×	0.035	TREM2
regulation of pronephros size	1	330.4×	0.035	HNF1B
pronephric nephron tubule development	1	330.4×	0.035	HNF1B

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Insulin Human, Latozinemab, Lithium Carbonate, Metformin, Oxytocin, Sodium Chloride.

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 13 · Phased (≥1): 13 · Undrugged: 43

Druggability breadth: 29 of 56 evidence-associated genes (52%) 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
SEM1	BORTEZOMIB
SQLE	AMIODARONE
TARDBP	MITOXANTRONE
LRRK2	PONATINIB
CHRNA4	VARENICLINE
CHRNB4	VARENICLINE
TUBB4A	COLCHICINE
CRHR1	CRINECERFONT
CSF1R	PONATINIB
TNIK	PONATINIB
ERBB4	MOBOCERTINIB
MAPT	BEPRIDIL
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPT	449	4
CSF1R	79	4
CHRNA4	64	4
ERBB4	47	4
TNIK	46	4
LRRK2	42	4
TUBB4A	21	4
CHRNB4	20	4
PSEN1	8	4
CRHR1	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	SEM1
CARFILZOMIB	4	SEM1
AMIODARONE	4	SQLE
TERBINAFINE	4	SQLE
MITOXANTRONE	4	TARDBP
PONATINIB	4	CHRNA4, CSF1R, LRRK2, TNIK
FEDRATINIB	4	CSF1R, ERBB4, LRRK2
AXITINIB	4	CSF1R, LRRK2, TNIK
RUXOLITINIB	4	LRRK2
PALBOCICLIB	4	CHRNA4, LRRK2
ENTRECTINIB	4	CSF1R, LRRK2
TOFACITINIB CITRATE	4	LRRK2
TOFACITINIB	4	LRRK2
VANDETANIB	4	CHRNA4, CSF1R, ERBB4, LRRK2, TNIK
BOSUTINIB	4	CSF1R, ERBB4, LRRK2, TNIK
BRIGATINIB	4	CSF1R, ERBB4, LRRK2
NINTEDANIB	4	CSF1R, LRRK2, TNIK
SUNITINIB	4	CHRNA4, CSF1R, LRRK2, TNIK
ERLOTINIB	4	ERBB4, LRRK2, TNIK
MIDOSTAURIN	4	CSF1R, ERBB4, LRRK2, TNIK
VARENICLINE	4	CHRNA4, CHRNB4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4, MAPT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
CSF1R	897	Binding:879, Functional:17, ADMET:1
LRRK2	809	Binding:799, ADMET:7, Functional:3
CHRNA4	624	Binding:497, Functional:125, Toxicity:1, ADMET:1
ERBB4	591	Binding:579, ADMET:8, Functional:4
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1
CHRNB4	407	Binding:309, Functional:96, ADMET:2
TNIK	257	Binding:257
CRHR1	193	Binding:139, Functional:54
MAPT	184	Binding:180, Functional:4
SEM1	26	Binding:26
SQLE	23	Binding:21, Functional:2
HNRNPA2B1	12	Binding:12
TARDBP	8	Binding:7, Functional:1
FUS	7	Binding:7
NDUFS1	5	Binding:5
ARSA	4	Binding:3, Functional:1
GFRA2	2	Binding:2
GRN	2	Binding:2
RRBP1	1	Binding:1
STMN2	1	Binding:1
TREM2	1	Binding:1
NEIL2	1	Functional:1
NSMCE2	1	Binding:1
DCTN1	1	Binding:1
WASHC5	1	Binding:1
JAG1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SQLE	1.14.14.17	squalene monooxygenase
NEIL2	3.2.2.23	DNA-formamidopyrimidine glycosylase
CSF1R	2.7.10.1	receptor protein-tyrosine kinase
ERBB4	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
LRRK2	809
CHRNA4	624
CHRNB4	407
TUBB4A	1,758
CRHR1	193
CSF1R	897
TNIK	257
ERBB4	591
MAPT	184
PSEN1	557

Pharmacogenomics

Cohort genes with a PharmGKB record: 56; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BORTEZOMIB	4	SEM1
CARFILZOMIB	4	SEM1
AMIODARONE	4	SQLE
TERBINAFINE	4	SQLE
MITOXANTRONE	4	TARDBP
PONATINIB	4	CHRNA4, CSF1R, LRRK2, TNIK
FEDRATINIB	4	CSF1R, ERBB4, LRRK2
AXITINIB	4	CSF1R, LRRK2, TNIK
RUXOLITINIB	4	LRRK2
PALBOCICLIB	4	CHRNA4, LRRK2
ENTRECTINIB	4	CSF1R, LRRK2
TOFACITINIB CITRATE	4	LRRK2
TOFACITINIB	4	LRRK2
VANDETANIB	4	CHRNA4, CSF1R, ERBB4, LRRK2, TNIK
BOSUTINIB	4	CSF1R, ERBB4, LRRK2, TNIK
BRIGATINIB	4	CSF1R, ERBB4, LRRK2
NINTEDANIB	4	CSF1R, LRRK2, TNIK
SUNITINIB	4	CHRNA4, CSF1R, LRRK2, TNIK
ERLOTINIB	4	ERBB4, LRRK2, TNIK
MIDOSTAURIN	4	CSF1R, ERBB4, LRRK2, TNIK
VARENICLINE	4	CHRNA4, CHRNB4
CHLOROPROCAINE	4	CHRNA4
ANISOTROPINE	4	CHRNA4
PALONOSETRON	4	CHRNA4
CHLORPHENTERMINE	4	CHRNA4
PYRVINIUM	4	CHRNA4
DIPHEMANIL	4	CHRNA4
SERTINDOLE	4	CHRNA4
ATRACURIUM	4	CHRNA4
NITAZOXANIDE	4	CHRNA4, MAPT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	13	SEM1, SQLE, TARDBP, LRRK2, CHRNA4, CHRNB4, TUBB4A, CRHR1, CSF1R, TNIK (+3 more)
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	5	TREM2, HLA-DRA, HLA-DRB5, ARSA, NECTIN2
D	Druggable family + AlphaFold only, no drug	1	BTNL2
E	Difficult family or no structure, no drug	37	RNASE4, BDH1, RRBP1, STMN2, HNF1B, ATP9B, PALM2, CCNF, ACTN3, OPTN (+27 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM106B	0	TARDBP, MAPT
FUS	7	TARDBP
HNRNPA2B1	12	TARDBP
RNASE4	0	—
BDH1	0	—
RRBP1	1	—
STMN2	1	—
BTNL2	0	—
HNF1B	0	—
ATP9B	0	—
PALM2	0	—
CCNF	0	—
ACTN3	0	—
OPTN	0	—
PJA2	0	—
TREM2	1	—
ST18	0	—
NEIL2	1	—
STARD3NL	0	—
COL28A1	0	—
UNC13A	0	—
GLT8D1	0	—
TMEM184C	0	—
TEPSIN	0	—
NSMCE2	1	—
ZCCHC24	0	—
DCTN1	1	—
WASHC5	1	—
MARCHF4	0	—
CEP131	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 144.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	109
PHASE2	14
PHASE1/PHASE2	7
PHASE1	5
PHASE4	3
PHASE3	3
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT06093126	PHASE4	RECRUITING	Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial
NCT00376051	PHASE4	COMPLETED	Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
NCT00594737	PHASE3	COMPLETED	Open Label Pilot Study of the Effects of Memantine on FDG-PET in Frontotemporal Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT04374136	PHASE3	TERMINATED	A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)
NCT04220021	PHASE2	ACTIVE_NOT_RECRUITING	Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD
NCT04408625	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Phase 1/2 Clinical Trial of LY3884963 in Patients With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)
NCT04747431	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes
NCT05262023	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)
NCT05374278	PHASE1/PHASE2	RECRUITING	First-in-Human Evaluation of an Astrocytic Glutamate Transporter (EAAT2) PET Tracer in Dementia
NCT05742698	PHASE2	RECRUITING	Nabilone for Agitation in Frontotemporal Dementia
NCT06064890	PHASE1/PHASE2	RECRUITING	A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)
NCT06604520	PHASE2	RECRUITING	Vortioxetine for the Treatment of Mood and Cognitive Symptoms in Frontotemporal Dementia
NCT07154485	PHASE2	NOT_YET_RECRUITING	Investigator Initiated Study for the Safety and Efficacy in Frontotemporal Dementia
NCT00416169	PHASE2	COMPLETED	A Pilot Study to Explore the Safety and Tolerability of Galantamine HBr in the Treatment of Pick Complex/Frontotemporal Dementia
NCT01890343	PHASE2	COMPLETED	Imaging Characteristics of Florbetapir 18F in Patients With Frontotemporal Dementia, Alzheimer’s Disease and Normal Controls.
NCT01937013	PHASE2	COMPLETED	Impact of Emotional Mimicry and Oxytocin on Frontotemporal Dementia
NCT02676843	PHASE2	COMPLETED	Tau PET Imaging With 18F-AV-1451 in Subjects With MAPT Mutations
NCT02862210	PHASE2	COMPLETED	Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
NCT03260920	PHASE2	UNKNOWN	Intranasal Oxytocin for Frontotemporal Dementia
NCT03987295	PHASE2	COMPLETED	A Phase 2 Study to Evaluate Safety of Long-term AL001 Dosing in Frontotemporal Dementia (FTD) Patients (INFRONT-2)
NCT04489017	PHASE2	COMPLETED	Palmitoylethanolamide Combined With Luteoline in Frontotemporal Dementia Patients. A Randomized Controlled Trial
NCT04931862	PHASE1/PHASE2	TERMINATED	Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) or Frontotemporal Dementia (FTD)
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT04993755	PHASE2	COMPLETED	A Phase 2a Study of TPN-101 in Patients With C9ORF72 ALS/FTD
NCT05683860	PHASE1/PHASE2	TERMINATED	Open-label Extension (OLE) Study of WVE-004 in Patients With C9orf72-associated Amyotrophic Lateral Sclerosis (ALS) and/or Frontotemporal Dementia (FTD)
NCT05315661	PHASE1	ACTIVE_NOT_RECRUITING	The Safety and The Efficacy Evaluation of ET-STEM in Patients With Frontotemporal Dementia
NCT01386333	PHASE1	COMPLETED	Safety Study of Intranasal Oxytocin in Frontotemporal Dementia
NCT03040713	PHASE1	COMPLETED	Flortaucipir PET Imaging in Subjects With FTD
NCT03636204	PHASE1	COMPLETED	A First in Human Study in Healthy Volunteers and in Participants With Frontotemporal Dementia With Granulin (GRN) Mutation
NCT06705192	PHASE1	COMPLETED	Study in Asymptomatic GRN-FTD Patients to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001
NCT06891716	EARLY_PHASE1	RECRUITING	[18F]ACI-19626 PET in TDP-43 Proteinopathies
NCT03510572	EARLY_PHASE1	COMPLETED	Evaluation of [18F]PI-2620 as a Potential Positron Emission Computed Tomography Radioligand for Imaging Tau Protein in the Brain
NCT03625128	EARLY_PHASE1	COMPLETED	18F-PM-PBB3 PET Study in Tauopathy Including Alzheimer’s Disease, Other Dementias and Normal Controls
NCT01353430	Not specified	RECRUITING	Characterization of Inclusion Body Myopathy Associated With Paget’s Disease of Bone and Frontotemporal Dementia (IBMPFD)
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02795052	Not specified	RECRUITING	Neurologic Stem Cell Treatment Study
NCT02945774	Not specified	RECRUITING	Molecular Neuroimaging of Neuroinflammation in Neurodegenerative Dementias
NCT03225144	Not specified	RECRUITING	Investigating Complex Neurodegenerative Disorders Related to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CITALOPRAM	4	3
FLORBETAPIR	4	3
MEMANTINE	4	3
FLORTAUCIPIR F 18	4	2
ESCITALOPRAM	4	1
FLUDEOXYGLUCOSE F 18	4	1
GALANTAMINE HYDROBROMIDE	4	1
LEMBOREXANT	4	1
LITHIUM CARBONATE	4	1
NABILONE	4	1
ROTIGOTINE	4	1
VORTIOXETINE	4	1
LATOZINEMAB	3	3
FLUORIDE ION F-18	3	1
LEUCINE	3	1
COSFROVIXIMAB	2	1
PITTSBURGH COMPOUND B	2	1
CHEMBL498563	0	1
CHEMBL5189046	0	1
CHEMBL104383	0	1
F-18	0	1