late-onset Parkinson disease

Summary

late-onset Parkinson disease (MONDO:0008199) is a disease (an umbrella term covering 7 Mondo subtypes) caused by variants in GBA1 and MAPT, with 26 cohort genes and 12 clinical trials. Top therapeutic interventions include dexmedetomidine hydrochloride, methoxy polyethylene glycol-epoetin beta, and torsemide.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: GBA1 (GenCC Strong), MAPT (GenCC Strong)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 26
• ClinVar variants: 165
• Phenotypes (HPO): 34
• Clinical trials: 12

Clinical features

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0001300	Parkinsonism	Obligate (100%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002304	Akinesia	Frequent (30-79%)
HP:0002322	Resting tremor	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0002548	Parkinsonism with favorable response to dopaminergic medication	Frequent (30-79%)
HP:0004409	Hyposmia	Frequent (30-79%)
HP:0005340	Spastic/hyperactive bladder	Frequent (30-79%)
HP:0012450	Chronic constipation	Frequent (30-79%)
HP:0000338	Hypomimic face	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0000744	Low frustration tolerance	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002171	Gliosis	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002367	Visual hallucinations	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0004926	Orthostatic hypotension due to autonomic dysfunction	Occasional (5-29%)
HP:0031435	Monotonic speech	Occasional (5-29%)
HP:0100315	Lewy bodies	Occasional (5-29%)
HP:0100660	Dyskinesia	Occasional (5-29%)
HP:0100710	Impulsivity	Occasional (5-29%)
HP:0000726	Dementia	Very rare (<1-4%)
HP:0100753	Schizophrenia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	late-onset Parkinson disease
Mondo ID	MONDO:0008199
OMIM	168600
Orphanet	411602
DOID	DOID:0060892
SNOMED CT	716662004
UMLS	C3160718
MedGen	463618
GARD	0017684
Is cancer (heuristic)	no

Also known as: autosomal dominant late-onset Parkinson disease · hereditary late onset Parkinson disease · hereditary late-onset Parkinson disease · late-onset Parkinson disease · LOPD · PARK · Parkinson disease, age of onset, modifier, Multifactorial · Parkinson disease, late-onset · Parkinson disease, late-onset, susceptibility to, Multifactorial · Parkinson disease, susceptibility to, Multifactorial · PD

Data availability: 165 ClinVar variants · 5 GenCC gene-disease records · 662 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › Parkinson disease › late-onset Parkinson disease

Related subtypes (5): parkinsonian-pyramidal syndrome, Parkinson disease, mitochondrial, Parkinson disease 16, young-onset Parkinson disease, Parkinson disease 25, autosomal recessive early-onset, with impaired intellectual development

Subtypes (7): autosomal dominant Parkinson disease 1, autosomal dominant Parkinson disease 4, autosomal dominant Parkinson disease 8, autosomal recessive Parkinson disease 14, Parkinson disease 17, Parkinson disease 21, Parkinson disease 22, autosomal dominant

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

165 retrieved; paginated sample, class counts are floors:

74 uncertain significance, 21 pathogenic, 18 pathogenic/likely pathogenic, 11 likely pathogenic, 11 conflicting classifications of pathogenicity, 10 likely benign, 7 benign, 5 benign/likely benign, 4 pathogenic; risk factor, 2 pathogenic/likely pathogenic; risk factor, 2 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
4297	NM_001005741.2(GBA1):c.[1448T>C;1483G>C;1497G>C]		Pathogenic	criteria provided, multiple submitters, no conflicts
929858	NM_002973.4(ATXN2):c.16CAG[33_?] (p.6Gln[33_?])	ATXN2	Pathogenic; risk factor	no assertion criteria provided
3551	NM_004993.6(ATXN3):c.892CAG[8_36]	ATXN3	Pathogenic; risk factor	no assertion criteria provided
562101	NR_002717.2(ATXN8OS):n.1103CTG[(107_127)]	ATXN8	Pathogenic; risk factor	no assertion criteria provided
929501	NUBPL, 240-KB DEL AND 130-KB DUP	DTD2	Pathogenic	criteria provided, single submitter
3341091	NM_000156.6(GAMT):c.222_224del (p.Ala75del)	GAMT	Pathogenic	criteria provided, single submitter
1119997	NM_000157.4(GBA1):c.604C>T (p.Arg202Ter)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1211295	NM_000157.4(GBA1):c.1249T>G (p.Trp417Gly)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193611	NM_000157.4(GBA1):c.1265_1319del (p.Leu422fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
21072	NM_000157.4(GBA1):c.703T>C (p.Ser235Pro)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242383	NM_000157.4(GBA1):c.1603C>T (p.Arg535Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4290	NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)	GBA1	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
4292	NM_000157.4(GBA1):c.1297G>T (p.Val433Leu)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293	NM_000157.4(GBA1):c.1342G>C (p.Asp448His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4295	NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4298	NM_000157.4(GBA1):c.764T>A (p.Phe255Tyr)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4301	NM_000157.4(GBA1):c.754T>A (p.Phe252Ile)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4302	NM_000157.4(GBA1):c.84dup (p.Leu29fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4311	NM_000157.4(GBA1):c.1604G>A (p.Arg535His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4314	NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4321	NM_000157.4(GBA1):c.259C>T (p.Arg87Trp)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4326	NM_000157.4(GBA1):c.1192C>T (p.Arg398Ter)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4327	NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4328	NM_000157.4(GBA1):c.887G>A (p.Arg296Gln)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4687966	NM_000157.4(GBA1):c.745del (p.Ala249fs)	GBA1	Pathogenic	criteria provided, single submitter
632835	NM_000157.4(GBA1):c.595_596del (p.Leu199fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633240	NM_000157.4(GBA1):c.762-1G>C	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
642539	NM_000157.4(GBA1):c.222_224del (p.Thr75del)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813310	GRCh37/hg19 1q22(chr1:155188179-155209868)	GBA1	Pathogenic	criteria provided, single submitter
928837	NM_000157.4(GBA1):c.914del (p.Pro305fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 25 · Orphanet: 49 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
GBA1	Definitive	Autosomal dominant	Parkinson disease	17
MAPT	Strong	Autosomal dominant	late-onset Parkinson disease	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GBA1	Orphanet:2072	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
GBA1	Orphanet:411602	Hereditary late-onset Parkinson disease
GBA1	Orphanet:77259	Gaucher disease type 1
GBA1	Orphanet:77260	Gaucher disease type 2
GBA1	Orphanet:77261	Gaucher disease type 3
GBA1	Orphanet:85212	Fetal Gaucher disease
MAPT	Orphanet:100069	Semantic dementia
MAPT	Orphanet:100070	Progressive non-fluent aphasia
MAPT	Orphanet:240071	Classic progressive supranuclear palsy syndrome
MAPT	Orphanet:240085	Progressive supranuclear palsy-predominant parkinsonism syndrome
MAPT	Orphanet:240094	Progressive supranuclear palsy-pure akinesia with gait freezing syndrome
MAPT	Orphanet:240103	Progressive supranuclear palsy-corticobasal syndrome
MAPT	Orphanet:240112	Progressive supranuclear palsy-progressive non-fluent aphasia syndrome
MAPT	Orphanet:275864	Behavioral variant of frontotemporal dementia
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
ATXN8OS	Orphanet:98760	Spinocerebellar ataxia type 8
VPS35	Orphanet:411602	Hereditary late-onset Parkinson disease
PINK1	Orphanet:2828	Young-onset Parkinson disease
DNAJB6	Orphanet:34516	DNAJB6-related limb-girdle muscular dystrophy D1
DNAJB6	Orphanet:708126	DNAJB6-related distal myopathy
PARK7	Orphanet:2828	Young-onset Parkinson disease
PARK7	Orphanet:90020	Parkinson-dementia complex of Guam
LRRK2	Orphanet:2828	Young-onset Parkinson disease
LRRK2	Orphanet:411602	Hereditary late-onset Parkinson disease
DNAJC13	Orphanet:411602	Hereditary late-onset Parkinson disease
ATXN8	Orphanet:98760	Spinocerebellar ataxia type 8
EIF4G1	Orphanet:411602	Hereditary late-onset Parkinson disease
FGF20	Orphanet:1848	Renal agenesis, bilateral
GAMT	Orphanet:382	Guanidinoacetate methyltransferase deficiency
ATXN3	Orphanet:276238	Machado-Joseph disease type 1
ATXN3	Orphanet:276241	Machado-Joseph disease type 2
ATXN3	Orphanet:276244	Machado-Joseph disease type 3
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
NR4A2	Orphanet:1617	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion
NR4A2	Orphanet:660012	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to a NR4A2 point mutation
NR4A2	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
PODXL	Orphanet:2828	Young-onset Parkinson disease
PODXL	Orphanet:391411	Atypical juvenile parkinsonism
PSAP	Orphanet:139406	Encephalopathy due to prosaposin deficiency
PSAP	Orphanet:206436	Infantile Krabbe disease
PSAP	Orphanet:309252	Atypical Gaucher disease due to saposin C deficiency
PSAP	Orphanet:309256	Metachromatic leukodystrophy, late infantile form
PSAP	Orphanet:309263	Metachromatic leukodystrophy, juvenile form
PSAP	Orphanet:309271	Metachromatic leukodystrophy, adult form
RFC1	Orphanet:504476	Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Cohort genes → proteins

26 cohort genes, 25 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	26

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	gencc,clinvar
MAPT	HGNC:6893	ENSG00000186868	P10636	Microtubule-associated protein tau	gencc,clinvar
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	clinvar
ATXN8OS	HGNC:10561	ENSG00000230223	P0DMR3	Putative protein ATXN8OS	clinvar
SNCAIP	HGNC:11139	ENSG00000064692	Q9Y6H5	Synphilin-1	clinvar
VPS35	HGNC:13487	ENSG00000069329	Q96QK1	Vacuolar protein sorting-associated protein 35	clinvar
PINK1	HGNC:14581	ENSG00000158828	Q9BXM7	Serine/threonine-protein kinase PINK1, mitochondrial	clinvar
DNAJB6	HGNC:14888	ENSG00000105993	O75190	DnaJ homolog subfamily B member 6	clinvar
PARK7	HGNC:16369	ENSG00000116288	Q99497	Parkinson disease protein 7	clinvar
MTCH1	HGNC:17586	ENSG00000137409	Q9NZJ7	Mitochondrial carrier homolog 1	clinvar
LRRK2	HGNC:18618	ENSG00000188906	Q5S007	Leucine-rich repeat serine/threonine-protein kinase 2	clinvar
DTD2	HGNC:20277	ENSG00000129480	Q96FN9	D-aminoacyl-tRNA deacylase 2	clinvar
ADH1C	HGNC:251	ENSG00000248144	P00326	Alcohol dehydrogenase 1C	clinvar
DNAJC13	HGNC:30343	ENSG00000138246	O75165	DnaJ homolog subfamily C member 13	clinvar
ATXN8	HGNC:32925	ENSG00000288330	Q156A1	Ataxin-8	clinvar
EIF4G1	HGNC:3296	ENSG00000114867	Q04637	Eukaryotic translation initiation factor 4 gamma 1	clinvar
FGF20	HGNC:3677	ENSG00000078579	Q9NP95	Fibroblast growth factor 20	clinvar
PINK1-AS	HGNC:38872	ENSG00000117242		PINK1 antisense RNA	clinvar
GAMT	HGNC:4136	ENSG00000130005	Q14353	Guanidinoacetate N-methyltransferase	clinvar
GLUD2	HGNC:4336	ENSG00000182890	P49448	Glutamate dehydrogenase 2, mitochondrial	clinvar
ATXN3	HGNC:7106	ENSG00000066427	P54252	Ataxin-3	clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
NR4A2	HGNC:7981	ENSG00000153234	P43354	Nuclear receptor subfamily 4 group A member 2	clinvar
PODXL	HGNC:9171	ENSG00000128567	O00592	Podocalyxin	clinvar
PSAP	HGNC:9498	ENSG00000197746	P07602	Prosaposin	clinvar
RFC1	HGNC:9969	ENSG00000035928	P35251	Replication factor C subunit 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.
MAPT	Microtubule-associated protein tau	Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SNCAIP	Synphilin-1	Isoform 2 inhibits the ubiquitin ligase activity of SIAH1 and inhibits proteasomal degradation of target proteins.
VPS35	Vacuolar protein sorting-associated protein 35	Acts as a component of the retromer cargo-selective complex (CSC).
PINK1	Serine/threonine-protein kinase PINK1, mitochondrial	Serine/threonine-protein kinase which acts as a sensor of mitochondrial damage and protects against mitochondrial dysfunction during cellular stress.
DNAJB6	DnaJ homolog subfamily B member 6	Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70.
PARK7	Parkinson disease protein 7	Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease.
MTCH1	Mitochondrial carrier homolog 1	Protein insertase that mediates insertion of transmembrane proteins into the mitochondrial outer membrane.
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.
DTD2	D-aminoacyl-tRNA deacylase 2	Deacylates mischarged D-aminoacyl-tRNAs.
ADH1C	Alcohol dehydrogenase 1C	Alcohol dehydrogenase.
DNAJC13	DnaJ homolog subfamily C member 13	Involved in membrane trafficking through early endosomes, such as the early endosome to recycling endosome transport implicated in the recycling of transferrin and the early endosome to late endosome transport implicated in degradation of…
EIF4G1	Eukaryotic translation initiation factor 4 gamma 1	Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5’-terminal secondary structure and recruitment of mRNA to the ribosome.
FGF20	Fibroblast growth factor 20	Neurotrophic factor that regulates central nervous development and function.
GAMT	Guanidinoacetate N-methyltransferase	Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.
GLUD2	Glutamate dehydrogenase 2, mitochondrial	Important for recycling the chief excitatory neurotransmitter, glutamate, during neurotransmission.
ATXN3	Ataxin-3	Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	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.
NR4A2	Nuclear receptor subfamily 4 group A member 2	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.
PODXL	Podocalyxin	Involved in the regulation of both adhesion and cell morphology and cancer progression.
PSAP	Prosaposin	Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46).
RFC1	Replication factor C subunit 1	Subunit of the replication factor C (RFC) complex which acts during elongation of primed DNA templates by DNA polymerases delta and epsilon, and is necessary for ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto prime…

Protein-family classification

Druggable: 9 · Difficult: 1 · Unknown: 16 · Druggable fraction: 0.35

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	6	2.8×	0.090
Nuclear receptor	1	14.8×	0.163
Kinase	2	2.1×	0.402
Other/Unknown	16	1.1×	0.439
Scaffold/PPI	1	0.7×	0.788

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C
MAPT	Other/Unknown	no		MAP_tubulin-bd_rpt, Tau, MAP2/MAP4/Tau
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
ATXN8OS	Other/Unknown	no
SNCAIP	Scaffold/PPI	no		Ankyrin_rpt, SNCAIP_SNCA-bd, Ankyrin_rpt-contain_sf
VPS35	Other/Unknown	no		Vps35, ARM-type_fold, Vps35_C
PINK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
DNAJB6	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf
PARK7	Enzyme (other)	yes	3.5.1.124	DJ-1/PfpI, DJ-1, Class_I_gatase-like
MTCH1	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf
LRRK2	Kinase	yes		Prot_kinase_dom, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
DTD2	Other/Unknown	no		Daa-tRNA_deacyls_DTD, DTD-like_sf
ADH1C	Enzyme (other)	yes	1.1.1.1	ADH_Zn_CS, GroES-like_sf, ADH-like_C
DNAJC13	Other/Unknown	no		DnaJ_domain, ARM-like, ARM-type_fold
ATXN8	Other/Unknown	no
EIF4G1	Other/Unknown	no		W2_domain, MIF4G-like_typ-3, Initiation_fac_eIF4g_MI
FGF20	Other/Unknown	no		Fibroblast_GF_fam, IL1/FGF
PINK1-AS	Other/Unknown	no
GAMT	Enzyme (other)	yes	2.1.1.2	GuanidinoAc_N-MeTrfase, RMT2_dom, SAM-dependent_MTases_sf
GLUD2	Enzyme (other)	yes	1.4.1.3	Glu/Leu/Phe/Val/Trp_DH, Glu/Leu/Phe/Val/Trp_DH_C, Glu/Leu/Phe/Val/Trp_DH_dimer
ATXN3	Other/Unknown	no		UIM_dom, Josephin, Ataxin-3
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
NR4A2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
PODXL	Other/Unknown	no		CD34/Podocalyxin, PODXL
PSAP	Other/Unknown	no		SAP_A, SapB_1, SapB_2
RFC1	Enzyme (other)	yes	3.6.4.B8	BRCT_dom, AAA+_ATPase, ATPase_AAA_core

Expression context

Cohort genes with no expression data: 0.

23 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)	26
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	5
buccal mucosa cell	4
ventricular zone	4
cortical plate	3
monocyte	3
calcaneal tendon	3
stromal cell of endometrium	2
colonic epithelium	2
primordial germ cell in gonad	2
ganglionic eminence	2
germinal epithelium of ovary	2
adrenal tissue	2
leukocyte	2
islet of Langerhans	1
placenta	1
prefrontal cortex	1
superior frontal gyrus	1
olfactory bulb	1
male germ line stem cell (sensu Vertebrata) in testis	1
pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBA1	134	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, placenta
MAPT	141	broad	marker	cortical plate, superior frontal gyrus, prefrontal cortex
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
ATXN8OS	110		marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, pleura
SNCAIP	240	broad	marker	ventricular zone, ganglionic eminence, germinal epithelium of ovary
VPS35	149	ubiquitous	marker	ventricular zone, adrenal tissue, corpus callosum
PINK1	295	ubiquitous	marker	tendon of biceps brachii, gastrocnemius, gluteal muscle
DNAJB6	283	ubiquitous	marker	cortical plate, primordial germ cell in gonad, ganglionic eminence
PARK7	294	ubiquitous	marker	adult organism, tibia, deltoid
MTCH1	288	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
LRRK2	220	broad	marker	buccal mucosa cell, monocyte, leukocyte
DTD2	239	ubiquitous	yes	oviduct epithelium, epithelial cell of pancreas, ventricular zone
ADH1C	199	tissue_specific	marker	mucosa of transverse colon, jejunal mucosa, nasal cavity epithelium
DNAJC13	297	ubiquitous	marker	calcaneal tendon, buccal mucosa cell, saphenous vein
ATXN8	35			bone marrow cell, cortical plate, monocyte
EIF4G1	294	ubiquitous	marker	gastrocnemius, skin of leg, skin of abdomen
FGF20	119	tissue_specific	yes	buccal mucosa cell, cerebellar cortex, cerebellar hemisphere
PINK1-AS	135		marker	stromal cell of endometrium, gastrocnemius, skeletal muscle tissue
GAMT	258	ubiquitous	marker	hindlimb stylopod muscle, right lobe of liver, gastrocnemius
GLUD2	122	broad	marker	right testis, testis, left testis
ATXN3	269	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
NR4A2	278	ubiquitous	marker	mucosa of paranasal sinus, mucosa of stomach, trachea
PODXL	276	ubiquitous	marker	renal glomerulus, metanephric glomerulus, germinal epithelium of ovary
PSAP	295	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
RFC1	278	ubiquitous	marker	calcaneal tendon, ventricular zone, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRRK2	7,628
MAPT	7,289
PARK7	5,722
EIF4G1	4,901
PINK1	4,175
FGF20	3,798
VPS35	3,669
MT-ND1	3,537
DNAJB6	3,518
ATXN2	3,360

Intra-cohort edges

A	B	Sources
ATXN2	ATXN3	string_interaction
DNAJB6	GAMT	intact
DNAJC13	EIF4G1	string_interaction
DNAJC13	VPS35	string_interaction
EIF4G1	VPS35	string_interaction
GBA1	LRRK2	string_interaction
LRRK2	MAPT	string_interaction
LRRK2	PARK7	string_interaction
LRRK2	PINK1	string_interaction
LRRK2	SNCAIP	string_interaction
LRRK2	VPS35	string_interaction
PARK7	PINK1	string_interaction
PARK7	SNCAIP	string_interaction
PINK1	SNCAIP	string_interaction

Structural data

PDB: 19 · AlphaFold-only: 6 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPT	P10636	293
PARK7	Q99497	88
GBA1	P04062	58
LRRK2	Q5S007	44
PSAP	P07602	20
EIF4G1	Q04637	14
VPS35	Q96QK1	13
NR4A2	P43354	8
ATXN3	P54252	7
PINK1	Q9BXM7	6
MT-ND1	P03886	5
DNAJB6	O75190	4
RFC1	P35251	4
ADH1C	P00326	2
ATXN2	Q99700	1
SNCAIP	Q9Y6H5	1
FGF20	Q9NP95	1
GAMT	Q14353	1
GLUD2	P49448	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATXN8	Q156A1	97.39
DTD2	Q96FN9	96.31
DNAJC13	O75165	82.91
MTCH1	Q9NZJ7	76.29
PODXL	O00592	53.66
ATXN8OS	P0DMR3	38.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 133. Enrichment computed across 26 evidence-associated genes (19 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 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
FGFR3b ligand binding and activation	1	85.9×	0.108	FGF20
PTK6 promotes HIF1A stabilization	1	85.9×	0.108	LRRK2
Creatine metabolism	1	54.6×	0.108	GAMT
Signaling by activated point mutants of FGFR1	1	50.1×	0.108	FGF20
Signaling by activated point mutants of FGFR3	1	50.1×	0.108	FGF20
Caspase-mediated cleavage of cytoskeletal proteins	1	50.1×	0.108	MAPT
Josephin domain DUBs	1	50.1×	0.108	ATXN3
Ethanol oxidation	1	50.1×	0.108	ADH1C
Z-decay: degradation of maternal mRNAs by zygotically expressed factors	1	50.1×	0.108	EIF4G1
FGFR3c ligand binding and activation	1	46.2×	0.108	FGF20
FGFR2c ligand binding and activation	1	46.2×	0.108	FGF20
Phospholipase C-mediated cascade; FGFR3	1	46.2×	0.108	FGF20
FGFR4 ligand binding and activation	1	42.9×	0.108	FGF20
Polymerase switching	1	42.9×	0.108	RFC1
Glutamate and glutamine metabolism	1	42.9×	0.108	GLUD2
FGFR1c ligand binding and activation	1	40.1×	0.108	FGF20
Phospholipase C-mediated cascade; FGFR4	1	40.1×	0.108	FGF20
Translesion synthesis by REV1	1	37.6×	0.108	RFC1
FOXO-mediated transcription of cell death genes	1	37.6×	0.108	PINK1
Activated point mutants of FGFR2	1	35.4×	0.108	FGF20
Phospholipase C-mediated cascade: FGFR1	1	35.4×	0.108	FGF20
Translesion synthesis by POLI	1	35.4×	0.108	RFC1
Phospholipase C-mediated cascade; FGFR2	1	33.4×	0.108	FGF20
PI-3K cascade:FGFR3	1	33.4×	0.108	FGF20
Translesion synthesis by POLK	1	33.4×	0.108	RFC1
Translesion Synthesis by POLH	1	31.6×	0.108	RFC1
SHC-mediated cascade:FGFR3	1	31.6×	0.108	FGF20
Glycosphingolipid catabolism	2	30.8×	0.108	GBA1, PSAP
PI-3K cascade:FGFR4	1	30.1×	0.108	FGF20
Downstream signaling of activated FGFR1	1	28.6×	0.108	FGF20

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 23 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of late endosome to lysosome transport	2	732.7×	3e-04	VPS35, LRRK2
positive regulation of dopamine biosynthetic process	2	732.7×	3e-04	VPS35, PARK7
negative regulation of neuron apoptotic process	5	24.1×	3e-04	GBA1, PINK1, PARK7, FGF20, NR4A2
mitochondrion to lysosome vesicle-mediated transport	2	488.5×	3e-04	VPS35, PINK1
regulation of synaptic vesicle transport	2	488.5×	3e-04	PINK1, LRRK2
positive regulation of mitochondrial electron transport, NADH to ubiquinone	2	488.5×	3e-04	PINK1, PARK7
negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathway	2	488.5×	3e-04	PINK1, PARK7
positive regulation of dopamine receptor signaling pathway	2	366.4×	6e-04	VPS35, LRRK2
negative regulation of mitochondrial fission	2	293.1×	7e-04	MAPT, PINK1
negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxide	2	293.1×	7e-04	PINK1, PARK7
positive regulation of protein localization to cell periphery	2	293.1×	7e-04	VPS35, EIF4G1
cellular response to oxidative stress	4	26.9×	7e-04	PINK1, PARK7, LRRK2, NR4A2
intracellular distribution of mitochondria	2	209.3×	0.001	MAPT, LRRK2
regulation of mitochondrial fission	2	183.2×	0.002	MAPT, LRRK2
lysosome organization	3	40.0×	0.002	GBA1, VPS35, LRRK2
positive regulation of type 2 mitophagy	2	133.2×	0.003	GBA1, PINK1
regulation of autophagy	3	31.4×	0.003	MAPT, LRRK2, PSAP
negative regulation of autophagosome assembly	2	112.7×	0.003	PINK1, LRRK2
negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway	2	112.7×	0.003	PINK1, PARK7
negative regulation of macroautophagy	2	97.7×	0.004	PINK1, LRRK2
regulation of cellular response to heat	2	91.6×	0.005	MAPT, DNAJB6
regulation of synaptic vesicle endocytosis	2	77.1×	0.006	PARK7, LRRK2
regulation of mitochondrion organization	2	73.3×	0.006	VPS35, PINK1
respiratory electron transport chain	2	73.3×	0.006	GBA1, PINK1
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	2	73.3×	0.006	PARK7, LRRK2
negative regulation of gene expression	4	12.0×	0.006	MAPT, VPS35, PINK1, PARK7
positive regulation of mitochondrial fission	2	66.6×	0.007	VPS35, PINK1
regulation of reactive oxygen species metabolic process	2	63.7×	0.007	PINK1, LRRK2
mitochondrion organization	3	19.8×	0.007	PINK1, PARK7, LRRK2
exploration behavior	2	56.4×	0.009	LRRK2, ATXN3

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 8 · Undrugged: 18

Druggability breadth: 18 of 26 evidence-associated genes (69%) 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
GBA1	MIGALASTAT
MAPT	BEPRIDIL
LRRK2	PONATINIB
NR4A2	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPT	449	4
LRRK2	42	4
NR4A2	14	4
GBA1	12	4
VPS35	1	2
PARK7	1	2
PSAP	1	3
RFC1	1	2
ATXN2	0	0
ATXN8OS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1, MAPT
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1, MAPT
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
LRRK2	809	Binding:799, ADMET:7, Functional:3
GBA1	436	Binding:403, Functional:33
NR4A2	274	Binding:273, Functional:1
MAPT	184	Binding:180, Functional:4
PARK7	62	Binding:62
PINK1	24	Binding:24
ADH1C	12	Binding:12
PSAP	12	Binding:8, ADMET:4
VPS35	11	Binding:11
EIF4G1	8	Binding:8
RFC1	8	Binding:8
ATXN3	7	Binding:7
ATXN2	5	Binding:3, Functional:2
MT-ND1	5	Binding:5
DNAJB6	2	Binding:2
GAMT	2	ADMET:2
SNCAIP	1	Binding:1
DNAJC13	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA1	3.2.1.45	glucosylceramidase
PARK7	3.5.1.124, 4.2.1.130	protein deglycase, D-lactate dehydratase
ADH1C	1.1.1.1	alcohol dehydrogenase
GAMT	2.1.1.2	guanidinoacetate N-methyltransferase
GLUD2	1.4.1.3	glutamate dehydrogenase [NAD(P)+]
RFC1	3.6.4.B8

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GBA1	436
MAPT	184
LRRK2	809
NR4A2	274

Pharmacogenomics

Cohort genes with a PharmGKB record: 25; 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)
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1, MAPT
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1, MAPT
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	GBA1, MAPT, LRRK2, NR4A2
B	Phased (≥1) drug, not yet approved	4	VPS35, PARK7, PSAP, RFC1
C	Druggable family + PDB, no drug	4	PINK1, ADH1C, GAMT, GLUD2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	14	ATXN2, ATXN8OS, SNCAIP, DNAJB6, MTCH1, DTD2, DNAJC13, ATXN8, EIF4G1, FGF20 (+4 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PINK1	24	PARK7
DNAJC13	1	VPS35
ATXN2	5	—
ATXN8OS	0	—
SNCAIP	1	—
DNAJB6	2	—
MTCH1	0	—
DTD2	0	—
ADH1C	12	—
ATXN8	0	—
EIF4G1	8	—
FGF20	0	—
PINK1-AS	0	—
GAMT	2	—
GLUD2	0	—
ATXN3	7	—
MT-ND1	5	—
PODXL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE4	3
PHASE1/PHASE2	2
PHASE1	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT05810454	Not specified	NOT_YET_RECRUITING	iPACES v3 MCI NIA Protocol Copied for iPACES v4 PD NINDS
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease
NCT03893240	Not specified	COMPLETED	Neutralizing Antibody Seroprevalence Study With a Retrospective Component in Participants With Late-Onset Pompe Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXMEDETOMIDINE HYDROCHLORIDE	4	2
METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA	4	1
TORSEMIDE	4	1
SUMECIGREL	2	1
VANGLUSAGENE ENSIPARVOVEC	1	1