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Atlas / Disease / Hippocampal sclerosis of aging

Hippocampal sclerosis of aging

disease
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Summary

Hippocampal sclerosis of aging (MONDO:0005544) is a disease with 9 cohort genes (30 GWAS associations across 2 studies).

At a glance

  • Cohort genes: 9
  • GWAS associations: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

FieldValue
Canonical namehippocampal sclerosis of aging
Mondo IDMONDO:0005544
EFOEFO:0005678
UMLSC5691287
MedGen1801569
Anatomy (UBERON)UBERON:0001954
Is cancer (heuristic)no

Data availability: 30 GWAS associations (2 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebral cortex disorder › hippocampal sclerosis of aging

Related subtypes (5): visual cortex disorder, occipital lobe neoplasm, cerebral palsy, Pick disease, primary motor cortex epilepsy

Genetics & variants

GWAS landscape

30 GWAS associations across 2 studies. Top hits map to 9 distinct genes (as reported by GWAS).

Top associations by p-value

rsIDp-valueGeneRisk alleleOdds ratio
rs7041781e-09ABCC9G2.13
chr18:64349815e-08A2.56
rs96374547e-08KCNMB2-AS1, KCNMB2A0.5
rs341325833e-07SMAD1-AS2A0.92
chr3:168650138e-07T1.31
rs45895731e-06NPIPB13 - SMG1P5T2.02
rs80749801e-06CUEDC1A0.52
chr11:209550532e-06G0.9
rs30072432e-06RPL7P45 - DAOA-AS1G0.84
rs129503632e-06MRM1 - LHX1-DTT0.92
chr20:387250002e-06C1.73
rs112412612e-06KCNN2T0.54
chr6:1496527353e-06T1.74
rs286716663e-06THSD7A - TMEM106BA0.54
chr2:624862954e-06C0.58
rs109068244e-06ACBD7A0.97
rs123167034e-06SUDS3G0.66
chr16:591611244e-06G1.01
chr3:1928203854e-06A1.59
chr16:208992515e-06C1.26
chr3:1450974365e-06A1.14
rs124988065e-06H3P15 - RBM48P1C1.3
chr11:1266024877e-06G1.61
rs72358407e-06LINC01898 - LINC01893T0.56
rs622776178e-06SORCS2G0.74
chr8:2888848e-06A0.93
chr12:1279791378e-06T1.64
chr16:824531348e-06T1.5
chr3:1309382618e-06T1.34
chr12:31840069e-06T1.04

Top studies (by case count)

StudyLead authorYearCasesControlsTitle
GCST002589Beecham GW20143102,576Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias.
GCST002430Nelson PT20142411,998ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

TierVariants
Tier 1: coding0
Tier 2: splice/UTR0
Tier 3: regulatory0
Tier 4: intronic/intergenic30

MAF distribution

BucketVariants
common (>=0.05)10
low_freq (0.01-0.05)20
rare (<0.01)0
unknown0

Functional consequences

ConsequenceCount
unknown16
intron_variant12
intergenic_variant2

Top variants

rsIDChrPosAllelesMAFConsequenceGenep-valueTier
rs7041781221840544G>A,C,T0.49intron_variantABCC91e-09Tier 4: intronic/intergenic
chr18:64349810.015e-08Tier 4: intronic/intergenic
rs96374543178539774G>A0.279intron_variantKCNMB2-AS1, KCNMB27e-08Tier 4: intronic/intergenic
rs341325834145439605G>A0.042intron_variantSMAD1-AS23e-07Tier 4: intronic/intergenic
chr3:168650130.0178e-07Tier 4: intronic/intergenic
rs45895731630257460C>T0.015intergenic_variantNPIPB13 - SMG1P51e-06Tier 4: intronic/intergenic
rs80749801757933599G>A,C0.172intron_variantCUEDC11e-06Tier 4: intronic/intergenic
chr11:209550530.0442e-06Tier 4: intronic/intergenic
rs300724313105154603A>G,T0.041intron_variantRPL7P45 - DAOA-AS12e-06Tier 4: intronic/intergenic
rs129503631736659471G>A,C,T0.075intron_variantMRM1 - LHX1-DT2e-06Tier 4: intronic/intergenic
chr20:387250000.0182e-06Tier 4: intronic/intergenic
rs112412615114059784C>T0.149intron_variantKCNN22e-06Tier 4: intronic/intergenic
chr6:1496527350.0113e-06Tier 4: intronic/intergenic
rs28671666712144804G>A,C0.213intergenic_variantTHSD7A - TMEM106B3e-06Tier 4: intronic/intergenic
chr2:624862950.194e-06Tier 4: intronic/intergenic
rs109068241015086970G>A0.033intron_variantACBD74e-06Tier 4: intronic/intergenic
rs1231670312118402652A>G0.083intron_variantSUDS34e-06Tier 4: intronic/intergenic
chr16:591611240.034e-06Tier 4: intronic/intergenic
chr3:1928203850.0184e-06Tier 4: intronic/intergenic
chr16:208992510.0285e-06Tier 4: intronic/intergenic
chr3:1450974360.0415e-06Tier 4: intronic/intergenic
rs124988064126441942T>A,C0.017intron_variantH3P15 - RBM48P15e-06Tier 4: intronic/intergenic
chr11:1266024870.0177e-06Tier 4: intronic/intergenic
rs72358401876013245C>A,T0.148intron_variantLINC01898 - LINC018937e-06Tier 4: intronic/intergenic
rs6227761747458148A>G0.087intron_variantSORCS28e-06Tier 4: intronic/intergenic
chr8:2888840.0418e-06Tier 4: intronic/intergenic
chr12:1279791370.0158e-06Tier 4: intronic/intergenic
chr16:824531340.0188e-06Tier 4: intronic/intergenic
chr3:1309382610.0228e-06Tier 4: intronic/intergenic
chr12:31840060.0389e-06Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
KIRREL3Orphanet:178469Autosomal dominant non-syndromic intellectual disability
ABCC9Orphanet:130Brugada syndrome
ABCC9Orphanet:1517Cantú syndrome
ABCC9Orphanet:154Familial isolated dilated cardiomyopathy
ABCC9Orphanet:334Hereditary atrial fibrillation

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

SubsetGenes
gwas_only9

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SORCS2HGNC:16698ENSG00000184985Q96PQ0VPS10 domain-containing receptor SorCS2gwas
ACBD7HGNC:17715ENSG00000176244Q8N6N7Acyl-CoA-binding domain-containing protein 7gwas
NEK11HGNC:18593ENSG00000114670Q8NG66Serine/threonine-protein kinase Nek11gwas
KIRREL3HGNC:23204ENSG00000149571Q8IZU9Kin of IRRE-like protein 3gwas
DCUN1D3HGNC:28734ENSG00000188215Q8IWE4DCN1-like protein 3gwas
SUDS3HGNC:29545ENSG00000111707Q9H7L9Sin3 histone deacetylase corepressor complex component SDS3gwas
ABCC9HGNC:60ENSG00000069431O60706ATP-binding cassette sub-family C member 9gwas
KCNMB2HGNC:6286ENSG00000197584Q9Y691Calcium-activated potassium channel subunit beta-2gwas
NELL1HGNC:7750ENSG00000165973Q92832Protein kinase C-binding protein NELL1gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SORCS2VPS10 domain-containing receptor SorCS2The heterodimer formed by NGFR and SORCS2 functions as receptor for the precursor forms of NGF (proNGF) and BDNF (proBDNF).
ACBD7Acyl-CoA-binding domain-containing protein 7Binds medium- and long-chain acyl-CoA esters.
NEK11Serine/threonine-protein kinase Nek11Protein kinase which plays an important role in the G2/M checkpoint response to DNA damage.
KIRREL3Kin of IRRE-like protein 3Synaptic adhesion molecule required for the formation of target-specific synapses.
DCUN1D3DCN1-like protein 3Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes and may play a role in the cell cycle progression by regulati…
SUDS3Sin3 histone deacetylase corepressor complex component SDS3Regulatory protein which represses transcription and augments histone deacetylase activity of HDAC1.
ABCC9ATP-binding cassette sub-family C member 9Subunit of ATP-sensitive potassium channels (KATP).
KCNMB2Calcium-activated potassium channel subunit beta-2Regulatory subunit of the calcium activated potassium KCNMA1 (maxiK) channel.
NELL1Protein kinase C-binding protein NELL1Plays a role in the control of cell growth and differentiation.

Protein-family classification

Druggable: 5 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.56

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.

FamilyGenesFoldFDR
Antibody/Immunoglobulin26.5×0.180
Ion channel112.4×0.183
Transporter18.6×0.183
Kinase13.1×0.352
Other/Unknown40.8×0.847

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SORCS2Antibody/ImmunoglobulinyesPKD_dom, VPS10, Ig-like_fold
ACBD7Other/UnknownnoAcyl-CoA-binding_protein, FERM/acyl-CoA-bd_prot_sf, Acyl-CoA-binding_sf
NEK11KinaseyesProt_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
KIRREL3Antibody/ImmunoglobulinyesIg_sub2, Ig_sub, Ig-like_dom
DCUN1D3Other/UnknownnoPONY_dom, DCN-prot, DCN1-like_PONY
SUDS3Other/UnknownnoSds3
ABCC9TransporteryesABCC8/9, ABCC9, ABC_transporter-like_ATP-bd
KCNMB2Ion channelyesK_chnl_Ca-activ_BK_bsu, KCNMB2_ball_chain_dom, KCNMB2_ball/chain_dom_sf
NELL1Other/UnknownnoEGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)9
unknown0

Top tissues across cohort

TissueCohort genes
ventricular zone2
right uterine tube2
secondary oocyte2
corpus callosum1
sural nerve1
tibial nerve1
caudate nucleus1
putamen1
bronchial epithelial cell1
epithelium of bronchus1
Brodmann (1909) area 231
middle temporal gyrus1
nucleus accumbens1
epithelial cell of pancreas1
left ventricle myocardium1
oocyte1
oviduct epithelium1
gastrocnemius1
hindlimb stylopod muscle1
muscle of leg1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SORCS2191ubiquitousmarkercorpus callosum, tibial nerve, sural nerve
ACBD7127broadmarkercaudate nucleus, putamen, ventricular zone
NEK11215ubiquitousmarkerright uterine tube, bronchial epithelial cell, epithelium of bronchus
KIRREL3179broadmarkermiddle temporal gyrus, nucleus accumbens, Brodmann (1909) area 23
DCUN1D3228broadmarkersecondary oocyte, left ventricle myocardium, epithelial cell of pancreas
SUDS3254ubiquitousmarkeroviduct epithelium, secondary oocyte, oocyte
ABCC9195broadmarkergastrocnemius, muscle of leg, hindlimb stylopod muscle
KCNMB2156tissue_specificmarkerislet of Langerhans, right uterine tube, male germ line stem cell (sensu Vertebrata) in testis
NELL1178broadmarkerendothelial cell, buccal mucosa cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

SymbolInteractor count
NELL12,439
SUDS32,369
ABCC91,728
KIRREL31,290
SORCS21,157
ACBD7733
NEK11729
DCUN1D3553
KCNMB2288

Intra-cohort edges

ABSources
ABCC9KCNMB2string_interaction

Structural data

PDB: 6 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
SORCS2Q96PQ01
ACBD7Q8N6N71
KIRREL3Q8IZU91
DCUN1D3Q8IWE41
KCNMB2Q9Y6911
NELL1Q928321

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
ABCC9O6070681.72
SUDS3Q9H7L979.35
NEK11Q8NG6668.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 9 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome1815.7×0.025ABCC9
Potassium Channels238.4×0.025ABCC9, KCNMB2
ATP sensitive Potassium channels1407.9×0.033ABCC9
Ca2+ activated K+ channels1163.1×0.051KCNMB2
Nitric oxide stimulates guanylate cyclase1116.5×0.051KCNMB2
Inwardly rectifying K+ channels1102.0×0.051ABCC9
cGMP effects1102.0×0.051KCNMB2
Neuronal System212.7×0.051ABCC9, KCNMB2
Nephrin family interactions168.0×0.065KIRREL3
ABC transporter disorders162.8×0.065ABCC9
Mitochondrial Fatty Acid Beta-Oxidation154.4×0.068ACBD7
Platelet homeostasis139.8×0.084KCNMB2
Negative epigenetic regulation of rRNA expression137.1×0.084SUDS3
Ion homeostasis129.1×0.092ABCC9
Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A129.1×0.092NEK11
Disorders of transmembrane transporters119.9×0.111ABCC9
Cell-Cell communication119.7×0.111KIRREL3
Fatty acid metabolism118.8×0.111ACBD7
Deubiquitination117.7×0.111SUDS3
ABC-family protein mediated transport117.4×0.111ABCC9
HDACs deacetylate histones117.2×0.111SUDS3
Potential therapeutics for SARS116.3×0.111SUDS3
Cardiac conduction115.5×0.111ABCC9
NoRC negatively regulates rRNA expression115.0×0.111SUDS3
Chromatin organization111.7×0.134SUDS3
Muscle contraction111.0×0.134ABCC9
Chromatin modifying enzymes110.3×0.134SUDS3
Epigenetic regulation of gene expression110.2×0.134SUDS3
Disease23.7×0.134SUDS3, ABCC9
SARS-CoV Infections17.9×0.164SUDS3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO termCohort genesFoldFDRSample cohort genes
inter-male aggressive behavior1936.2×0.024KIRREL3
response to hydrogen sulfide1936.2×0.024ABCC9
negative regulation of protein neddylation1936.2×0.024DCUN1D3
principal sensory nucleus of trigeminal nerve development1624.1×0.024KIRREL3
glomerulus morphogenesis1624.1×0.024KIRREL3
action potential279.7×0.024ABCC9, KCNMB2
oxygen metabolic process1468.1×0.027ABCC9
positive regulation of protein neddylation1374.5×0.030DCUN1D3
cellular response to chemical stress1312.1×0.032ABCC9
reactive oxygen species biosynthetic process1208.1×0.032ABCC9
response to UV-C1187.2×0.032DCUN1D3
cardiac conduction1187.2×0.032ABCC9
cardiac muscle cell contraction1187.2×0.032ABCC9
regulation of mitotic cell cycle phase transition1187.2×0.032NEK11
negative regulation of osteoblast proliferation1170.2×0.032NELL1
regulation of osteoblast differentiation1144.0×0.032NELL1
detection of calcium ion1124.8×0.032KCNMB2
response to peptide1124.8×0.032ABCC9
fatty acid oxidation1117.0×0.032ABCC9
cellular response to potassium ion1117.0×0.032ABCC9
regulation of cell cycle process1110.1×0.032DCUN1D3
response to ATP1110.1×0.032ABCC9
mitotic intra-S DNA damage checkpoint signaling1104.0×0.032NEK11
positive regulation of ossification1104.0×0.032NELL1
obsolete inorganic cation transmembrane transport1104.0×0.032ABCC9
regulation of protein neddylation1104.0×0.032DCUN1D3
long-term synaptic depression198.5×0.032SORCS2
cellular response to ATP198.5×0.032ABCC9
regulation of vasoconstriction189.2×0.034KCNMB2
negative regulation of stem cell population maintenance185.1×0.035SUDS3

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 6

Druggability breadth: 4 of 9 evidence-associated genes (44%) 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.

SymbolExample approved molecule
NEK11VEMURAFENIB
ABCC9PINACIDIL ANHYDROUS

Top cohort targets by molecule count

SymbolMoleculesMax phase
NEK1154
ABCC954
SUDS312
SORCS200
ACBD700
KIRREL300
DCUN1D300
KCNMB200
NELL100

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
VEMURAFENIB4NEK11
FEDRATINIB4NEK11
BOSUTINIB4NEK11
DASATINIB4NEK11
PINACIDIL ANHYDROUS4ABCC9
GLYBURIDE4ABCC9
PROPAFENONE4ABCC9
R-4062NEK11
MOLIBRESIB2SUDS3
CROMAKALIM2ABCC9
CLAMIKALANT2ABCC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

SymbolAssaysType breakdown
NEK11141Binding:141
ABCC961Functional:46, Binding:15
SUDS37Binding:7
DCUN1D36Binding:6

Cohort genes with high screening signal

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

SymbolChEMBL assays
NEK11141

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

11 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.

CompoundMax phaseCohort target (bioactivity)
VEMURAFENIB4NEK11
FEDRATINIB4NEK11
BOSUTINIB4NEK11
DASATINIB4NEK11
PINACIDIL ANHYDROUS4ABCC9
GLYBURIDE4ABCC9
PROPAFENONE4ABCC9
R-4062NEK11
MOLIBRESIB2SUDS3
CROMAKALIM2ABCC9
CLAMIKALANT2ABCC9

Druggability pyramid

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

TierDefinitionGenesSymbols
AApproved (phase 4 drug)2NEK11, ABCC9
BPhased (≥1) drug, not yet approved1SUDS3
CDruggable family + PDB, no drug3SORCS2, KIRREL3, KCNMB2
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug3ACBD7, DCUN1D3, NELL1

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
SORCS20—
ACBD70—
KIRREL30—
DCUN1D36—
KCNMB20—
NELL10—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
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Sources 68

This page pulls from 68 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityfantom5_genefantom5_promotergenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterpromedgenmeshmimmondomondochildmondoparentorphanetpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptuberonufeatureumlsuniprot