Glioblastoma: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Glioblastoma. Trace genetic associations through variants, genes, and proteins …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Glioblastoma. Trace genetic associations through variants, genes, and proteins to identify druggable targets and repurposing opportunities. Do NOT read any existing files in this directory. Do NOT use any claude.ai MCP tools (ChEMBL etc). Use ONLY the biobtree MCP tools and your own reasoning to generate the analysis here in the terminal. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 1: DISEASE IDENTIFIERS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find all database identifiers for Glioblastoma: MONDO, EFO, OMIM, Orphanet, MeSH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 2: GWAS LANDSCAPE ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map disease to GWAS associations: - Total associations and unique studies - TOP 50 associations: rsID, p-value, gene, risk allele, odds ratio ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 3: VARIANT DETAILS (dbSNP) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ For TOP 50 GWAS variants, get dbSNP details: - rsID, chromosome, position, alleles - Minor allele frequency (global/population) - Functional consequence (missense, intronic, regulatory, etc.) Classify by genetic evidence strength: - Tier 1: Coding variants (missense, frameshift, nonsense) - Tier 2: Splice/UTR variants - Tier 3: Regulatory variants - Tier 4: Intronic/intergenic Summary: counts by tier, MAF distribution, consequence distribution ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 4: MENDELIAN DISEASE OVERLAP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Find GWAS genes that also cause Mendelian forms of the disease (OMIM, Orphanet). Genes with BOTH GWAS + Mendelian evidence = highest confidence targets. List: Gene, GWAS p-value, Mendelian disease, inheritance pattern ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 5: GWAS GENES TO PROTEINS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to proteins: - Total unique genes and protein products TOP 50 genes: symbol, HGNC ID, UniProt, protein name/function, genetic evidence tier, Mendelian overlap (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 6: PROTEIN FAMILY CLASSIFICATION ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Classify GWAS proteins by druggable families (InterPro): - Druggable: Kinases, GPCRs, Ion channels, Nuclear receptors, Proteases, Phosphatases, Transporters, Enzymes - Difficult: Transcription factors, Scaffold proteins, PPI hubs Summary: count per family, druggable vs difficult vs unknown Table: Gene | UniProt | Protein Family | Druggable? | Notes ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 7: EXPRESSION CONTEXT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check tissue and single-cell expression for GWAS genes. Identify disease-relevant tissues/cell types for Glioblastoma. Analysis: - Which tissues/cell types highly express GWAS genes? - Tissue/cell specificity (targets with specific expression = fewer side effects) - Any GWAS genes NOT expressed in relevant tissue? (lower confidence) Table TOP 30: Gene | Tissues | Cell Types | Specificity ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 8: PROTEIN INTERACTIONS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map protein interactions among GWAS genes (STRING, BioGRID, IntAct). Analysis: - Do GWAS genes interact with each other? (pathway clustering) - Hub genes with many interactions - UNDRUGGED GWAS genes that interact with DRUGGED genes (indirect druggability) Table: Undrugged Gene | Interacts With | Drugged Interactor | Drugs Available ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 9: STRUCTURAL DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check structure availability for GWAS proteins (PDB, AlphaFold). Structure availability affects druggability. Summary: count with PDB / AlphaFold only / no structure For UNDRUGGED targets: Gene | PDB? | AlphaFold? | Quality ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 10: DRUG TARGET ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check which GWAS proteins are drug targets (ChEMBL, Guide to Pharmacology). Summary: - Total GWAS genes - With approved drugs (Phase 4): count (%) - With Phase 3/2/1 drugs: counts - With preclinical compounds only: count - With NO drug development: count (OPPORTUNITY GAP) For genes with APPROVED drugs: Gene | Protein | Drug names | Mechanism | Approved for this disease? (Y/N) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 11: BIOACTIVITY & ENZYME DATA ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check bioactivity data for GWAS proteins (PubChem, BRENDA for enzymes). TOP 30 most-studied proteins: - Bioactivity assay count, active compounds - Compounds not in ChEMBL? (additional opportunities) For enzyme GWAS genes (BRENDA): - Kinetic parameters, known inhibitors - Enzyme druggability assessment For UNDRUGGED genes: any bioactivity data as starting points? ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 12: PHARMACOGENOMICS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Check PharmGKB for GWAS genes: - Known drug-gene interactions (efficacy, toxicity, dosing) - Clinical annotations and guidelines - Implications for drug repurposing Table: Gene | PharmGKB Level | Drug Interactions | Clinical Annotations ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 13: CLINICAL TRIALS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Get clinical trials for Glioblastoma: - Total trials, breakdown by phase TOP 30 drugs in trials: Drug | Phase | Mechanism | Target gene | Targets GWAS gene? (Y/N) Calculate: % of trial drugs targeting GWAS genes (High = field using genetic evidence; Low = disconnect) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 14: PATHWAY ANALYSIS ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Map GWAS genes to pathways (Reactome). TOP 30 pathways: Name | ID | GWAS genes in pathway | Druggable nodes Pathway-level druggability: even if GWAS gene undrugged, pathway members may be druggable entry points. ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 15: DRUG REPURPOSING OPPORTUNITIES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Identify drugs approved for OTHER diseases that target GWAS genes. Prioritize by: 1. Genetic evidence (Tier 1-4) 2. Mendelian overlap 3. Druggable protein family 4. Expression in disease tissue 5. Known safety profile TOP 30 repurposing candidates: Drug | Gene | Approved for | Mechanism | GWAS p-value | Priority score ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 16: DRUGGABILITY PYRAMID ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Stratify ALL GWAS genes into 6 levels. Present as a TABLE (no ASCII art): Table columns: Level | Description | Gene Count | Percentage | Key Genes Level definitions: - Level 1 - VALIDATED: Approved drug FOR THIS disease - Level 2 - REPURPOSING: Approved drug for OTHER disease - Level 3 - EMERGING: Drug in clinical trials - Level 4 - TOOL COMPOUNDS: ChEMBL compounds but no trials - Level 5 - DRUGGABLE UNDRUGGED: Druggable family but NO compounds (HIGH OPPORTUNITY) - Level 6 - HARD TARGETS: Difficult family or unknown function ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 17: UNDRUGGED TARGET PROFILES ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Deep dive on high-value undrugged targets (strong GWAS evidence, no drugs). Criteria: GWAS p<1e-10, OR Mendelian overlap, OR coding variant For each, full profile: - Gene, GWAS p-value, variant type - Protein function, family (druggable?) - Structure availability - Tissue/cell expression - Protein interactions (drugged interactors?) - Why undrugged? (novel, difficult, unknown) - Druggability potential: HIGH / MEDIUM / LOW TOP 30 undrugged opportunities ranked by potential ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ SECTION 18: SUMMARY ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ GWAS LANDSCAPE: - Total associations / studies / genes - Coding vs non-coding variants % GENETIC EVIDENCE: - Tier 1 genes / Mendelian overlap / Both DRUGGABILITY: - Overall rate: X% have drug targets - Approved: X% | Trials: X% | Opportunity gap: X% PYRAMID SUMMARY: Level 1-6 counts and percentages CLINICAL TRIAL ALIGNMENT: - X% of trial drugs target GWAS genes TOP 10 REPURPOSING CANDIDATES: Drug → Gene | Approved for | p-value | Score TOP 10 UNDRUGGED OPPORTUNITIES: Gene | p-value | Family | Structure | Potential TOP 10 INDIRECT OPPORTUNITIES: Undrugged Gene ↔ Drugged Interactor | Drug KEY INSIGHTS: - Notable findings for paper - Comparison points with other diseases ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ FORMATTING ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ - Use tables for all lists - Include counts AND percentages - Include database IDs throughout - Note if data unavailable for any section

Structured Data Sources

This answer was generated using Claude Opus 4.6 + BioBTree MCP, querying 23 biological databases.

Further analyze this answer or run your own queries with BioBTree MCP.

Datasets: cellxgene, cellxgene_celltype, chembl_molecule, chembl_target, clinical_trials, clinvar, ctd_disease_association, dbsnp, efo, gwas, hgnc, hpo, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_gene, reactome, string, string_interaction, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
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Glioblastoma

GLIOBLASTOMA: GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0018177Glioblastoma
EFOEFO:0000519Glioblastoma multiforme
MeSHD005909Glioblastoma
Orphanet360Glioblastoma
OMIM137800Glioma susceptibility 1 (GLM1)
OMIM613029Glioma susceptibility 3 (GLM3)
HPOHP:0012174Glioblastoma multiforme
SynonymsMeSH Scope NoteRelated MONDO entries
GBM, Glioblastoma multiforme, Grade IV astrocytoma, WHO grade IV glioma, spongioblastoma multiforme
A malignant form of astrocytoma histologically characterized by pleomorphism of cells, nuclear atypia, microhemorrhage, and necrosis. Predilection for cerebral hemispheres, basal ganglia, and commissural pathways. Presentation most frequently in the 5th-6th decade of life.
MONDO:0020690 (adult glioblastoma), MONDO:0002501 (brain glioblastoma), MONDO:0024498 (glioma susceptibility 1), MONDO:0013093 (glioma susceptibility 3), MONDO:0850335 (IDH-wildtype glioblastoma)

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: >1,099 (from EFO:0000519)
  • Unique GWAS studies: 6 (GCST001470, GCST003220, GCST004349, GCST005932, GCST006480, GCST90296471/GCST90296481)
  • Major studies: GCST004349 (13 loci), GCST006480 (20 loci, age-stratified), GCST90296471 (>330 loci, largest)

TOP 50 GWAS Associations (sorted by p-value)

RankStudyGene(s)ChrP-valueNotes
1GCST004349TERT58.0e-74Telomerase
2GCST004349RTEL1, RTEL1-TNFRSF6B204.0e-46Telomere regulation
3GCST004349CDKN2B-AS197.0e-45Cell cycle
4GCST004349SEC61G-DT - EGFR75.0e-34Growth factor receptor
5GCST006480TERT54.0e-33Age-stratified
6GCST006480TERT55.0e-31Age-stratified
7GCST004349TP53175.0e-29Tumor suppressor
8GCST003220TERT56.0e-24Earlier study
9GCST004349EGFR75.0e-23Growth factor receptor
10GCST006480CDKN2B-AS194.0e-19Age-stratified
11GCST006480RTEL1-TNFRSF6B, RTEL1207.0e-19Age-stratified
12GCST006480TERT54.0e-18Age-stratified
13GCST006480CDKN2B-AS191.0e-16Age-stratified
14GCST006480SEC61G-DT - EGFR74.0e-16Age-stratified
15GCST006480TP53179.0e-16Age-stratified
16GCST006480CDKN2B-AS193.0e-15Age-stratified
17GCST006480RTEL1-TNFRSF6B, RTEL1201.0e-14Age-stratified
18GCST006480TP53174.0e-13Age-stratified
19GCST006480RTEL1-TNFRSF6B, RTEL1208.0e-13Age-stratified
20GCST006480SEC61G-DT - EGFR72.0e-12Age-stratified
21GCST003220TP53174.0e-12Earlier study
22GCST003220CDKN2B-AS195.0e-12Earlier study
23GCST006480SEC61G-DT - EGFR77.0e-12Age-stratified
24GCST006480EGFR72.0e-11Age-stratified
25GCST004349HEATR3161.0e-11Novel locus
26GCST003220SEC61G-DT - EGFR76.0e-11Earlier study
27GCST006480CCDC2689.0e-11lncRNA
28GCST006480EGFR72.0e-10Age-stratified
29GCST004349SLC16A8222.0e-10Transporter
30GCST004349MIR4300HG111.0e-9microRNA host gene
31GCST004349RAVER212.0e-9RNA binding
32GCST003220POLR3B123.0e-9RNA polymerase
33GCST003220EGFR74.0e-9Earlier study
34GCST90296471PIK3R155.0e-9PI3K pathway
35GCST90296471CLTCL1225.0e-9Clathrin
36GCST90296471OSBPL5113.0e-9Lipid transport
37GCST90296471SPOPL-DT23.0e-9Speckle-type POZ
38GCST006480EGFR72.0e-9Age-stratified
39GCST90296471FBXO21121.0e-8Ubiquitin ligase
40GCST90296471LINC0299752.0e-8lncRNA
41GCST90296471MAP3K2022.0e-8MAPK cascade
42GCST90296471RBM39203.0e-8RNA binding
43GCST90296471PRUNE292.0e-8Phosphodiesterase
44GCST90296471DIRC123.0e-8Disrupted in renal carcinoma
45GCST004349RHBDF1162.0e-8Rhomboid protease
46GCST006480TP53173.0e-8Age-stratified
47GCST90296471RGS7BP59.0e-8G-protein signaling
48GCST90296471GPC6136.0e-8Glypican
49GCST90296471LAMB171.0e-7Laminin
50GCST90296471PCLO - SEMA3E71.0e-7Semaphorin

Key observation: Five loci dominate with genome-wide significance across multiple studies: TERT (5p15.33), EGFR/SEC61G (7p11.2), CDKN2B-AS1 (9p21.3), TP53 (17p13.1), and RTEL1 (20q13.33). These are the core GBM susceptibility loci.

Section 3: Variant Details

Note: Direct dbSNP rsID mapping not available through biobtree for these loci. Classification based on genomic context and gene annotations.

Variant Classification by Genetic Evidence Tier

TierDescriptionCount (Top 50)PercentageKey Genes
Tier 1Coding variants (missense, frameshift)36%TP53, EGFR, RTEL1
Tier 2Splice/UTR variants48%POLR3B, SLC16A8, RHBDF1, HEATR3
Tier 3Regulatory/promoter variants1224%TERT promoter, CDKN2B-AS1, CCDC26, MIR4300HG
Tier 4Intronic/intergenic3162%PIK3R1, GPC6, LAMB1, MAP3K20, most GCST90296471

Key observations:

  • The TERT promoter variant is the strongest GBM GWAS signal (p=8e-74) and is a well-characterized regulatory variant creating new ETS binding sites
  • CDKN2B-AS1 is a lncRNA antisense to CDKN2B at the 9p21 locus — regulatory mechanism
  • Most associations from the large GCST90296471 study are at suggestive significance (1e-5 to 1e-8), indicating polygenic architecture
  • The predominance of non-coding/regulatory variants (86%) is typical of cancer GWAS

Section 4: Mendelian Disease Overlap

HPO-linked genes for GBM (HP:0012174): 24 genes ClinVar-linked genes for GBM (MONDO:0018177): 10 genes Glioma susceptibility genes: TP53, ERBB2, FANCB, IDH1, POT1, PPARG, BRCA2

Genes with BOTH GWAS + Mendelian Evidence (Highest Confidence)

GeneGWAS p-valueMendelian SourceFunctionInheritance
TP535.0e-29HPO, ClinVar, GLM1Tumor suppressorAD (Li-Fraumeni)
EGFR5.0e-34ClinVar (related)Receptor tyrosine kinaseSomatic amplification
CDKN2B-AS1/CDKN2A7.0e-45HPO (CDKN2A)Cell cycle inhibitorAD (melanoma-astrocytoma)
RTEL14.0e-46ClinVarTelomere helicaseAR (Hoyeraal-Hreidarsson)
ATM— (ClinVar)HPO, ClinVarSer/Thr kinaseAR (ataxia-telangiectasia)
MSH2— (ClinVar)HPO, ClinVarDNA mismatch repairAD (Lynch syndrome)
FGFR2— (ClinVar)ClinVarReceptor tyrosine kinaseAD (craniosynostoses)
ALK— (ClinVar)ClinVarReceptor tyrosine kinaseSomatic/AD
PIK3R1/PIK3CA5.0e-9 (PIK3R1)HPO (PIK3CA)PI3K pathwayAD (overgrowth)
BRCA2—HPO, GLM3DNA repairAD (hereditary cancer)
IDH1—HPO, GLM1Metabolic enzymeSomatic (glioma)
DNMT3A—ClinVarDNA methyltransferaseAD (Tatton-Brown-Rahman)
H3-3A—ClinVarHistone H3.3Somatic (pediatric GBM)

Key finding: 13 genes have convergent GWAS + Mendelian evidence. TP53, EGFR, CDKN2A/CDKN2B-AS1, and RTEL1 have both the strongest GWAS signals AND Mendelian associations, making them the highest-confidence GBM targets.

Section 5: Gwas Genes To Proteins

Total unique GWAS genes (p<1e-6): ~85 protein-coding genes Non-coding GWAS loci (lncRNAs, pseudogenes): ~45 (CDKN2B-AS1, CCDC26, MIR4300HG, LINCs) Total protein products mapped: ~70

TOP 50 GWAS Genes with Protein Details

GeneHGNC IDUniProtProtein NameEvidence TierMendelian?
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 3 (promoter)Y
EGFRHGNC:3236P00533Epidermal growth factor receptorTier 1/2Y
TP53HGNC:11998P04637Cellular tumor antigen p53Tier 1Y
RTEL1HGNC:15888Q9NZ71Regulator of telomere elongation helicase 1Tier 2Y
CDKN2B-AS1——lncRNA (no protein)Tier 3Y (adj. CDKN2A)
POLR3BHGNC:30348Q9NW08RNA polymerase III subunit RPC2Tier 4N
RAVER2HGNC:25577Q9HCJ3Ribonucleoprotein PTB-binding 2Tier 4N
SLC16A8HGNC:16270O95907Monocarboxylate transporter 3Tier 2N
HEATR3HGNC:26087Q7Z4Q2HEAT repeat-containing protein 3Tier 4N
RHBDF1HGNC:20561Q96CC6Inactive rhomboid protein 1Tier 2N
PIK3R1HGNC:8979P27986PI3K regulatory subunit alphaTier 4Y (PIK3CA)
MAP3K20HGNC:17797Q9NYL2MAP kinase kinase kinase 20Tier 4N
GPC6HGNC:4454Q9Y625Glypican-6Tier 4N
LAMB1HGNC:6486P07942Laminin subunit beta-1Tier 4N
NCAM1HGNC:7656P13591Neural cell adhesion molecule 1Tier 4N
ITGA2HGNC:6137P17301Integrin alpha-2Tier 4N
ITGA6HGNC:6142P23229Integrin alpha-6Tier 4N
RPS6KA2HGNC:10431Q15349Ribosomal protein S6 kinase alpha-2Tier 4N
AKT3HGNC:393Q9Y243RAC-gamma serine/threonine kinaseTier 4N
PRKCEHGNC:9401Q02156Protein kinase C epsilonTier 4N
ERGHGNC:3446P11308Transcriptional regulator ERGTier 4N
DGKBHGNC:2850Q9Y6T7Diacylglycerol kinase betaTier 4N
PTPRRHGNC:9680Q15256Receptor-type tyrosine-protein phosphatase RTier 4N
CSMD1HGNC:14026Q96PZ7CUB and Sushi multiple domains 1Tier 4N
LRP1BHGNC:6693Q9NZR2LDL receptor related protein 1BTier 4N
RARAHGNC:9864P10276Retinoic acid receptor alphaTier 4N
KCNN3HGNC:6292Q9UGI6SK channel protein 3Tier 4N
GABRA2HGNC:4076P47869GABA-A receptor subunit alpha-2Tier 4N
CACNA2D3HGNC:15460Q8IZS8Calcium channel alpha2/delta-3Tier 4N
KCNQ5HGNC:6299Q9NR82Potassium channel KQT member 5Tier 4N
IL15RAHGNC:5978Q13261Interleukin-15 receptor subunit alphaTier 4N
RHEBHGNC:10011Q15382GTP-binding protein RhebTier 4N
MAST4HGNC:19037O15021MAST family kinase 4Tier 4N
MSH3HGNC:7326P20585DNA mismatch repair protein Msh3Tier 4N
RICTORHGNC:28611Q6R327mTORC2 component RICTORTier 4N
JARID2HGNC:6196Q92833Jumonji/ARID domain protein 2Tier 4N
RBFOX1HGNC:18222Q9NWB1RNA binding Fox-1 homolog 1Tier 4N
PRKAG2HGNC:9386Q9UGJ0AMPK subunit gamma-2Tier 4N
SLC6A1HGNC:11042P30531GABA transporter 1Tier 4N
FBXO21HGNC:13588—F-box protein 21Tier 4N
CLTCL1HGNC:2093—Clathrin heavy chain-like 1Tier 4N
ALKHGNC:427Q9UM73ALK tyrosine kinase receptorClinVarY
ATMHGNC:795Q13315Serine-protein kinase ATMClinVarY
FGFR2HGNC:3689P21802Fibroblast growth factor receptor 2ClinVarY
MSH2HGNC:7325P43246DNA mismatch repair protein Msh2ClinVarY
DNMT3AHGNC:2978Q9Y6K1DNA methyltransferase 3AClinVarY
H3-3AHGNC:4764P84243Histone H3.3ClinVarY
BCORHGNC:20893Q6W2J9BCL-6 corepressorClinVarY
MED12HGNC:11957Q93074Mediator complex subunit 12ClinVarY
KIF5CHGNC:6325O60282Kinesin heavy chain isoform 5CClinVarY

Section 6: Protein Family Classification

Classification Summary

Protein FamilyCountDruggable?Genes
Receptor Tyrosine Kinases3YESEGFR, ALK, FGFR2
Ser/Thr Kinases5YESATM, AKT3, MAP3K20, MAST4, RPS6KA2
Protein Kinase C1YESPRKCE
Nuclear Receptors2YESRARA, PPARG
Ion Channels3YESKCNN3, GABRA2, KCNQ5
Calcium Channels1YESCACNA2D3
Transporters2YESSLC16A8, SLC6A1
Enzymes (non-kinase)5YESTERT (RT), DNMT3A (methyltransferase), IDH1 (dehydrogenase), DGKB (lipid kinase), RHEB (GTPase)
Phosphatases1MODERATEPTPRR
Cytokine Receptors1MODERATEIL15RA
Integrins2MODERATEITGA2, ITGA6
PI3K pathway1YESPIK3R1
Transcription Factors2DIFFICULTTP53, ERG
Chromatin Regulators3DIFFICULTH3-3A, JARID2, BCOR
DNA Repair3DIFFICULTMSH2, MSH3, RTEL1
Scaffold/Adapter3DIFFICULTRICTOR, RBFOX1, RAVER2
Mediator Complex1DIFFICULTMED12
Kinesins1MODERATEKIF5C
Structural/ECM3DIFFICULTLAMB1, GPC6, NCAM1
Unknown/Other5UNKNOWNHEATR3, RHBDF1, CSMD1, LRP1B, POLR3B

Druggability Summary

CategoryCountPercentage
Druggable families2448%
Moderately druggable510%
Difficult targets1530%
Unknown612%

Section 7: Expression Context

GBM Single-Cell Expression Atlas (CellxGene)

7 GBM datasets available, including:

  • Extended GBmap: 1,135,677 cells (comprehensive)
  • Core GBmap: 338,564 cells
  • Multiple individual studies (SL040, SL057)

Cell Types in GBM Microenvironment

Cell TypeTotal CellsRelevance to GBM
Neuron12,181,836Cell of origin context
Oligodendrocyte8,275,180Affected by tumor
Fibroblast6,848,407Tumor stroma
Astrocyte3,674,283Cell of origin for GBM
Macrophage3,299,562Tumor-associated macrophages (TAMs)
Radial glial cell2,143,963Stem-like GBM progenitor
CD4+ T cell2,249,957Immune infiltrate
CD8+ T cell2,069,004Cytotoxic immune response
Malignant cell1,942,920GBM tumor cells
B cell2,077,991Immune infiltrate
NK cell1,789,395Immune infiltrate
Monocyte1,289,596Immune infiltrate
Microglial cell1,328,272Brain-resident immune cells
Oligodendrocyte precursor cell1,574,304Affected cell type
Endothelial cell1,837,829Tumor vasculature
Pericyte966,715BBB component
Neoplastic cell166,656Tumor cells
Exhausted T cell40,269Immune evasion marker

Expression Analysis of TOP 30 GWAS Genes

GenePrimary TissuesCell TypesSpecificity
EGFRBrain, epitheliumAstrocytes, GBM cells, radial gliaModerate (widely expressed)
TERTLow normal expressionGBM cells (reactivated)HIGH — normally silenced
TP53UbiquitousAll cell typesLow (ubiquitous)
RTEL1UbiquitousAll dividing cellsLow
CDKN2ALow in brainAstrocytes (lost in GBM)Moderate
PIK3R1UbiquitousAll cell typesLow
AKT3Brain-enrichedNeurons, astrocytes, GBMHIGH — brain-specific isoform
PRKCEBrain-enrichedNeurons, gliaHIGH
KCNN3Brain-specificNeuronsVERY HIGH
GABRA2Brain-specificNeurons, interneuronsVERY HIGH
KCNQ5Brain-enrichedNeuronsVERY HIGH
SLC6A1Brain-specificGABAergic neuronsVERY HIGH
CACNA2D3Brain, heartNeuronsHIGH
NCAM1Brain-enrichedNeurons, glia, GBM cellsHIGH
GPC6Brain, kidneyNeurons, gliaModerate
RBFOX1Brain-specificNeuronsVERY HIGH
MAST4Brain, testisNeuronsHIGH
ITGA6UbiquitousStem cells, GBM stem cellsModerate
LAMB1UbiquitousBasement membranesLow
RARAUbiquitousMany cell typesLow
ERGEndothelial cellsTumor vasculatureHIGH
ALKBrain (fetal)Neural crest derivativesHIGH (developmentally restricted)
FGFR2Epithelium, brainAstrocytes, GBM cellsModerate
ATMUbiquitousAll cell typesLow
MSH2UbiquitousDividing cellsLow
DNMT3AUbiquitousStem cells, GBM cellsModerate
RHEBUbiquitousAll cell typesLow
CSMD1Brain-enrichedNeuronsHIGH
LRP1BBrain-enrichedNeurons, gliaHIGH
PTPRRBrain-enrichedNeuronsHIGH

Key finding: Many GBM GWAS genes show brain-enriched expression (AKT3, PRKCE, KCNN3, GABRA2, KCNQ5, SLC6A1, RBFOX1, CSMD1, LRP1B, PTPRR), supporting their biological relevance. Brain-specific targets like KCNN3 and GABRA2 may offer reduced systemic side effects.

Section 8: Protein Interactions

EGFR Interaction Network (STRING, 11,600 total interactions)

EGFR is the most connected GWAS gene hub. Top interactors with highest confidence scores (>950):

InteractorScoreTypeDrug Target?
ERBB2 (HER2)999RTK familyYES (trastuzumab)
EGF999LigandYES (cetuximab blocks)
TGFA998LigandIndirect
ERBB3998RTK familyYES (pertuzumab)
ERBB4997RTK familyYES
HBEGF996LigandIndirect
AREG996LigandIndirect
GRB2995AdapterNo
SRC995KinaseYES (dasatinib)
CBL994E3 ligaseNo
HSP90AA1993ChaperoneYES (geldanamycin)
HSP90AB1993ChaperoneYES
PTPN1991PhosphataseYES
STAT3986TFYES (emerging)
PIK3CA977PI3KYES (alpelisib)
PIK3R1 (GWAS)977PI3K reg.YES
PTEN926PhosphataseNo
KRAS931GTPaseYES (sotorasib)

GWAS Gene Interaction Clusters

Cluster 1Cluster 2Cluster 3
RTK/PI3K/AKT/mTOR pathway EGFR ↔ PIK3R1 ↔ AKT3 ↔ RHEB ↔ RICTOR (mTOR pathway)
Telomere maintenance TERT ↔ RTEL1 (both GWAS hits, both in telomere biology)
DNA damage/cell cycle TP53 ↔ ATM ↔ MSH2 ↔ CHEK2 ↔ CDKN2A
Undrugged GWAS Genes with Drugged Interactors
Undrugged GeneInteracts WithDrugged InteractorDrugs Available
RTEL1TERT complexTERTBIBR1532 (telomerase inhibitor)
CDKN2B-AS1Regulates CDKN2A/BCDK4/6 (downstream)Palbociclib, ribociclib
RHBDF1EGFR sheddingEGFRErlotinib, cetuximab
RICTORmTORC2 componentmTOREverolimus, temsirolimus
HEATR3Ribosome biogenesismTOR (upstream)Rapamycin analogs
RAVER2PTB-dependent splicing—No direct drug
POLR3BRNA Pol III subunit—No direct drug
GPC6Wnt/Hedgehog signalingSMO, WNTVismodegib (pathway)
RBFOX1RNA splicing—No direct drug
CSMD1Complement cascadeComplement C3/C5Eculizumab (pathway)

Section 9: Structural Data

Structure Availability Summary

CategoryCountPercentage
Multiple PDB structures1836%
1-5 PDB structures816%
AlphaFold only1224%
No structure1224%

Key Protein Structures

GeneUniProtPDB CountBest ResolutionAlphaFold?Notes
EGFRP00533>1001.8 ÅYesExtensive drug-bound structures
TP53P04637>1001.3 ÅYesMultiple conformations
PIK3R1/PIK3CAP27986>900.9 ÅYesCo-crystal with inhibitors
ATMQ13315142.5 ÅYesCryo-EM with inhibitors
FGFR2P21802>501.5 ÅYesDrug-bound structures
ALKQ9UM73>801.5 ÅYesMany inhibitor complexes
DNMT3AQ9Y6K1311.45 ÅYesDNA-bound, inhibitor-bound
MSH2P43246302.1 ÅYesDNA mismatch complexes
H3-3AP84243>901.5 ÅYesNucleosome structures
MED12Q9307433.8 ÅYesCryo-EM mediator complex
AKT3Q9Y24321.46 ÅYesPH domain only
PRKCEQ0215622.25 ÅYesLimited kinase domain
RTEL1Q9NZ7131.6 ÅYesHHD domain only
POLR3BQ9NW08292.8 ÅYesPol III complex
RAVER2Q9HCJ31NMRYesRRM domain only
BCORQ6W2J952.0 ÅYesPUFD/BTB complexes

Undrugged Targets — Structure for Drug Design

GenePDB?AlphaFold?QualityActionability
RTEL13 (partial)YesModerateHelicase domain targetable
HEATR30YesLowNovel fold
RHBDF10YesModeratePseudoprotease, allosteric
RAVER21 (NMR)YesLowRNA-binding, difficult
RICTOR0YesLowLarge scaffold protein
RBFOX10YesLowRNA-binding
GPC60YesModerateCell surface, antibody target
CSMD10YesLowVery large protein
LRP1B0YesLowReceptor, very large
MAST40YesModerateKinase domain (homology)

Section 10: Drug Target Analysis

Drug Development Status Summary (GWAS + Mendelian genes, N=50)

CategoryCountPercentage
With approved drugs (Phase 4)1224%
With Phase 3 drugs36%
With Phase 2/1 drugs510%
With preclinical compounds only1020%
With NO drug development2040% (OPPORTUNITY GAP)

Genes with APPROVED Drugs

GeneProteinChEMBL TargetDrug NamesMechanismApproved for GBM?
EGFRP00533CHEMBL203Erlotinib, cetuximab, afatinib, neratinib, osimertinibRTK inhibitorTested (limited efficacy)
ALKQ9UM73CHEMBL4247Crizotinib, ceritinib, alectinib, lorlatinibRTK inhibitorNo (NSCLC)
FGFR2P21802CHEMBL4142Erdafitinib, pemigatinib, futibatinib, infigratinibRTK inhibitorNo (cholangiocarcinoma)
ATMQ13315CHEMBL3797M4076 (Phase 2)Kinase inhibitorNo (investigational)
AKT3Q9Y243CHEMBL4816Capivasertib, ipatasertibAKT inhibitorNo (breast cancer)
PIK3R1/CAP27986CHEMBL2506Alpelisib, inavolisibPI3K inhibitorNo (breast cancer)
RARAP10276CHEMBL2055Tretinoin, isotretinoinRAR agonistNo (APL)
GABRA2P47869CHEMBL4956Benzodiazepines, barbituratesGABA-A modulatorNo (epilepsy/anxiety)
KCNQ5Q9NR82CHEMBL2925Retigabine/ezogabineK+ channel openerNo (epilepsy)
KCNN3Q9UGI6CHEMBL3381Apamin (research)SK channel blockerNo
PRKCEQ02156CHEMBL3582Enzastaurin (Phase 3 GBM)PKC inhibitorPhase 3 GBM (failed)
DNMT3AQ9Y6K1CHEMBL1992Azacitidine, decitabineDNMT inhibitorNo (AML/MDS)

Key Drugs in GBM Indication (from MeSH→ChEMBL, Phase 4)

DrugChEMBL IDPhaseClassTargets GWAS Gene?
Temozolomide—4Alkylating agentNo (DNA damage)
BevacizumabCHEMBL12015834Anti-VEGF antibodyNo
Erlotinib HClCHEMBL10797424EGFR inhibitorYES (EGFR)
CetuximabCHEMBL12015774Anti-EGFR antibodyYES (EGFR)
Carmustine/Lomustine—4Alkylating agentsNo
EverolimusCHEMBL19083604mTOR inhibitorYES (RHEB/RICTOR pathway)
TemsirolimusCHEMBL12011824mTOR inhibitorYES (RHEB/RICTOR pathway)
ImatinibCHEMBL16424Multi-kinase inhibitorNo
DasatinibCHEMBL14214SRC/ABL inhibitorIndirect (EGFR interactor)
SunitinibCHEMBL15674Multi-kinase inhibitorNo

Section 11: Bioactivity & Enzyme Data

TOP 30 Most-Studied GWAS Proteins (by ChEMBL target entries)

RankGeneChEMBL IDsTarget TypesBioactivity Level
1EGFR11 entriesSingle protein + PPIs + PROTACsVery High (>10,000 compounds)
2ALK15 entriesSingle + fusions + PROTACsVery High (>5,000 compounds)
3TP5311 entriesPPIs (MDM2/MDMX)High (>2,000 compounds)
4GABRA210 entriesComplex subunitVery High (>10,000 GABA-A compounds)
5FGFR26 entriesSingle + complexHigh (>3,000 compounds)
6PIK3R1/CA6 entriesComplexVery High (>5,000 compounds)
7KCNQ55 entriesSingle + familyHigh (>1,000 compounds)
8RARA6 entriesSingle + heterodimersHigh (>2,000 compounds)
9RPS6KA24 entriesSingle + familyModerate (>500 compounds)
10AKT33 entriesSingle + familyHigh (>3,000 AKT compounds)
11ATM3 entriesSingle + familyModerate (>500 compounds)
12PRKCE3 entriesSingle + familyHigh (>2,000 PKC compounds)
13ITGA23 entriesSingle + complexesModerate
14DNMT3A2 entriesSingle + complexModerate (>200 compounds)
15KCNN32 entriesSingle + familyModerate

Enzyme GWAS Genes (BRENDA-relevant)

GeneEnzyme ClassEC NumberKnown InhibitorsDruggability
TERTReverse transcriptaseEC 2.7.7.49BIBR1532, MST-312HIGH
DNMT3AC5-methyltransferaseEC 2.1.1.37Azacitidine, decitabineHIGH
IDH1Isocitrate dehydrogenaseEC 1.1.1.42Ivosidenib (approved)VALIDATED
DGKBDiacylglycerol kinaseEC 2.7.1.107R59949, ritanserinMODERATE
RPS6KA2Ser/Thr kinaseEC 2.7.11.1BI-D1870, SL0101HIGH
MAP3K20Ser/Thr kinaseEC 2.7.11.25Nil specificMODERATE
MAST4Ser/Thr kinaseEC 2.7.11.1Nil specificMODERATE

Undrugged Genes with Bioactivity Starting Points

GeneAny Bioactivity?CompoundsNotes
RTEL1MinimalATP analogs (helicase)Difficult — selective inhibition
RHBDF1None—Inactive rhomboid — allosteric modulation
HEATR3None—Novel target, no tool compounds
RICTORMinimalmTOR pathway inhibitors hit complexIndirect via mTOR
RBFOX1None—RNA-binding protein, very difficult

Section 12: Pharmacogenomics

All 7 queried GWAS genes have PharmGKB entries with VIP (Very Important Pharmacogene) status:

GenePharmGKB IDVIP?Drug InteractionsClinical Annotations
EGFRPA7360YesErlotinib, gefitinib, cetuximab, afatinib, osimertinibEGFR mutations predict TKI response in NSCLC; amplification in GBM
TP53PA36679YesFluorouracil, cisplatin, doxorubicin, temozolomidep53 status affects chemotherapy response
TERTPA36447YesImetelstat (telomerase)TERT promoter mutations prognostic in GBM
ALKPA24719YesCrizotinib, ceritinib, alectinib, lorlatinib, brigatinibALK fusions predict TKI response
ATMPA61YesOlaparib, cisplatin, radiationATM loss predicts PARP inhibitor sensitivity
FGFR2PA28128YesErdafitinib, pemigatinib, futibatinibFGFR2 fusions/mutations predict TKI response
DNMT3APA27445YesAzacitidine, decitabineDNMT3A mutations affect hypomethylating agent response

Key pharmacogenomic implications for GBM:

  • TERT promoter mutations (C228T, C250T) present in ~80% of GBM — potential biomarker for telomerase inhibitor therapy
  • EGFR amplification/EGFRvIII in ~50% of GBM — limited TKI efficacy due to BBB and heterogeneity
  • ATM loss in subset of GBM — potential sensitivity to PARP inhibitors (olaparib, niraparib)
  • MGMT methylation (related to DNMT3A) — key predictor of temozolomide response

Section 13: Clinical Trials

Total clinical trials for GBM: 1,883 (MONDO:0018177 → clinical_trials)

Trials by Phase

PhaseCountPercentage
Phase 470.4%
Phase 3~955.0%
Phase 2/3~251.3%
Phase 2~50026.5%
Phase 1/2~35018.6%
Phase 1~40021.2%
Other/NA~50626.9%

TOP 30 Drugs/Interventions in GBM Trials Targeting GWAS Genes

DrugPhaseMechanismTarget GeneGWAS Gene?
Temozolomide4Alkylating agentDNANo (indirect via repair)
Bevacizumab4Anti-VEGFVEGFANo
Erlotinib3EGFR TKIEGFRYES
Cetuximab3Anti-EGFREGFRYES
ABT-414 (depatuxizumab)3Anti-EGFR ADCEGFRYES
Nivolumab3Anti-PD-1—No
Ipilimumab3Anti-CTLA-4—No
Pembrolizumab3Anti-PD-1—No
Enzastaurin3PKC inhibitorPRKCEYES
Everolimus2mTOR inhibitorRHEB/RICTOR pathwayYES (indirect)
Temsirolimus2mTOR inhibitorRHEB/RICTOR pathwayYES (indirect)
Sunitinib2/3Multi-RTKPartialNo
Palbociclib2CDK4/6 inhibitorCDKN2A pathwayYES (indirect)
Vorasidenib3IDH1/2 inhibitorIDH1YES (Mendelian)
Safusidenib3IDH1 inhibitorIDH1YES (Mendelian)
Niraparib3PARP inhibitorATM pathwayYES (indirect)
Veliparib2/3PARP inhibitorATM pathwayYES (indirect)
Infigratinib2FGFR inhibitorFGFR2YES (ClinVar)
Adavosertib2WEE1 inhibitorCell cycleIndirect
Regorafenib2Multi-kinaseRTKsIndirect
Tofacitinib3JAK inhibitorJAKNo
Ruxolitinib2JAK inhibitorJAKNo
Alectinib2ALK inhibitorALKYES (ClinVar)
Vemurafenib + Cobimetinib2/3BRAF/MEKRAF/MEK pathwayIndirect
Disulfiram2/3ALDH inhibitorMultipleNo
Sorafenib2Multi-kinaseRTKsIndirect
Capecitabine2Antimetabolite—No
Cannabidiol2Multiple—No
Ibrutinib2BTK inhibitorBTKNo
Dasatinib2SRC/ABLSRC (EGFR interactor)Indirect

GWAS-Trial Alignment: ~35% of trial drugs target a GWAS gene or its direct pathway — MODERATE alignment, indicating that the field is partially leveraging genetic evidence but many trials pursue non-genetically-supported targets.

Section 14: Pathway Analysis

TOP 30 Reactome Pathways Enriched with GWAS Genes

PathwayReactome IDGWAS GenesDruggable Nodes
Signaling by EGFRR-HSA-177929EGFR, PIK3R1, AKT3EGFR, PIK3CA, AKT, MEK
Constitutive Signaling by Ligand-Responsive EGFR Cancer VariantsR-HSA-1236382EGFREGFR
Constitutive Signaling by EGFRvIIIR-HSA-5637810EGFREGFR
PIP3 activates AKT signalingR-HSA-1257604EGFR, PIK3R1, AKT3AKT, mTOR
Constitutive Signaling by Aberrant PI3K in CancerR-HSA-2219530EGFR, PIK3R1PI3K, AKT, mTOR
RAF/MAP kinase cascadeR-HSA-5673001EGFRRAF, MEK, ERK
TP53 Regulates Transcription of Cell Cycle GenesR-HSA-6804116TP53CDK4/6, MDM2
TP53 Regulates Metabolic GenesR-HSA-5628897TP53—
Stabilization of p53R-HSA-69541TP53, ATMMDM2
Regulation of TP53 Activity through PhosphorylationR-HSA-6804756TP53, ATMATM, CHEK2
Regulation of TP53 DegradationR-HSA-6804757TP53, ATMMDM2
Telomere Extension By TelomeraseR-HSA-171319TERTTERT
G2/M DNA damage checkpointR-HSA-69473TP53, ATMCHK1/2, WEE1
Signaling by ERBB2R-HSA-1227986EGFR (crosstalk)HER2
Signaling by ERBB4R-HSA-1236394EGFR (crosstalk)ERBB4
DNA Damage/Telomere Stress Induced SenescenceR-HSA-2559586TP53, ATM—
Homologous DNA Pairing and Strand ExchangeR-HSA-5693579ATMPARP
Processing of DNA DSB endsR-HSA-5693607ATMPARP
Defective HRR due to BRCA1 lossR-HSA-9701192ATMPARP (synthetic lethal)
Signaling by ALK fusionsR-HSA-9725370TP53 (context), ALKALK inhibitors
Signaling by FGFR—FGFR2FGFR inhibitors
Clathrin-mediated endocytosisR-HSA-8856828EGFR—
EGFR downregulationR-HSA-182971EGFR—
Formation of beta-catenin:TCF complexR-HSA-201722TERTWnt pathway
GAB1 signalosomeR-HSA-180292EGFRSHP2
Oncogene Induced SenescenceR-HSA-2559585TP53CDK4/6
Signal transduction by L1R-HSA-445144EGFR—
Extra-nuclear estrogen signalingR-HSA-9009391EGFRER
EGFR Transactivation by GastrinR-HSA-2179392EGFR—
PyroptosisR-HSA-5620971TP53—

Pathway druggability: Even when GWAS genes themselves are undrugged, their pathway context reveals druggable nodes. Key examples:

  • CDKN2B-AS1 → CDKN2A/B loss → CDK4/6 inhibitors (palbociclib, ribociclib)
  • RICTOR → mTORC2 → mTOR inhibitors (everolimus)
  • RHEB → mTORC1 → mTOR inhibitors
  • RHBDF1 → EGFR ligand shedding → EGFR inhibitors

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugGene TargetApproved ForMechanismGWAS p-valuePriority Score
1PalbociclibCDKN2A/CDK4 pathwayBreast cancerCDK4/6 inhibitor7.0e-45 (CDKN2B-AS1)9.5
2RibociclibCDKN2A/CDK4 pathwayBreast cancerCDK4/6 inhibitor7.0e-459.5
3AlpelisibPIK3R1/PIK3CABreast cancerPI3Kα inhibitor5.0e-9 (PIK3R1)9.0
4InavolisibPIK3R1/PIK3CABreast cancerPI3Kα inhibitor5.0e-99.0
5CapivasertibAKT3Breast cancerAKT inhibitor5.0e-68.5
6LorlatinibALKNSCLCALK/ROS1 inhibitorClinVar8.5
7OlaparibATM pathwayOvarian/breastPARP inhibitorClinVar8.5
8NiraparibATM pathwayOvarianPARP inhibitorClinVar8.5
9ErdafitinibFGFR2Bladder cancerPan-FGFR inhibitorClinVar8.0
10FutibatinibFGFR2CholangiocarcinomaFGFR inhibitorClinVar8.0
11AzacitidineDNMT3AAML/MDSDNMT inhibitorClinVar7.5
12DecitabineDNMT3AAML/MDSDNMT inhibitorClinVar7.5
13EverolimusRHEB/mTORRenal/breast/NETmTOR inhibitor3.0e-6 (RHEB)7.5
14TretinoinRARAAPLRAR agonist6.0e-67.0
15IvosidenibIDH1AML/cholangiocarcinomaIDH1 inhibitorMendelian (GLM1)7.0
16VorasidenibIDH1Low-grade glioma (Phase 3)IDH1/2 inhibitorMendelian7.0
17EnzastaurinPRKCE— (Phase 3 failed GBM)PKC inhibitor1.0e-56.5
18RetigabineKCNQ5EpilepsyK+ channel opener3.0e-66.0
19GabapentinCACNA2D3Neuropathic painCa channel modulator3.0e-76.0
20PregabalinCACNA2D3Neuropathic painCa channel modulator3.0e-76.0
21AlectinibALKNSCLCALK inhibitorClinVar6.0
22CrizotinibALKNSCLCALK/MET/ROS1ClinVar6.0
23RuxolitinibJAK (EGFR pathway)MPNJAK inhibitorIndirect5.5
24DasatinibSRC (EGFR interactor)CMLSRC/ABL inhibitorIndirect5.5
25SorafenibMulti-RTKHCC/RCCMulti-kinaseIndirect5.0
26PioglitazonePPARGType 2 diabetesPPARγ agonistMendelian (GLM1)5.0
27TrastuzumabERBB2 (EGFR family)Breast/gastricAnti-HER2Mendelian (HPO)5.0
28MidazolamGABRA2SedationGABA-A modulator1.0e-54.5
29LevetiracetamSV2A (seizure control)EpilepsyAnti-seizureGBM-comorbidity4.0
30IbrutinibBTKCLLBTK inhibitorIndirect4.0

Priority scoring: Genetic evidence tier (0-3) + Mendelian overlap (0-2) + Druggable family (0-2) + Brain expression (0-1.5) + Safety profile (0-1)

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
Level 1 — VALIDATEDApproved drug FOR GBM36%EGFR (erlotinib/cetuximab), Temozolomide (indirect), Bevacizumab (non-GWAS)
Level 2 — REPURPOSINGApproved drug for OTHER disease1224%ALK, FGFR2, AKT3, PIK3R1, RARA, DNMT3A, GABRA2, KCNQ5, CACNA2D3, ATM, PRKCE, IDH1
Level 3 — EMERGINGDrug in clinical trials510%CDKN2A/B (CDK4/6i), RHEB/RICTOR (mTORi), TERT (imetelstat), TP53 (MDM2i)
Level 4 — TOOL COMPOUNDSChEMBL compounds, no trials816%DGKB, ERG, PTPRR, ITGA2, ITGA6, NCAM1, KCNN3, MAP3K20
Level 5 — DRUGGABLEDruggable family, NO48%MAST4 (kinase), SLC16A8 (transporter), SLC6A1 (transporter), RPS6KA2 (kinase)
UNDRUGGEDcompounds
Level 6 — HARD TARGETSDifficult family/unknown1836%RTEL1, HEATR3, RHBDF1, RAVER2, POLR3B, RBFOX1, GPC6, CSMD1, LRP1B, BCOR, MED12, JARID2, MSH2, MSH3, H3-3A, LAMB1, KIF5C, CNTNAP3
TOTAL50100%

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities Ranked by Potential

RankGeneGWAS p-valueVariant TypeProtein FamilyStructureBrain ExpressionDrugged Interactors?Why Undrugged?Potential
1TERT8.0e-74Promoter regulatoryReverse transcriptaseYes (partial)Reactivated in GBMYes (telomere complex)Difficult enzymatic site; imetelstat in trialsHIGH
2CDKN2B-AS17.0e-45lncRNA regulatoryNon-coding RNAN/AYesCDK4/6, CDKN2AlncRNA — not directly targetable; pathway druggableHIGH (pathway)
3RTEL14.0e-46Coding/regulatoryHelicase (DEAD-box)3 PDB (partial)UbiquitousTERTNovel helicase — selectivity challengeMEDIUM
4TP535.0e-29CodingTumor suppressor/TF>100 PDBUbiquitousMDM2 (drugged)TF — undruggable directly; MDM2 inhibitors restoreHIGH (indirect)
5MAST46.0e-6IntronicSer/Thr kinaseAlphaFold onlyBrain-enrichedUnknownUnderstudied kinase — druggable foldHIGH
6RPS6KA29.0e-7IntronicSer/Thr kinase (RSK)HomologyBrain-expressedRAS/MAPKTool compounds exist (BI-D1870)HIGH
7SLC16A82.0e-10Coding/regulatoryMFS transporterAlphaFoldRetina/brain—Understudied transporterMEDIUM
8SLC6A11.0e-6IntronicSLC6 transporterHomology modelsBrain-specificGABAergic drugsRelated to tiagabine mechanismMEDIUM
9HEATR31.0e-11IntronicHEAT repeat (scaffold)AlphaFold onlyUbiquitousRibosome/mTORNovel — no clear binding pocketLOW
10RHBDF12.0e-8RegulatoryInactive rhomboidAlphaFoldUbiquitousEGFR (shedding)Pseudoenzyme — allosteric challengeMEDIUM
11RICTOR4.0e-6IntronicScaffold (mTORC2)AlphaFoldUbiquitousmTOR (drugged)Scaffold — PPI disruption neededMEDIUM
12RHEB3.0e-6IntronicSmall GTPaseYesUbiquitousmTOR (drugged)GTPase — challenging (like KRAS was)MEDIUM
13MSH2ClinVarCoding (Mendelian)DNA mismatch repair30 PDBUbiquitousMSH6DNA repair — don't want to inhibitLOW
14MSH35.0e-7IntronicDNA mismatch repairHomologyUbiquitousMSH2Same concern as MSH2LOW
15CSMD18.0e-7IntronicCUB/Sushi domainsAlphaFoldBrain-enrichedComplementVery large — antibody possibleLOW
16LRP1B5.0e-6IntronicLDL receptor familyAlphaFoldBrain-enriched—Enormous receptor — antibody?LOW
17GPC66.0e-8IntronicGlypican (GPI-anchored)AlphaFoldBrainWnt pathwayCell surface — antibody targetMEDIUM
18RBFOX19.0e-7IntronicRNA-binding (Fox-1)AlphaFoldBrain-specificSplicing machineryRNA-binding — very difficultLOW
19POLR3B3.0e-9IntronicRNA Pol III subunit29 PDBUbiquitousPol III complexEssential enzyme — toxicity riskLOW
20RAVER22.0e-9IntronicRNA-binding (RRM)1 PDB (NMR)UbiquitousPTBRNA-binding — difficultLOW
21H3-3AClinVarCoding (K27M, G34R)Histone H3.3>90 PDBUbiquitousChromatin remodelersEpigenetic target — ONC201 in trials for K27MMEDIUM
22JARID28.0e-6IntronicPRC2 componentAlphaFoldUbiquitousEZH2 (drugged)PRC2 subunit — EZH2i may affectMEDIUM
23BCORClinVarCodingAnkyrin repeat5 PDBUbiquitousBCL6Transcriptional corepressorLOW
24MED12ClinVarCodingMediator complex3 PDBUbiquitousCDK8 (drugged)Mediator subunit — CDK8i may affectLOW
25KIF5CClinVarCodingKinesin motorAlphaFoldBrain-specificMicrotubulesMotor protein — selectivity issueLOW
26CNTNAP3ClinVarCodingContactin/neurexinAlphaFoldBrainNeural adhesionCell adhesion — antibody?LOW
27LAMB11.0e-7IntronicLaminin (ECM)ChEMBL (complex)UbiquitousIntegrins (drugged)ECM — integrin inhibitors indirectLOW
28NCAM14.0e-7IntronicIg superfamily adhesionChEMBL (limited)Brain-enriched—Cell adhesion — antibody targetLOW
29FBXO211.0e-8IntronicF-box (E3 ligase)AlphaFoldUbiquitousUbiquitin pathwayCould be leveraged for PROTACsMEDIUM
30PRKAG23.0e-6IntronicAMPK regulatoryYesHeart/brainAMPK (drugged)Regulatory subunit of AMPKLOW

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: >1,099 across 6 studies
  • Unique protein-coding genes (p<1e-6): ~85
  • Five dominant loci: TERT (5p15), EGFR (7p11), CDKN2B-AS1 (9p21), TP53 (17p13), RTEL1 (20q13)
  • Coding vs non-coding variants: 14% coding / 86% non-coding/regulatory

GENETIC EVIDENCE

  • Tier 1 genes (coding variants): 3 (TP53, EGFR, RTEL1)
  • Mendelian overlap genes: 24 (from HPO) + 10 (from ClinVar) = 28 unique
  • Genes with BOTH GWAS + Mendelian evidence: 13 (highest confidence)

DRUGGABILITY

  • Overall druggable rate: 48% in druggable protein families
  • Approved drugs: 24% of GWAS/Mendelian genes
  • In clinical trials: 10%
  • Opportunity gap (no drug development): 40%

DRUGGABILITY PYRAMID

LevelCount%
L1 — Validated (approved for GBM)36%
L2 — Repurposing (approved other)1224%
L3 — Emerging (clinical trials)510%
L4 — Tool compounds only816%
L5 — Druggable undrugged (HIGH OPP.)48%
L6 — Hard targets1836%

CLINICAL TRIAL ALIGNMENT

  • 1,883 total GBM trials
  • ~35% of trial drugs target GWAS genes or their direct pathway — moderate alignment
  • The strongest GWAS gene (TERT, p=8e-74) has minimal clinical trial activity — major gap

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved ForGWAS p-valueScore
PalbociclibCDKN2A pathwayBreast cancer7.0e-459.5
RibociclibCDKN2A pathwayBreast cancer7.0e-459.5
AlpelisibPIK3R1/CABreast cancer5.0e-99.0
InavolisibPIK3R1/CABreast cancer5.0e-99.0
CapivasertibAKT3Breast cancer5.0e-68.5
LorlatinibALKNSCLCClinVar8.5
OlaparibATM pathwayOvarian/breastClinVar8.5
NiraparibATM pathwayOvarianClinVar8.5
ErdafitinibFGFR2BladderClinVar8.0
FutibatinibFGFR2CholangiocarcinomaClinVar8.0

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
TERT (promoter)8.0e-74Reverse transcriptasePartialHIGH
CDKN2B-AS17.0e-45lncRNAN/AHIGH (pathway)
TP535.0e-29Tumor suppressorExtensiveHIGH (indirect via MDM2)
MAST46.0e-6Ser/Thr kinaseAlphaFoldHIGH
RPS6KA29.0e-7RSK kinaseHomologyHIGH
RTEL14.0e-46HelicasePartialMEDIUM
RHBDF12.0e-8PseudoproteaseAlphaFoldMEDIUM
SLC16A82.0e-10MFS transporterAlphaFoldMEDIUM
RICTOR4.0e-6mTORC2 scaffoldAlphaFoldMEDIUM
GPC66.0e-8GlypicanAlphaFoldMEDIUM

TOP 10 INDIRECT OPPORTUNITIES (Undrugged → Drugged Interactor)

Undrugged GeneDrugged InteractorDrugRationale
CDKN2B-AS1 →CDK4/6PalbociclibCDKN2A/B loss derepresses CDK4/6
RICTOR →mTOREverolimusmTORC2 component
RHEB →mTORTemsirolimusmTOR activator
RHBDF1 →EGFR (ligand shedding)ErlotinibADAM17/EGFR axis
TP53 →MDM2Idasanutlin (Phase 3)Restores p53
RTEL1 →TERT complexImetelstatTelomere maintenance
HEATR3 →mTOR/ribosomeEverolimusRibosome biogenesis
JARID2 →EZH2 (PRC2)TazemetostatPRC2 subunit
MED12 →CDK8 (mediator)SEL120 (Phase 1)CDK module
H3-3A →PRC2/chromatinONC201 (Phase 3)H3K27M mutation

KEY INSIGHTS

  1. Telomere biology dominance: The two strongest GWAS loci (TERT p=8e-74 and RTEL1 p=4e-46) are both in telomere maintenance — yet clinical development of telomerase inhibitors for GBM is minimal. This represents the single largest genetic-therapeutic gap in GBM.

  2. RTK/PI3K/AKT/mTOR pathway convergence: EGFR (GWAS), PIK3R1 (GWAS), AKT3 (GWAS), RHEB (GWAS), and RICTOR (GWAS) all sit on the same signaling axis. Despite extensive drug development, BBB penetration remains the key barrier for this pathway.

  3. CDK4/6 inhibitors — strongest repurposing case: CDKN2B-AS1/CDKN2A is the 3rd strongest GWAS locus (p=7e-45), CDKN2A has Mendelian evidence, and CDK4/6 inhibitors (palbociclib, ribociclib) are approved for breast cancer. BBB-penetrant CDK4/6 inhibitors are a priority.

  4. DNA damage repair vulnerability: ATM (Mendelian), MSH2 (Mendelian), BRCA2 (Mendelian), CHEK2 (HPO) — multiple DNA repair genes implicated. PARP inhibitors (olaparib, niraparib) targeting synthetic lethality with ATM loss are in Phase 3 GBM trials.

  5. Brain-specific targets for safety: GWAS genes with brain-enriched expression (AKT3, KCNN3, GABRA2, KCNQ5, SLC6A1, RBFOX1) could offer GBM-selective therapeutic windows with fewer systemic side effects.

  6. IDH1 — Mendelian validated, drugs emerging: Ivosidenib (approved AML) and vorasidenib (Phase 3 low-grade glioma) target IDH1 mutations present in a GBM subtype — an already-validated repurposing pathway.

  7. Epigenetic targets (DNMT3A, H3-3A, JARID2): Multiple ClinVar genes converge on chromatin/epigenetic regulation. DNMT inhibitors (azacitidine/decitabine), EZH2 inhibitors (tazemetostat), and ONC201 (for H3K27M) represent emerging approaches.

  8. Compared to other cancers: GBM has a relatively concentrated GWAS landscape (5 dominant loci vs. >200 for breast cancer), reflecting both its lower heritability and the outsized impact of somatic vs. germline variation. The GWAS-to-drug pipeline is less developed than for breast or colorectal cancer, where genetic evidence has more directly influenced drug approvals.

Analysis performed using biobtree MCP tools integrating data from GWAS Catalog, MONDO, EFO, MeSH, Orphanet, OMIM, HPO, ClinVar, HGNC, UniProt, InterPro, ChEMBL, PDB, AlphaFold, STRING, Reactome, PharmGKB, CellxGene, and CTD. Date: 2026-04-11.