Chronic Lymphocytic Leukemia: GWAS to Drug Target Druggability Analysis

Perform a comprehensive GWAS-to-drug-target druggability analysis for Chronic Lymphocytic Leukemia. Trace genetic associations through variants, …

Perform a comprehensive GWAS-to-drug-target druggability analysis for Chronic Lymphocytic Leukemia. 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 Chronic Lymphocytic Leukemia: 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 Chronic Lymphocytic Leukemia. 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 Chronic Lymphocytic Leukemia: - 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 19 biological databases.

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

Datasets: chembl_molecule, chembl_target, clinical_trials, clinvar, efo, gencc, go, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_gene, reactome, string_interaction, uniprot
Generated: 2026-04-11 — For the latest data, query BioBTree directly via MCP or API.
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Chronic Lymphocytic Leukemia

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS

Chronic Lymphocytic Leukemia (CLL)

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0004948B-cell chronic lymphocytic leukemia
EFOEFO:0000095Chronic lymphocytic leukemia
OMIM151400 (primary); 109543, 609630, 612557, 612558, 612559CLL susceptibility loci
Orphanet67038B-cell chronic lymphocytic leukemia
MeSHD015451Leukemia, Lymphocytic, Chronic, B-Cell
HPOHP:0005550Chronic lymphatic leukemia

Synonyms: CLL, B-CLL, BCLL, Small lymphocytic lymphoma (SLL), CLL/SLL

Section 2: Gwas Landscape

Overview

MetricCount
Total GWAS associations225
Unique GWAS studies21
Unique loci/genes identified~65

TOP 50 GWAS Associations (by p-value)

RankGWAS IDGene(s)ChrP-valueStudy Trait
1GCST004146_28GRAMD1B114.0e-58CLL
2GCST90624738_15DRAIC155.0e-40CLL
3GCST003468_19GRAMD1B112.0e-40CLL
4GCST002073_18GRAMD1B114.0e-39CLL
5GCST004146_16SP14024.0e-32CLL
6GCST004146_31DRAIC152.0e-31CLL
7GCST90079641_1(intergenic)—9.0e-30CLL (ICD10)
8GCST90624738_2MIR4435-2HG21.0e-29CLL
9GCST004146_32IRF8161.0e-28CLL
10GCST004146_21IRF461.0e-28CLL
11GCST004146_14MIR4435-2HG, ACOXL22.0e-27CLL
12GCST90624738_10FAS101.0e-26CLL
13GCST002299_15GRAMD1B114.0e-24CLL
14GCST002073_12SP14021.0e-22CLL
15GCST90624738_13BMF156.0e-22CLL
16GCST003468_12IRF469.0e-22CLL
17GCST90624738_7TERT54.0e-22CLL
18GCST003468_23IRF8161.0e-22CLL
19GCST004146_22HLA-DRB1/DQA163.0e-20CLL
20GCST000224_5IRF462.0e-20CLL
21GCST90079124_1(intergenic)—1.0e-20CLL (UKB)
22GCST003468_8MIR4435-2HG, ACOXL25.0e-20CLL
23GCST002073_14IRF466.0e-20CLL
24GCST90624738_23PALD1103.0e-19CLL
25GCST004146_30BMF/BUB1B157.0e-19CLL
26GCST002073_9ACOXL22.0e-18CLL
27GCST004146_12MNS1/ZNF280D152.0e-18CLL
28GCST002299_18DRAIC158.0e-18CLL
29GCST90624738_11C11orf21114.0e-18CLL
30GCST90624738_24EXOC6102.0e-18CLL
31GCST002073_20DRAIC151.0e-17CLL
32GCST002073_11MIR4435-2HG, ACOXL24.0e-17CLL
33GCST002073_21IRF8165.0e-17CLL
34GCST004146_24CASC19, PCAT187.0e-16CLL
35GCST000224_1DRAIC155.0e-12CLL
36GCST001570_1BAK169.0e-16CLL
37GCST004146_9BAK166.0e-16CLL
38GCST003468_13HLA-DRB1/DQA166.0e-16CLL
39GCST004146_26FAS101.0e-15CLL
40GCST90624738_8IPCEF163.0e-15CLL
41GCST90624738_16NFE2L3P1186.0e-15CLL
42GCST002299_7ACOXL25.0e-15CLL
43GCST002073_3FAS101.0e-14CLL
44GCST90624738_3CASP824.0e-14CLL
45GCST004099_2ACOXL23.0e-14B-cell pleiotropy
46GCST90624738_17SAE1192.0e-14CLL
47GCST002073_19MNS1/ZNF280D152.0e-13CLL
48GCST004146_36MDS215.0e-13CLL
49GCST002299_9SP14025.0e-13CLL
50GCST003468_17FAS109.0e-14CLL

Section 3: Variant Details

Functional Classification by Genetic Evidence Tier

TierDescriptionCount%Key Genes
Tier 1Coding variants (missense, frameshift, nonsense)~57.7%CASP8, CASP10, SP140, POT1, RPS15
Tier 2Splice/UTR variants~812.3%BCL2, CFLAR, BAK1, BMF, FAS
Tier 3Regulatory variants (promoter, enhancer, TF binding)~2233.8%IRF4, IRF8, TERT, HLA-DQA1, GRAMD1B
Tier 4Intronic/intergenic~3046.2%DRAIC, MIR4435-2HG, CASC19, LINC loci

Summary Statistics

  • Total unique variant loci: ~65
  • Coding variant rate: 7.7% (higher than many GWAS — reflects cancer biology)
  • Regulatory variant rate: 33.8%
  • Intronic/intergenic rate: 46.2%
  • MAF distribution: Most lead variants have MAF 0.05–0.35 (common variants); CLL risk alleles show population frequencies consistent with a polygenic architecture

Section 4: Mendelian Disease Overlap

Orphanet-Registered CLL Genes (Mendelian/Familial Forms)

GeneHGNC IDProteinMendelian DiseaseGWAS Evidence?
TP53HGNC:11998Tumor protein p53Li-Fraumeni syndrome / Familial CLLClinVar: Yes
ATMHGNC:795ATM serine/threonine kinaseAtaxia-telangiectasia / CLL susceptibilityGWAS: indirect
POT1HGNC:17284Protection of telomeres 1Familial CLL (OMIM:612559)GWAS: p=3e-8
RPS15HGNC:10388Ribosomal protein S15CLL driver mutationOrphanet: Yes
IKZF3HGNC:13178IKAROS family zinc finger 3 (Aiolos)CLL-associated (Orphanet)GWAS: indirect
CCND1HGNC:1582Cyclin D1Mantle cell lymphoma / CLL overlapOrphanet: Yes
P2RX7HGNC:8537Purinergic receptor P2X7CLL susceptibilityOrphanet: Yes
ARL11HGNC:24046ARF-like GTPase 11CLL susceptibility (ARLTS1)Orphanet: Yes
IGHG1HGNC:5525Immunoglobulin heavy constant gamma 1Ig gene rearrangement in CLLOrphanet: Yes
IGHV3-21HGNC:5586Immunoglobulin heavy variable 3-21Poor-prognosis CLL subsetOrphanet: Yes

Genes with BOTH GWAS + Mendelian Evidence (Highest Confidence)

GeneBest GWAS p-valueMendelian DiseaseConfidence
POT13.0e-08Familial CLL (OMIM:612559)VERY HIGH
TP53ClinVar linkLi-Fraumeni / CLLVERY HIGH
ATMIndirect GWASAtaxia-telangiectasia / CLLHIGH

Section 5: Gwas Genes To Proteins

Summary

MetricCount
Total unique protein-coding genes from GWAS~48
Total unique protein products mapped~45
Non-coding loci (lncRNA/miRNA)~17

TOP 50 Gene-to-Protein Mapping

GeneHGNC IDUniProtProtein NameEvidence TierMendelian?
GRAMD1BHGNC:29214Q3KR37GRAM domain containing 1BTier 3N
IRF4HGNC:6119Q15306Interferon regulatory factor 4Tier 3N
SP140HGNC:17133Q13342SP140 nuclear body proteinTier 1N
IRF8HGNC:5358Q02556Interferon regulatory factor 8Tier 3N
BCL2HGNC:990P10415Apoptosis regulator Bcl-2Tier 2N
FASHGNC:11920P25445TNF receptor superfamily member 6Tier 2N
TERTHGNC:11730O14746Telomerase reverse transcriptaseTier 3N
BAK1HGNC:949Q16611BCL2 antagonist/killer 1Tier 2N
BMFHGNC:24132Q96LC9Bcl2 modifying factorTier 2N
CASP8HGNC:1509Q14790Caspase-8Tier 1N
LEF1HGNC:6551Q9UJU2Lymphoid enhancer binding factor 1Tier 3N
BANK1HGNC:18233Q8NDB2B-cell scaffold protein w/ ankyrin repeats 1Tier 3N
EOMESHGNC:3372O95936EomesoderminTier 3N
BCL2L11HGNC:994O43521BCL2-like 11 (BIM)Tier 2N
CFLARHGNC:1876O15519CASP8/FADD-like apoptosis regulator (c-FLIP)Tier 2N
PRKD2HGNC:17293Q9BZL6Protein kinase D2Tier 3N
HLA-DQA1HGNC:4942P01909MHC class II DQ alpha 1Tier 3N
CAMK2DHGNC:1462Q13557CaM kinase II deltaTier 3N
POT1HGNC:17284Q9NUX5Protection of telomeres 1Tier 3Y
FARP2HGNC:16460O94887FERM/RhoGEF/pleckstrin domain protein 2Tier 4N
CLPTM1LHGNC:24308Q96KA5CLPTM1-likeTier 3N
RHOUHGNC:17794Q7L0Q8Ras homolog family member UTier 3N
MDS2HGNC:29633Q8NDY4MDS2 translocation associatedTier 4N
OAS3HGNC:8088Q9Y6K52'-5'-oligoadenylate synthetase 3Tier 3N
SMAD3HGNC:6769P84022SMAD family member 3Tier 3N
GPR37HGNC:4494O15354G protein-coupled receptor 37Tier 3N
MAP2K2HGNC:6842P36507MAP kinase kinase 2 (MEK2)Tier 3N
DRD2HGNC:3023P14416Dopamine receptor D2Tier 3N
SAE1HGNC:30660Q9UBE0SUMO1 activating enzyme subunit 1Tier 3N
RFX7HGNC:25777Q2KHR2Regulatory factor X7Tier 3N
PALD1HGNC:23530Q9ULE6Phosphatase domain-containing paladin 1Tier 3N
CD70HGNC:11937P32970CD70 moleculeTier 3N
CASP10HGNC:1500Q92851Caspase-10Tier 1N
JARID2HGNC:6196Q92833Jumonji/ARID domain protein 2Tier 3N
ENPP1HGNC:3356P22413Ectonucleotide pyrophosphatase 1Tier 3N
SERPINB6HGNC:8950P35237Serpin B6Tier 3N
DLEU1HGNC:13747O43261Deleted in lymphocytic leukemia 1Tier 4N
TP53HGNC:11998P04637Tumor protein p53ClinVarY
ATMHGNC:795Q13315ATM serine/threonine kinaseOrphanetY
IKZF3HGNC:13178Q9UKT9IKAROS family zinc finger 3 (Aiolos)OrphanetY
CCND1HGNC:1582P24385Cyclin D1OrphanetY
P2RX7HGNC:8537Q99572Purinergic receptor P2X7OrphanetY
ARL11HGNC:24046Q969Q4ARF-like GTPase 11 (ARLTS1)OrphanetY

Section 6: Protein Family Classification (Interpro)

GeneUniProtProtein FamilyDruggable?Notes
BCL2P10415Bcl-2 family (apoptosis regulator)YESVenetoclax target
CASP8Q14790Cysteine protease (Caspase C14)YESProtease
CASP10Q92851Cysteine protease (Caspase C14)YESProtease
TERTO14746Reverse transcriptaseYESEnzyme
PRKD2Q9BZL6Ser/Thr protein kinaseYESKinase
CAMK2DQ13557Ser/Thr protein kinase (CaMK)YESKinase
MAP2K2P36507MAP kinase kinase (MEK2)YESKinase — trametinib, cobimetinib
DRD2P14416GPCR (Rhodopsin family)YESDopamine receptor
GPR37O15354GPCR (Rhodopsin family)YESOrphan receptor
P2RX7Q99572Ion channel (P2X family)YESLigand-gated
FASP25445TNF receptor superfamilyYESDeath receptor
HLA-DQA1P01909MHC class IIModerateImmune target
CD70P32970TNF superfamily ligandYESCusatuzumab target
ENPP1P22413Phosphodiesterase (Enzyme)YESEnzyme
OAS3Q9Y6K5NucleotidyltransferaseYESEnzyme
SAE1Q9UBE0E1-like activating enzyme (SUMO)YESEnzyme
SMAD3P84022SMAD/Dwarfin TFDifficultTF/signaling
IRF4Q15306Interferon regulatory factorDifficultTranscription factor
IRF8Q02556Interferon regulatory factorDifficultTranscription factor
LEF1Q9UJU2TCF/LEF TF (Wnt pathway)DifficultTranscription factor
EOMESO95936T-box TFDifficultTranscription factor
RFX7Q2KHR2RFX transcription factorDifficultTranscription factor
JARID2Q92833Jumonji/ARID chromatin remodelerModerateEpigenetic
SP140Q13342Nuclear body/bromodomain proteinModerateBromodomain = emerging target
GRAMD1BQ3KR37GRAM domain lipid-bindingUnknownFunction unclear
BANK1Q8NDB2Scaffold/adaptor proteinDifficultPPI hub
BCL2L11O43521Bcl-2 family (BH3-only)ModerateIndirect via BCL2
BMFQ96LC9Bcl-2 family (BH3-only)ModerateIndirect via BCL2
BAK1Q16611Bcl-2 family (pro-apoptotic)ModeratePart of apoptotic machinery
CFLARO15519Caspase-like (c-FLIP)ModerateDED domain
POT1Q9NUX5Shelterin/OB-foldDifficultDNA-binding
PALD1Q9ULE6Phosphatase domain-containingModeratePhosphatase
CLPTM1LQ96KA5Transmembrane proteinUnknownCancer susceptibility
RHOUQ7L0Q8Small GTPase (Rho family)ModerateGTPase

Summary

CategoryCount%
Druggable (Kinases, GPCRs, Ion channels, Proteases, Enzymes)1633.3%
Moderately druggable (Receptors, phosphatases, epigenetic, BH3-only)1020.8%
Difficult (TFs, scaffold, DNA-binding)918.8%
Unknown function36.3%
Non-coding loci1020.8%

Section 7: Expression Context

CLL-relevant tissues: B lymphocytes, lymph nodes, bone marrow, spleen, blood

GeneDisease-Relevant ExpressionSpecificityNotes
BCL2B cells, lymph node, bone marrowModerateOverexpressed in CLL vs normal B cells
IRF4B cells, lymphoid tissuesHigh lymphoidMaster regulator of B-cell differentiation
IRF8Myeloid/B cells, spleenHigh hematopoieticMonocyte/B-cell lineage TF
SP140B cells, macrophagesHigh leukocyteLeukocyte-specific nuclear body protein
FASLymphocytes, ubiquitousModerateDeath receptor on activated lymphocytes
CASP8UbiquitousLow specificityUniversal apoptosis machinery
TERTLow/silenced in normal cells; active in CLLCancer-specificReactivated in malignancy
LEF1T/B lymphocytes, lymphoidHigh lymphoidWnt pathway — overexpressed in CLL
BAK1UbiquitousLow specificityMitochondrial apoptosis
BMFHematopoietic, intestineModerateBH3-only sensor
BANK1B cellsVery high B-cell specificExcellent specificity for CLL
EOMEST/NK cellsHigh lymphoidT-cell exhaustion marker
PRKD2UbiquitousLow specificitySignaling kinase
CAMK2DHeart, brain, ubiquitousLow specificitySafety concern: cardiac expression
MAP2K2UbiquitousLow specificityMAPK pathway
DRD2Brain (striatum)Very high brainNOT expressed in B cells — weak CLL link
GPR37BrainVery high brainNOT expressed in B cells — weak CLL link
HLA-DQA1Immune cells (APCs)Moderate immuneMHC class II on B cells
CD70Activated lymphocytesHigh lymphoidSurface marker on CLL cells
POT1Ubiquitous (low)Low specificityTelomere protection
SMAD3UbiquitousLow specificityTGF-beta pathway
DLEU1Deleted in CLL (13q14)CLL-specificTumor suppressor locus
CFLARUbiquitousLow specificityAnti-apoptotic (c-FLIP)
BCL2L11HematopoieticModerateBIM — key apoptosis trigger
ENPP1Bone, liver, ubiquitousModerateNucleotide metabolism
OAS3Interferon-induced, ubiquitousModerateAntiviral innate immunity
PALD1Endothelial cellsModerateVascular biology
SAE1UbiquitousLow specificitySUMO pathway
RFX7UbiquitousLow specificityTranscription factor
JARID2UbiquitousLow specificityPolycomb chromatin remodeling

Key findings: BANK1, SP140, and IRF4 show high B-cell/leukocyte specificity — ideal for CLL-targeted therapies with fewer off-target effects. DRD2 and GPR37 are brain-specific, suggesting their GWAS signal may act through immune-brain crossover mechanisms or represent pleiotropic loci.

Section 8: Protein Interactions

BCL2 Interaction Hub (STRING score ≥ 900)

BCL2 (P10415) has 7,722 STRING interactions, making it a major hub. Key interactors among GWAS genes:

BCL2 InteractorUniProtScoreAlso GWAS Gene?
BCL2L11 (BIM)O43521999YES
TP53P04637999YES (Mendelian)
BAK1Q16611969YES
CASP8Q14790955YES
BMFQ96LC9995YES
CCND1P24385958YES (Mendelian)
CFLAR (c-FLIP)O15519—YES

Pathway Clustering

The GWAS genes cluster into two major interacting modules:

  1. Apoptosis module: BCL2 ↔ BCL2L11 ↔ BAK1 ↔ BMF ↔ FAS ↔ CASP8 ↔ CFLAR
  2. Immune regulation module: IRF4 ↔ IRF8 ↔ SP140 ↔ HLA-DQA1

Undrugged GWAS Genes with Drugged Interactors

Undrugged GeneInteracts WithDrugged InteractorDrugs Available
BMFBCL2BCL2Venetoclax, navitoclax
BCL2L11 (BIM)BCL2BCL2Venetoclax, navitoclax
BAK1BCL2BCL2Venetoclax
CFLARCASP8CASP8Preclinical compounds
LEF1CCND1CCND1Palbociclib (CDK4/6i)
EOMES—Checkpoint pathwayAnti-PD1 agents
SP140—Bromodomain classBET inhibitors (experimental)
BANK1BCR signalingBTKIbrutinib, acalabrutinib

Section 9: Structural Data

Structure Availability Summary

CategoryCount%
PDB structures available2552.1%
AlphaFold only1837.5%
No structure510.4%

Key Protein Structures

ProteinPDB CountBest ResolutionDrug Co-crystals?
BCL2551.25 ÅYES — venetoclax (6O0K), navitoclax (4LVT), S55746 (6GL8), sonrotoclax (8HOG)
CASP8361.2 ÅYES — multiple inhibitors
TERT23VariousYES — substrate/inhibitor complexes
IRF4181.71 ÅDNA complexes only
MAP2K2Multiple<2 ÅYES — trametinib, cobimetinib
DRD2Many<3 ÅYES — haloperidol, ropinirole
SP14051.85 ÅPHD/Bromodomain structures available

Undrugged Target Structure Status

Undrugged GenePDB?AlphaFold?Quality
GRAMD1BNoYesModerate
BANK1NoYesModerate
BMFYes (in BCL2 complex)YesGood
BCL2L11Yes (in BCL2 complex)YesGood
LEF1Yes (DNA complex)YesGood
EOMESPartialYesModerate
RFX7NoYesLow
PALD1NoYesModerate
CLPTM1LNoYesLow

Section 10: Drug Target Analysis

Summary

CategoryCount%
Total GWAS protein-coding genes48100%
With approved drugs (Phase 4)1225.0%
With Phase 3 drugs36.3%
With Phase 2/1 drugs510.4%
With preclinical compounds only1020.8%
With NO drug development1837.5% ← OPPORTUNITY GAP

Genes with APPROVED Drugs

GeneProteinApproved Drug(s)MechanismApproved for CLL?
BCL2Apoptosis regulator Bcl-2VenetoclaxBH3 mimetic / BCL2 inhibitorYES
MAP2K2MEK2Trametinib, cobimetinib, selumetinib, binimetinibMEK inhibitorN (melanoma)
DRD2Dopamine D2 receptorHaloperidol, ropinirole, cabergoline, apomorphineD2 antagonist/agonistN (neuro)
CAMK2DCaMK II deltaRuxolitinib, momelotinib, fedratinib, palbociclibKinase inhibitor (off-target)N
PRKD2Protein kinase D2Momelotinib, rucaparib, neratinib, palbociclibKinase inhibitor (off-target)N
TERTTelomerase RTIxabepilone (indirect)Various mechanismsN
HLA-DQA1MHC class IIImmune modulatorsImmune modulationIndirect
CASP8Caspase-8Preclinical inhibitors (drug bank entries)Caspase inhibitionN
P2RX7P2X7 receptorPreclinical/Phase 1 compoundsIon channel blockerN
CD70CD70CusatuzumabAnti-CD70 antibodyPhase 2 CLL
SMAD3SMAD3Preclinical compoundsTGF-beta pathwayN
ENPP1ENPP1Preclinical compoundsEnzyme inhibitionN

Section 11: Bioactivity & Enzyme Data

Most-Studied GWAS Proteins (by ChEMBL/PubChem Activity Data)

ProteinChEMBL ActivitiesBindingDBPubChem AssaysActive Compounds
BCL26,0874,902454>1,000
DRD2>10,000>5,000>500>5,000
TERT978771380>500
MAP2K2>500>400>200>300
CASP8414434128>200
CAMK2D>300>200>100>200
PRKD2>300>200>100>200
SMAD357——~50
FAS——8 assaysLow
P2RX7>100>100>50>100

Enzyme Targets (BRENDA-linked)

Enzyme GeneEC ClassKnown InhibitorsDruggability
CASP8EC 3.4.22.61 (Cysteine protease)Z-IETD-FMK, Z-DEVD-CHOHIGH
TERTEC 2.7.7.49 (RNA-directed DNA polymerase)BIBR 1532, nucleoside analogsHIGH
ENPP1EC 3.1.4.1 (Phosphodiesterase)MultipleHIGH
OAS3EC 2.7.7.84 (2'-5'-OAS)LimitedMODERATE
SAE1EC 6.2.1.- (SUMO E1)TAK-981 (investigational)MODERATE

Section 12: Pharmacogenomics (Pharmgkb)

All 10 queried GWAS genes are VIP (Very Important Pharmacogenes) in PharmGKB:

GenePharmGKB IDVIP?Key Drug InteractionsClinical Annotations
BCL2PA25302YesVenetoclax efficacyResponse prediction in CLL
CASP8PA26092YesApoptosis-inducing agentsCancer treatment response
FASPA36613YesDeath receptor agonistsApoptosis sensitivity
IRF4PA29918YesLenalidomide responseMyeloma/lymphoma response
IRF8PA29606YesInterferon responseImmune modulation
TERTPA36447YesTelomerase inhibitorsCancer susceptibility
BAK1PA25253YesPro-apoptotic drug responseChemosensitivity
LEF1PA30331YesWnt pathway inhibitorsCancer prognosis
PRKD2PA134903505YesKinase inhibitorsVariable response
DRD2PA27478YesAntipsychotics (haloperidol, etc.)Dosing guidelines

Section 13: Clinical Trials

CLL Clinical Trial Overview

MetricCount
Total clinical trials (via MONDO)>1,274
Unique drugs in trials>200
Phase 4 (approved)~80
Phase 3~25
Phase 2~40
Phase 1~20

TOP 30 Drugs in CLL Clinical Trials

DrugPhaseMechanismTarget GeneGWAS Gene?
Venetoclax4BCL2 inhibitorBCL2YES
Ibrutinib4BTK inhibitorBTKN (but BCR pathway)
Acalabrutinib4BTK inhibitorBTKN
Zanubrutinib4BTK inhibitorBTKN
Rituximab4Anti-CD20CD20/MS4A1N
Obinutuzumab4Anti-CD20CD20/MS4A1N
Idelalisib4PI3Kδ inhibitorPIK3CDN
Duvelisib4PI3Kδ/γ inhibitorPIK3CD/PIK3CGN
Pirtobrutinib4Non-covalent BTK inhibitorBTKN
Ofatumumab4Anti-CD20CD20/MS4A1N
Lenalidomide4Cereblon modulatorCRBN→IKZF1/3Indirect (IKZF3)
Chlorambucil4Alkylating agentDNAN
Fludarabine4Purine analogDNA synthesisN
Bendamustine4Alkylating/antimetaboliteDNAN
Alemtuzumab4Anti-CD52CD52N
Sonrotoclax3BCL2 inhibitor (next-gen)BCL2YES
Navitoclax3BCL2/BCL-XL inhibitorBCL2YES
Dinaciclib3CDK inhibitorCDK1/2/5/9N
Alvocidib3CDK9 inhibitorCDK9N
Nemtabrutinib3BTK inhibitorBTKN
Orelabrutinib3BTK inhibitorBTKN
Umbralisib4PI3Kδ/CK1ε inhibitorPIK3CDN
Ublituximab4Anti-CD20CD20/MS4A1N
Dasatinib4Multi-kinase inhibitorBCR-ABL, SRCN
Ruxolitinib4JAK1/2 inhibitorJAK1/2N
Dexamethasone4GlucocorticoidNR3C1N
Prednisone4GlucocorticoidNR3C1N
Ipilimumab4Anti-CTLA4CTLA4N
Nivolumab4Anti-PD1PDCD1N
Sorafenib4Multi-kinase inhibitorRAF, VEGFRN

GWAS–Trial Alignment

  • Drugs directly targeting GWAS genes: Venetoclax, sonrotoclax, navitoclax (BCL2) + lenalidomide (IKZF3 degradation) = ~4 out of top 30 (13.3%)
  • Total % of trial drugs targeting GWAS genes: ~5–8% directly
  • This is moderate — BCL2 inhibition is strongly GWAS-validated, but most other trial drugs (BTK inhibitors, anti-CD20) target non-GWAS genes, suggesting significant untapped GWAS potential.

Section 14: Pathway Analysis (Reactome)

TOP 30 Pathways Containing GWAS Genes

PathwayReactome IDGWAS GenesDruggable Nodes
FasL/CD95L signalingR-HSA-75157FAS, CASP8, CFLARFAS, CASP8
Caspase activation via Death ReceptorsR-HSA-140534FAS, CASP8CASP8
BH3-only proteins inactivate BCL2R-HSA-111453BCL2, BCL2L11, BMF, BAK1BCL2
Activation of BAD → mitochondriaR-HSA-111447BCL2, BAK1BCL2
TRAIL signalingR-HSA-75158CASP8CASP8, TRAIL-R
Apoptotic execution phaseR-HSA-75153CASP8Caspase cascade
Regulation by c-FLIPR-HSA-3371378FAS, CASP8, CFLARCASP8, c-FLIP
RIPK1-mediated necrosisR-HSA-5213460FAS, CASP8RIPK1
TNFR1 proapoptotic signalingR-HSA-5357786CASP8TNF pathway
NF-kB via FADD/RIP-1/CASP8R-HSA-933543CASP8NF-kB pathway
Interleukin-4/13 signalingR-HSA-6785807BCL2JAK/STAT
Estrogen-dependent gene expressionR-HSA-9018519BCL2ER pathway
NLRP1 inflammasomeR-HSA-844455BCL2Inflammasome
NOD1/2 signalingR-HSA-168638CASP8Pattern recognition
Dimerization of procaspase-8R-HSA-69416FAS, CASP8CASP8
Regulation of necroptotic deathR-HSA-5675482CASP8RIPK1/3, MLKL
TP53 regulates death receptorsR-HSA-6803211FAS, TP53p53 pathway
Apoptotic cleavage of proteinsR-HSA-111465CASP8Caspase substrates
Wnt/beta-catenin signaling—LEF1Beta-catenin, GSK3
TGF-beta/SMAD signaling—SMAD3TGF-beta receptors
Telomere maintenance—TERT, POT1TERT
B-cell receptor signaling—BANK1, IRF4BTK, PI3K, SYK
MHC class II presentation—HLA-DQA1Immune checkpoint
MAPK/ERK signaling—MAP2K2RAF, MEK, ERK

Pathway-level druggability: Even undrugged GWAS genes like BMF and BCL2L11 sit in the apoptosis pathway, where BCL2 is a validated, drugged node. Similarly, BANK1 sits in the BCR signaling pathway targetable by ibrutinib.

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugTarget GeneCurrently Approved ForMechanismGWAS p-valuePriority Score
1TrametinibMAP2K2MelanomaMEK inhibitor~5e-89.2
2CobimetinibMAP2K2MelanomaMEK inhibitor~5e-89.0
3SelumetinibMAP2K2NeurofibromatosisMEK inhibitor~5e-88.8
4BinimetinibMAP2K2MelanomaMEK inhibitor~5e-88.6
5RuxolitinibCAMK2D (off-target)MyelofibrosisJAK/kinase inhibitor~3e-98.0
6PalbociclibCAMK2D/PRKD2 (off-target)Breast cancerCDK4/6 inhibitor~3e-97.8
7DasatinibMAP2K2 (off-target)CMLMulti-kinase inhibitor~5e-87.5
8EnzastaurinCAMK2D/PRKD2Phase 3 DLBCLPKC/kinase inhibitor~3e-97.3
9NavitoclaxBCL2/BCL-XLPhase 3 variousBH3 mimetic~4e-117.0
10MomelotinibPRKD2 (off-target)MyelofibrosisJAK1/2 inhibitor4e-96.8
11NeratinibPRKD2 (off-target)HER2+ breast caPan-HER kinase inh.4e-96.5
12SorafenibMAP2K2 pathwayHCC, RCCMulti-kinase inhibitor~5e-86.3
13HaloperidolDRD2SchizophreniaD2 antagonist~2e-115.0
14CabergolineDRD2ProlactinomaD2 agonist~2e-114.8
15RopiniroleDRD2Parkinson'sD2 agonist~2e-114.5
16RucaparibPRKD2 (off-target)Ovarian cancerPARP inhibitor4e-94.3
17LenalidomideIKZF3 (degradation)MyelomaCereblon modulatorOrphanet8.5
18CusatuzumabCD70Phase 2 AMLAnti-CD70 antibody~3e-87.2
19VemurafenibMAP2K2 pathwayMelanomaBRAF/MEK~5e-85.5
20FedratinibCAMK2D (off-target)MyelofibrosisJAK2 inhibitor~3e-95.0
21Valproic acidHDAC/apoptosisEpilepsyHDAC inhibitorTrial in CLL4.5
22ImiquimodTLR7/immuneSkin cancerImmune activatorTrial in CLL4.0
23SimvastatinHMG-CoA/apoptosisHyperlipidemiaStatinCLL indication data3.8
24MetforminAMPK/metabolismDiabetesMetabolic modulatorCLL indication data3.5
25HydroxychloroquineAutophagyMalaria/RAAutophagy inhibitorCLL indication data3.3
26AuranofinThioredoxin reductaseRARedox modulatorCLL indication data3.0
27BepridilDRD2 (off-target)AnginaCalcium channel blocker~2e-112.8
28ImatinibMulti-kinaseCMLBCR-ABL/kinaseTrial in CLL2.5
29TocilizumabIL-6RRAAnti-IL6RCLL indication data2.3
30NiraparibPARP1/2Ovarian cancerPARP inhibitorCLL indication data2.0

Priority scoring: Genetic evidence tier (40%) + Mendelian overlap (15%) + Druggable family (15%) + Disease tissue expression (15%) + Safety profile (15%)

Section 16: Druggability Pyramid

LevelDescriptionGene Count%Key Genes
Level 1 — VALIDATEDApproved drug FOR CLL36.3%BCL2 (venetoclax), IKZF3 (lenalidomide), [CD70 phase 2]
Level 2 — REPURPOSINGApproved drug for OTHER disease714.6%MAP2K2, DRD2, CAMK2D, PRKD2, TERT, HLA-DQA1, ENPP1
Level 3 — EMERGINGDrug in clinical trials48.3%CD70, SMAD3, CASP8, P2RX7
Level 4 — TOOL COMPOUNDSChEMBL compounds, no trials612.5%CASP10, OAS3, FAS, BAK1, BCL2L11, CFLAR
Level 5 — DRUGGABLE UNDRUGGEDDruggable family, NO compounds714.6%GPR37, SAE1, PALD1, RHOU, SERPINB6, SP140 (bromodomain), CLPTM1L
Level 6 — HARD TARGETSDifficult family or unknown2143.7%IRF4, IRF8, LEF1, EOMES, GRAMD1B, BANK1, RFX7, POT1, JARID2, MDS2, DLEU1, non-coding loci

Section 17: Undrugged Target Profiles

TOP 30 High-Value Undrugged Targets

RankGeneGWAS p-valueVariant TierProtein FamilyStructureExpressionDrugged Interactors?Potential
1SP1404.0e-32Tier 1Bromodomain/nuclear bodyPDB: 5 structuresB-cell specificIndirect (BET class)HIGH
2IRF41.0e-28Tier 3TF (IRF family)PDB: 18 structuresB-cell specificLenalidomide (degradation)HIGH
3GRAMD1B4.0e-58Tier 3GRAM domain (unknown)AlphaFold onlyUnknown specificityNone knownMEDIUM
4IRF81.0e-28Tier 3TF (IRF family)AlphaFoldHematopoieticIndirect (IFN pathway)MEDIUM
5BMF6.0e-22Tier 2BH3-only (BCL2 family)In BCL2 complexHematopoieticBCL2 (venetoclax)HIGH
6BCL2L111.0e-11Tier 2BH3-only (BCL2 family)In BCL2 complexHematopoieticBCL2 (venetoclax)HIGH
7FAS1.0e-26Tier 2TNF receptor SFPDB: 7 structuresLymphocytesCASP8, apoptosisMEDIUM
8BAK16.0e-16Tier 2BCL2 family (pro-apop)PDB availableUbiquitousBCL2 (venetoclax)MEDIUM
9BANK11.0e-10Tier 3Scaffold/adaptorAlphaFold onlyB-cell specificBTK pathway (ibrutinib)HIGH
10CFLAR5.0e-11Tier 2Caspase-like (c-FLIP)AlphaFold + partialUbiquitousCASP8MEDIUM
11LEF16.0e-9Tier 3TF (TCF/LEF)PDB (DNA complex)LymphoidWnt pathway targetsLOW
12EOMES2.0e-9Tier 3T-box TFPartialT/NK cellsCheckpoint pathwayLOW
13POT13.0e-8Tier 3OB-fold DNA bindingPDB availableUbiquitousShelterin complexMEDIUM
14GPR379.0e-9Tier 3GPCR (orphan)AlphaFoldBrain-specific—HIGH (if deorphanized)
15RFX74.0e-12Tier 3TF (RFX family)AlphaFold onlyUbiquitousNone knownLOW
16PALD13.0e-19Tier 3Phosphatase domainAlphaFold onlyEndothelialNone knownMEDIUM
17SAE12.0e-14Tier 3E1 enzyme (SUMO)PDB availableUbiquitousTAK-981 (clinical)HIGH
18CLPTM1L2.0e-7Tier 3TransmembraneAlphaFold onlyUbiquitousNone knownLOW
19SERPINB62.0e-8Tier 3Serpin (protease inh.)PDB availableImmune cellsProtease targetsMEDIUM
20DLEU11.0e-8Tier 4Non-coding RNAN/ACLL-specific deletion—LOW
21RHOU1.0e-10Tier 3Small GTPaseAlphaFoldUbiquitousRAS pathwayMEDIUM
22MDS25.0e-13Tier 4Unknown functionAlphaFold onlyUnknownNone knownLOW
23JARID23.0e-8Tier 3Jumonji/ARID (chromatin)PDB availableUbiquitousPRC2 complexMEDIUM
24CD703.0e-8Tier 3TNF ligand superfamilyPDB availableActivated lymphocytesCusatuzumab (Ph2)HIGH
25CASP107.0e-9Tier 1Cysteine proteasePDB availableImmune cellsCASP8, FASMEDIUM
26C11orf214.0e-18Tier 4UnknownAlphaFoldUnknownNone knownLOW
27FARP23.0e-11Tier 4RhoGEF domainAlphaFoldUbiquitousRho GTPasesLOW
28ACOXL2.0e-18Tier 3Acyl-CoA oxidase-likeAlphaFoldUnknownNone knownLOW
29OAS35.0e-8Tier 3NucleotidyltransferasePDB availableIFN-inducedNone knownMEDIUM
30SMAD31.0e-7Tier 3SMAD/TFPDB availableUbiquitousTGF-beta receptors (drugged)MEDIUM

Section 18: Summary

GWAS LANDSCAPE

MetricValue
Total associations225
Unique GWAS studies21
Unique protein-coding genes~48
Coding vs non-coding variants7.7% coding / 92.3% non-coding

GENETIC EVIDENCE

MetricValue
Tier 1 (coding) genes5
Mendelian overlap genes10 (Orphanet)
Both GWAS + Mendelian3 (POT1, TP53, ATM)

DRUGGABILITY

MetricValue
Overall druggable rate56.3% have drug targets or druggable families
Approved drugs (Level 1)6.3% (3 genes)
Clinical trials (Level 2-3)22.9% (11 genes)
Opportunity gap (Level 5-6)58.3% (28 genes)

PYRAMID SUMMARY

LevelCount%
Level 1 — Validated36.3%
Level 2 — Repurposing714.6%
Level 3 — Emerging48.3%
Level 4 — Tool Compounds612.5%
Level 5 — Druggable Undrugged714.6%
Level 6 — Hard Targets2143.7%

CLINICAL TRIAL ALIGNMENT

  • ~13% of top CLL trial drugs target GWAS-identified genes
  • BTK inhibitors (ibrutinib, acalabrutinib) dominate trials but target non-GWAS genes
  • BCL2 inhibition (venetoclax) is the strongest GWAS-validated therapeutic approach

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
TrametinibMAP2K2Melanoma5e-89.2
CobimetinibMAP2K2Melanoma5e-89.0
SelumetinibMAP2K2NF15e-88.8
LenalidomideIKZF3MyelomaOrphanet8.5
BinimetinibMAP2K2Melanoma5e-88.6
RuxolitinibCAMK2DMyelofibrosis3e-98.0
PalbociclibCAMK2D/PRKD2Breast cancer3e-97.8
DasatinibMAP2K2CML5e-87.5
EnzastaurinCAMK2D/PRKD2DLBCL (Ph3)3e-97.3
CusatuzumabCD70AML (Ph2)3e-87.2

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
SP1404.0e-32BromodomainPDB ✓HIGH
IRF41.0e-28TF (degradable)PDB ✓HIGH
BMF6.0e-22BH3-onlyPDB ✓HIGH
BCL2L111.0e-11BH3-onlyPDB ✓HIGH
BANK11.0e-10ScaffoldAlphaFoldHIGH
GPR379.0e-9GPCR (orphan)AlphaFoldHIGH
SAE12.0e-14E1 enzymePDB ✓HIGH
CD703.0e-8TNF ligandPDB ✓HIGH
PALD13.0e-19PhosphataseAlphaFoldMEDIUM
POT13.0e-8OB-foldPDB ✓MEDIUM

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
BMFBCL2Venetoclax
BCL2L11 (BIM)BCL2Venetoclax
BAK1BCL2Venetoclax
CFLAR (c-FLIP)CASP8Caspase modulators
BANK1BTK (pathway)Ibrutinib
LEF1β-catenin/WntWnt inhibitors
EOMESPD-1/CTLA4Nivolumab, ipilimumab
SP140BRD4 (class)BET inhibitors
SMAD3TGF-β receptorsTGFβR inhibitors
IRF4CRBNLenalidomide (degrader)

KEY INSIGHTS

  1. CLL has remarkably strong apoptosis pathway GWAS enrichment: BCL2, BCL2L11, BMF, BAK1, FAS, CASP8, CFLAR — all cluster in the intrinsic/extrinsic apoptosis pathway. Venetoclax’s clinical success in CLL is directly validated by GWAS genetics.

  2. SP140 is the most compelling undrugged target: With a p-value of 4.0e-32, B-cell–specific expression, bromodomain structure (amenable to small molecules), and PDB structures available, SP140 represents a high-value novel target for CLL drug development.

  3. MEK inhibitors (trametinib class) represent the strongest repurposing opportunity: MAP2K2 has GWAS support, kinase domain structures, and multiple approved inhibitors — yet none are being trialed in CLL.

  4. IRF4 is druggable via protein degradation: While classically “undruggable” as a TF, lenalidomide already degrades IKZF1/3 which regulate IRF4. Direct IRF4-targeting degraders represent a frontier opportunity.

  5. 13q14 deletion (DLEU1/DLEU7) — the most common cytogenetic abnormality in CLL — has GWAS validation, confirming this region’s importance in CLL susceptibility beyond somatic events.

6. Low GWAS-trial alignment (~13%) compared to some diseases suggests the CLL drug development field has significant room to incorporate genetic evidence into target selection.

  1. Comparison with other cancers: CLL shows higher Mendelian overlap (10 genes) than most solid tumors, reflecting its familial clustering. The apoptosis pathway enrichment is more specific than the broadly immune/proliferative signals seen in breast or colorectal cancer GWAS.