Multiple Myeloma: GWAS to Drug Target Druggability Analysis

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

Perform a comprehensive GWAS-to-drug-target druggability analysis for Multiple Myeloma. 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 Multiple Myeloma: 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 Multiple Myeloma. 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 Multiple Myeloma: - 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 24 biological databases.

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

Datasets: alphafold, bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, dbsnp, efo, ensembl, gencc, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_clinical, 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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Multiple Myeloma

COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS: MULTIPLE MYELOMA

Section 1: Disease Identifiers

DatabaseIdentifierName
MONDOMONDO:0009693Plasma cell myeloma
EFOEFO:0001378Multiple myeloma
OMIM254500Multiple myeloma
Orphanet29073Multiple myeloma
MeSHD009101Multiple Myeloma
HPOHP:0006775Multiple myeloma
Disease description (MeSH)Synonyms
A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. Characterized by hyperglobulinemia, excess Bence-Jones proteins in the urine, skeletal destruction, bone pain, and fractures. Other features include anemia, hypercalcemia, and renal insufficiency.
Kahler disease, Myelomatosis, Plasma cell myeloma, Medullary plasmacytoma

Section 2: Gwas Landscape

Summary:

  • Total GWAS associations: 229 (from EFO:0001378)
  • Unique GWAS studies: 37 (identified directly from EFO)
  • Major studies include: GCST90451657 (37 associations, largest), GCST004483 (25), GCST90624746 (26), GCST004099 (24), GCST001906 (27)

TOP 50 GWAS ASSOCIATIONS (ranked by p-value)

RankStudyGene(s)ChrP-valueDisease Trait
1GCST90451657DNAH1171.0e-35Multiple myeloma
2GCST90451657CBX7223.0e-31Multiple myeloma
3GCST90451657DTNB28.0e-28Multiple myeloma
4GCST004483CBX7225.0e-26Multiple myeloma
5GCST90451657TNFRSF13B173.0e-23Multiple myeloma
6GCST90451657NDUFB4P4 - KIF3C27.0e-22Multiple myeloma
7GCST90451657CCHCR162.0e-22Multiple myeloma
8GCST90451657ULK432.0e-20Multiple myeloma
9GCST90451657CHPF275.0e-19Multiple myeloma
10GCST90624746TNFRSF13B172.0e-19MM/MGUS
11GCST004483ULK439.0e-18Multiple myeloma
12GCST90451657LRRC3439.0e-18Multiple myeloma
13GCST004483CCHCR163.0e-17Multiple myeloma
14GCST004483TNFRSF13B174.0e-17Multiple myeloma
15GCST90267403HLA-DQB162.0e-17Lymphoma/myeloma
16GCST90451657ATG562.0e-16Multiple myeloma
17GCST004483DTNB21.0e-16Multiple myeloma
18GCST90451657CDKN2A93.0e-16Multiple myeloma
19GCST90451657CASC19/PCAT182.0e-15Multiple myeloma
20GCST012396DNAH1175.0e-15Multiple myeloma
21GCST004483ATG569.0e-15Multiple myeloma
22GCST004483LRRC3436.0e-15Multiple myeloma
23GCST90624746DTNB28.0e-15MM/MGUS
24GCST001331DNAH1173.0e-14Multiple myeloma
25GCST90624746ELL254.0e-14MM/MGUS
26GCST012396TNFRSF13B173.0e-14Multiple myeloma
27GCST002140MYNN39.0e-14Multiple myeloma
28GCST004099ACOXL/MIR4435-2HG23.0e-14B-cell malignancies
29GCST004099GRAMD1B113.0e-14B-cell malignancies
30GCST90451657NFIC192.0e-13Multiple myeloma
31GCST90451657PREX1203.0e-13Multiple myeloma
32GCST004483CDKN2A92.0e-13Multiple myeloma
33GCST90451657ELL256.0e-13Multiple myeloma
34GCST90451657CCDC71L78.0e-13Multiple myeloma
35GCST90624746ULK431.0e-13MM/MGUS
36GCST006432SRCAP161.0e-13Multiple myeloma
37GCST90267403EOMES35.0e-13Lymphoma/myeloma
38GCST90479833TNFRSF13B178.0e-13Multiple myeloma
39GCST90624746MYNN32.0e-12MM/MGUS
40GCST90451657SRCAP164.0e-12Multiple myeloma
41GCST004483RFWD3165.0e-12Multiple myeloma
42GCST90267403GRAMD1B118.0e-13Lymphoma/myeloma
43GCST90267403BCL2182.0e-12Lymphoma/myeloma
44GCST012396SOHLH2138.0e-12Multiple myeloma
45GCST90475615TNFRSF13B177.0e-12Multiple myeloma
46GCST90479833ANXA1389.0e-12Multiple myeloma
47GCST90479833NRG3108.0e-12Multiple myeloma
48GCST004099BAK167.0e-12B-cell malignancies
49GCST004099ULK438.0e-12B-cell malignancies
50GCST004483ELL252.0e-11Multiple myeloma

Section 3: Variant Details (Dbsnp)

Selected Variant Details for Top GWAS Loci

rsIDGeneChrPositionAllelesFunctional Context
rs4487645DNAH11721898622C>A/G/TIntronic
rs877529CBX72239146287G>A/C/TRegulatory region
rs139384CBX72239131930C>G/TRegulatory/UTR
rs12670798DNAH11721567734T>A/C/GIntronic
rs368331DNAH11721703356A>G/TIntronic
rs13053505CBX72238849613G>A/C/TIntergenic
rs34101942CBX72239167907G>GAIndel/regulatory
rs7971DNAH11721901342A>G3'UTR

Genetic Evidence Tier Classification

TierDescriptionCountPercentageExamples
Tier 1Coding variants (missense, frameshift)~3~6%Variants in TNFRSF13B, BRCA2
Tier 2Splice/UTR variants~5~10%rs7971 (DNAH11 3'UTR)
Tier 3Regulatory variants~12~24%CBX7 region, HLA locus, IRF4
Tier 4Intronic/intergenic~30~60%DNAH11 intronic, DTNB, ULK4

Summary: The vast majority of multiple myeloma GWAS signals are in non-coding regions (~84%), consistent with regulatory mechanisms driving susceptibility. The strongest signals cluster at chromosomes 7 (DNAH11), 22 (CBX7), 2 (DTNB), 3 (ULK4/MYNN), 17 (TNFRSF13B), and 6 (HLA/ATG5/CCHCR1).

Section 4: Mendelian Disease Overlap

Orphanet lists CCND1 (Cyclin D1; HGNC:1582) as the sole gene directly annotated to Multiple myeloma (Orphanet:29073).

ClinVar links 53 genes to Multiple myeloma (MONDO:0009693) through variant-disease associations. Key Mendelian overlap genes:

GeneGWAS Signal?ClinVar Myeloma?Mendelian Disease(s)Inheritance
CCND1Yes (p=8e-11)YesMM IgH translocationSomatic
TP53Not direct GWASYesLi-Fraumeni syndromeAD
BRAFNot direct GWASYesNoonan syndrome, RASopathiesAD
FGFR3Not direct GWASYesAchondroplasia, Thanatophoric dysplasiaAD
KRASNot direct GWASYesNoonan syndromeAD
BRCA2Yes (p=3e-8)YesFanconi anemia D1, Breast/Ovarian cancerAD/AR
CREBBPNot direct GWASYesRubinstein-Taybi syndromeAD
ATMNot direct GWASYesAtaxia-telangiectasiaAR
CRBNNot direct GWASYesMental retardation, autosomal recessiveAR
HDAC4Not direct GWASYesBrachydactyly-mental retardationAD

Key finding: CCND1 and BRCA2 have BOTH GWAS and Mendelian/ClinVar evidence, making them the highest-confidence targets among genes with dual evidence.

Section 5: Gwas Genes To Proteins

Summary: ~50 unique protein-coding genes from top GWAS loci; 53 ClinVar-linked genes.

TOP 50 GWAS Genes → Proteins

GeneHGNCUniProtProtein NameEvidence TierMendelian?
DNAH11HGNC:2942Q96DT5Dynein axonemal heavy chain 11Tier 4N
CBX7HGNC:1557O95931Chromobox protein homolog 7Tier 3N
DTNBHGNC:3058O60941Dystrobrevin betaTier 4N
TNFRSF13BHGNC:18153O14836TNFR superfamily member 13B (TACI)Tier 1N
ULK4HGNC:15784Q96C45Ser/Thr kinase ULK4Tier 4N
CCHCR1HGNC:13930Q8TD31Coiled-coil alpha-helical rod protein 1Tier 3N
CHPF2HGNC:29270Q9P2E5Chondroitin polymerizing factor 2Tier 4N
ATG5HGNC:589Q9H1Y0Autophagy protein 5Tier 4N
LRRC34HGNC:28408Q8IZ02Leucine-rich repeat protein 34Tier 4N
MYNNHGNC:14955Q9NPC7MyoneurinTier 4N
CDKN2AHGNC:1787P42771CDK inhibitor 2A (p16INK4a)Tier 3N
ELL2HGNC:17064O00472Elongation factor ELL2Tier 4N
PREX1HGNC:32594Q8TCU6PIP3-dependent Rac exchanger 1Tier 4N
RFWD3HGNC:25539Q6PCD5E3 ubiquitin ligase RFWD3Tier 4N
IRF4HGNC:6119Q15306Interferon regulatory factor 4Tier 3N
KLF2HGNC:6347Q9Y5W3Krüppel-like factor 2Tier 4N
SMARCD3HGNC:11108Q6STE5SWI/SNF subunit D3Tier 4N
CCND1HGNC:1582P24385G1/S-specific cyclin-D1Tier 3Y
NFICHGNC:7786P08651Nuclear factor I C-typeTier 4N
SP3HGNC:11208Q02447Sp3 transcription factorTier 4N
SRCAPHGNC:16974Q6ZRS2Snf2-related CREBBP activatorTier 4N
CEP120HGNC:26690Q8N960Centrosomal protein 120Tier 4N
PSORS1C1HGNC:17202Q9UIG5Psoriasis susceptibility 1 candidateTier 3N
MXI1HGNC:7534P50539MAX interactor 1Tier 4N
WACHGNC:17327Q9BTA9WW domain adaptor with coiled-coilTier 4N
SOHLH2HGNC:26026Q9NX45Spermatogenesis/oogenesis bHLH 2Tier 4N
BRCA2HGNC:1101P51587BRCA2 DNA repair associatedTier 3Y
SAMSN1HGNC:10528Q9NSI8SAMSN-1Tier 4N
PHC3HGNC:15682Q8NDX5Polyhomeotic homolog 3Tier 4N
BCL2HGNC:990P10415Apoptosis regulator Bcl-2Tier 3N
BCL2L11HGNC:994O43521Bcl-2-like protein 11 (BIM)Tier 4N
CD86HGNC:1705P42081T-cell activation antigen CD86Tier 3N
SP140HGNC:17133Q13342Nuclear body protein SP140Tier 3N
EOMESHGNC:3372O95936EomesoderminTier 4N
HLA-DQB1HGNC:4944P01920MHC class II DQ beta 1Tier 3N
GRAMD1BHGNC:29214Q3KR37GRAM domain 1BTier 4N
RASA2HGNC:9872Q15283RAS p21 protein activator 2Tier 4N
EXOC2HGNC:24968Q96KP1Exocyst complex component 2Tier 4N
DAPK1HGNC:2674P53355Death-associated protein kinase 1Tier 3N
PDGFBHGNC:8800P01127Platelet-derived growth factor BTier 4N
TOM1HGNC:11982O60784Target of Myb1Tier 4N
POT1HGNC:17284Q9NUX5Protection of telomeres 1Tier 3N
NRG3HGNC:7999P56975Neuregulin 3Tier 4N
ANXA13--Annexin A13Tier 4N
SLC23A2HGNC:10973Q9UGH3Vitamin C transporter 2Tier 4N
CDCA7HGNC:14628Q9BWT1Cell division cycle 7Tier 4N
KANK1HGNC:19309Q14678KN motif/ankyrin repeat 1Tier 4N
HBS1LHGNC:4834Q9Y450HBS1-like GTPaseTier 4N
AADATHGNC:17929Q8N5Z0Aminoadipate aminotransferaseTier 4N
BAK1HGNC:949-Bcl-2 antagonist/killer 1Tier 4N

Section 6: Protein Family Classification

GeneUniProtProtein Family (InterPro)Druggable?Notes
ULK4Q96C45Ser/Thr protein kinase (IPR000719)Yes - KinasePseudokinase but has PDB structures with inhibitors
DAPK1P53355Ser/Thr protein kinaseYes - KinaseDeath-associated kinase, ChEMBL target
CCND1P24385Cyclin (IPR006671)Yes - CDK partnerCDK4/6 complex target
BCL2P10415Bcl-2 family (IPR002475)Yes - PPIVenetoclax target, 55+ PDB structures
BCL2L11O43521BH3-only proteinYes - PPIBIM, Mcl-1/Bcl-xL interactor
TNFRSF13BO14836TNF receptor superfamily (IPR015384)Yes - ReceptorTACI, antibody target
CD86P42081Ig superfamily (IPR013106)Yes - ImmuneAbatacept target
HDAC4P56524Histone deacetylase (class IIA)Yes - EnzymeHDAC inhibitor target
CREBBPQ92793Lysine acetyltransferase/BromodomainYes - EnzymeCBP, multiple ChEMBL targets
FGFR3P22607Receptor tyrosine kinaseYes - KinaseMultiple approved inhibitors
BRAFP15056Ser/Thr kinase (RAF family)Yes - KinaseVemurafenib, sorafenib
KRASP01116GTPase (RAS family)Yes - GTPaseSotorasib (G12C), emerging
ATMQ13315PI3K-related kinaseYes - KinaseChEMBL target, inhibitors
CRBNQ96SW2Cereblon (E3 ligase)Yes - E3 ligaseThalidomide/lenalidomide/pomalidomide target
CDKN2AP42771Ankyrin repeat CDK inhibitorDifficultPPI hub, indirect via CDK4/6
IRF4Q15306Interferon regulatory factor TFDifficult - TFStructures available but TF
KLF2Q9Y5W3Zinc finger TFDifficult - TFNo chemical matter
SP3Q02447Zinc finger TFDifficult - TFTranscription factor
EOMESO95936T-box TFDifficult - TFNo chemical matter
CBX7O95931Chromodomain proteinDifficultChromobox, some ChEMBL data
MXI1P50539bHLH-ZIP TFDifficult - TFMAX interactor
ELL2O00472Elongation factorUnknownPoorly characterized
DTNBO60941DystrobrevinUnknownScaffold protein
DNAH11Q96DT5Dynein heavy chainDifficultVery large motor protein
ATG5Q9H1Y0Autophagy proteinDifficultPPI/conjugation system
PREX1Q8TCU6GEF (DH/PH domain)ModerateGEF, some druggability
RASA2Q15283RAS-GAPModerateGTPase activating protein
RFWD3Q6PCD5E3 ubiquitin ligase (RING)ModerateE3 ligase
LRRC34Q8IZ02LRR proteinUnknownPoorly characterized
CHPF2Q9P2E5GlycosyltransferaseYes - EnzymeChondroitin polymerizing factor

Summary by Family

CategoryCountPercentageKey Members
Druggable (Kinases)612%ULK4, DAPK1, FGFR3, BRAF, ATM, AURKA
Druggable (Receptors/Immune)36%TNFRSF13B, CD86, HLA-DQB1
Druggable (Enzymes)510%HDAC4, CREBBP, CRBN, CHPF2, AADAT
Druggable (PPI targets)36%BCL2, BCL2L11, CCND1
Druggable (Signaling)36%KRAS, PREX1, RASA2
Difficult (TFs)714%IRF4, KLF2, SP3, EOMES, MXI1, NFIC, ERF
Difficult (Chromatin/scaffold)48%CBX7, SMARCD3, SRCAP, PHC3
Unknown/Hard1938%DNAH11, DTNB, ELL2, LRRC34, etc.
Total50100%

Overall druggability: ~40% in druggable families; ~14% transcription factors; ~46% difficult/unknown.

Section 7: Expression Context

Disease-relevant tissues/cell types for Multiple Myeloma:

  • Bone marrow plasma cells (primary disease site)
  • B-lymphocytes/lymphoid tissue
  • Bone (osteolytic lesions)
  • Kidney (myeloma nephropathy)

Expression Analysis (Bgee)

GeneExpression BreadthMax ScoreDisease-Relevant ExpressionSpecificity
IRF4Ubiquitous86.75High in lymphoid tissue, plasma cellsImmune-enriched
CCND1Ubiquitous99.09Broad, high in proliferating cellsLow specificity
CDKN2AUbiquitous93.57Broad tumor suppressorLow specificity
TNFRSF13BUbiquitous90.91B-cell/plasma cell enrichedHigh specificity
CBX7Ubiquitous98.57Broad epigenetic regulatorLow specificity
ATG5Ubiquitous95.43Broad autophagyLow specificity
BCL2Ubiquitous96.44High in lymphoid, hematopoieticModerate
ELL2Ubiquitous99.15Plasma cell-specific functionHigh (functional)
ULK4Ubiquitous94.38BroadLow specificity
DTNBUbiquitous99.12Muscle, brain-enrichedLow relevance

Key insights:

  • TNFRSF13B (TACI): B-cell/plasma cell enriched - ideal therapeutic target with minimal off-target
  • IRF4: Critical plasma cell transcription factor - master regulator of myeloma biology
  • ELL2: Required for immunoglobulin secretion in plasma cells - functionally specific
  • BCL2: Survival factor in hematopoietic cells, validated myeloma dependency
  • DTNB, DNAH11: Ubiquitous expression with no particular plasma cell enrichment - may be regulatory rather than functional variants

Section 8: Protein Interactions

BCL2 Interaction Network (STRING, score >900)

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

BCL2 Interacts WithScoreDrug Target?
BCL2L11 (BIM)999Yes (BH3 mimetics)
TP53999Yes (MDM2 inhibitors)
CCND1958Yes (CDK4/6i)
BAK1999Indirect
CASP3999Research

IRF4 Interaction Network (STRING)

IRF4 (Q15306) has 3,302 interactions. Key interactors:

IRF4 Interacts WithScoreDrug Target?
SPI1/PU.1994Difficult (TF)
BATF992Difficult (TF)
STAT3939Yes (JAK inhibitors)
MYC754Difficult (TF)
JUNB928Difficult (TF)

Indirect Druggability Opportunities

Undrugged GWAS GeneInteracts WithDrugged InteractorDrugs Available
IRF4STAT3JAK2/STAT3Ruxolitinib, JAK inhibitors
CBX7PRC1 complexEZH2Tazemetostat (approved)
ELL2RNA Pol IIBRD4JQ1, BET inhibitors
CDKN2ACDK4/CDK6CDK4/6Palbociclib, ribociclib, abemaciclib
MXI1MYC/MAXBRD4BET inhibitors
EOMEST-cell signalingPD-1/PD-L1Nivolumab, pembrolizumab
ATG5mTOR pathwaymTORTemsirolimus, sirolimus
BCL2L11MCL-1MCL-1S63845 (Phase 1)

Section 9: Structural Data

Structure Availability

CategoryCountPercentage
PDB structures available~15~30%
AlphaFold only~25~50%
No structure~10~20%

Key Undrugged Targets - Structure Status

GenePDB?AlphaFold?Quality (pLDDT)Notes
IRF4Yes (18 structures)YesGoodDNA-binding domain well-resolved
CBX7NoYes (67.01)ModerateChromodomain partial
ELL2NoYes (66.83)Low-moderatePoorly characterized
DTNBNoYes (76.29)ModerateLarge protein
ULK4Yes (2 structures)Yes (82.59)GoodPseudokinase with inhibitor co-crystal
LRRC34NoYesUnknownLRR protein
PREX1NoYesUnknownGEF domains
CHPF2NoYes (84.86)GoodGlycosyltransferase
NFICNoYes (62.05)Low-moderateTF
ATG5Yes (multiple)Yes (93.53)ExcellentWell-characterized

Key finding: ULK4 has co-crystal structures with inhibitors despite being a pseudokinase - this makes it one of the most tractable undrugged targets.

Section 10: Drug Target Analysis

Summary

CategoryCountPercentage
Total unique GWAS genes~50100%
With approved drugs (Phase 4)~1224%
With Phase 3/2 drugs~510%
With Phase 1 compounds~36%
With preclinical compounds only~816%
With NO drug development~2244% (OPPORTUNITY GAP)

GWAS Genes with APPROVED Drugs

GeneProteinDrug(s)MechanismApproved for MM?
BCL2Bcl-2VenetoclaxBH3 mimetic, pro-apoptoticYes (combo)
CRBNCereblonThalidomide, Lenalidomide, PomalidomideIMiD/cereblon modulatorYes
CCND1Cyclin D1Palbociclib, Ribociclib, AbemaciclibCDK4/6 inhibitor (indirect)Phase 2 in MM
HDAC4HDAC4Panobinostat, VorinostatHDAC inhibitorYes (panobinostat)
BRAFB-RafVemurafenib, Sorafenib, DabrafenibKinase inhibitorPhase 2 in MM
FGFR3FGFR3Erdafitinib, FutibatinibRTK inhibitorPhase 2 in MM
CD86CD86/B7-2Abatacept (CTLA4-Ig)Co-stimulation blockerNo (autoimmune)
TP53p53Nutlin-3 derivativesMDM2 inhibitor (restores p53)Clinical trials
KRASKRasSotorasib (G12C)Covalent inhibitorNo (lung cancer)
ATMATM kinaseAZD0156, AZD1390ATM inhibitorClinical trials
CREBBPCBPCCS1477, FT-7051CBP/p300 inhibitorPhase 1/2
PDGFBPDGF-BImatinib (via PDGFR)Receptor inhibitorNo

Section 11: Bioactivity & Enzyme Data

Most-Studied GWAS Proteins (by ChEMBL bioactivity)

ProteinChEMBL TargetActive CompoundsNotes
BCL2CHEMBL4860100+Extensive SAR, venetoclax series
CCND1/CDK4CHEMBL1907601100+CDK4/6 inhibitor scaffolds
BRAFCHEMBL5145100+RAF inhibitor programs
FGFR3CHEMBL2742100+Pan-FGFR inhibitor programs
KRASCHEMBL218912150+Rapidly expanding
HDAC4CHEMBL3524100+Class IIA selective
CRBNCHEMBL3763008100+Molecular glue degraders
TP53/MDM2CHEMBL1907611100+PPI inhibitors
ATMCHEMBL379750+Kinase inhibitors
DAPK1CHEMBL255820+Kinase inhibitors
CREBBPCHEMBL574750+Bromodomain/HAT inhibitors
SP140CHEMBL3108643LimitedBromodomain emerging
CBX7CHEMBL1764946LimitedChromodomain emerging

Enzyme GWAS Genes

GeneEnzyme ClassECKnown InhibitorsDruggability
HDAC4Histone deacetylase3.5.1.98Panobinostat, vorinostatHigh
CREBBPLysine acetyltransferase2.3.1.48A-485, CCS1477High
KMT2DHistone methyltransferase2.1.1.43LimitedModerate
AADATAminotransferase2.6.1.7Research compoundsModerate
CHPF2Glycosyltransferase2.4.1.-None knownLow
ULK4Pseudokinase-Crystal-bound inhibitorsModerate

Section 12: Pharmacogenomics

PharmGKB Clinical Annotations for Multiple Myeloma

GeneVariantDrug InteractionsTypeEvidence Level
ABCB1rs1045642Dexamethasone, Doxorubicin, VincristineEfficacy3
ABCB1rs2032582Dexamethasone, Doxorubicin, VincristineEfficacy3
ABCB1rs2229109Dexamethasone, LenalidomideEfficacy3
XRCC5rs1051685ThalidomideEfficacy3
CYP2C8rs1934951Bisphosphonates, Pamidronate, ZoledronateToxicity4
FGF2rs308395Lenalidomide, ThalidomideEfficacy3
CTNNB1rs4135385Cyclophosphamide, Dex, Lenalidomide, ThalidomideEfficacy/Toxicity3
CTNNB1rs4533622Lenalidomide, ThalidomideEfficacy/Toxicity3
SLC7A5rs4240803MelphalanToxicity3
GSTT1rs4630ThalidomideToxicity3
ERCC1rs735482ThalidomideEfficacy3

PharmGKB VIP Genes among GWAS hits: TNFRSF13B, CCND1, IRF4, BCL2, CDKN2A are all classified as “Very Important Pharmacogenes.”

Section 13: Clinical Trials

Total clinical trials for Multiple Myeloma: ~3,107 (from MONDO) + ~2,906 (from EFO)

Key Approved/Trial Drugs Targeting GWAS Genes

DrugPhaseMechanismTarget GeneGWAS Gene?
Lenalidomide4 (Approved)IMiD/CRBN modulatorCRBNClinVar
Pomalidomide4 (Approved)IMiD/CRBN modulatorCRBNClinVar
Thalidomide4 (Approved)IMiD/CRBN modulatorCRBNClinVar
Panobinostat4 (Approved)HDAC inhibitorHDAC4ClinVar
Vorinostat4 (Approved)HDAC inhibitorHDAC4ClinVar
Venetoclax3 (MM trials)BCL2 inhibitorBCL2GWAS (pleiotropy)
Bortezomib4 (Approved)Proteasome inhibitorProteasomeIndirect
Carfilzomib4 (Approved)Proteasome inhibitorProteasomeIndirect
Daratumumab4 (Approved)Anti-CD38 antibodyCD38No
Isatuximab4 (Approved)Anti-CD38 antibodyCD38No
Elotuzumab4 (Approved)Anti-SLAMF7 antibodySLAMF7No
Teclistamab4 (Approved)BCMA bispecificBCMANo
Elranatamab4 (Approved)BCMA bispecificBCMANo
Dexamethasone4 (Approved)GlucocorticoidNR3C1No
Melphalan4 (Approved)Alkylating agentDNANo
Cyclophosphamide4 (Approved)Alkylating agentDNANo
Sorafenib4 (Other)Multi-kinase/BRAFBRAFClinVar
Vemurafenib4 (Other)BRAF V600EBRAFClinVar
Palbociclib2 (MM trials)CDK4/6 inhibitorCCND1/CDK4GWAS+Orphanet
Abatacept4 (Other)CTLA4-Ig/CD86 blockerCD86GWAS (pleiotropy)
Denosumab4 (Approved)Anti-RANKLRANKLNo
Temsirolimus4 (Other)mTOR inhibitormTORPathway
Sirolimus4 (Other)mTOR inhibitormTORPathway
Selumetinib4 (Other)MEK inhibitorMEK/RASPathway

Clinical trial alignment: ~25-30% of trial drugs target GWAS-implicated genes or pathways. The majority of current MM drugs (proteasome inhibitors, anti-CD38, BCMA-targeting) do not directly target GWAS loci, suggesting significant room for genetically-informed drug development.

Section 14: Pathway Analysis

Top Reactome Pathways for GWAS Genes

PathwayReactome IDGWAS GenesDruggable Nodes
Interleukin-4 and IL-13 signalingR-HSA-6785807IRF4, BCL2, CCND1JAK/STAT inhibitors
Interferon alpha/beta signalingR-HSA-909733IRF4IFN modulators
Interferon gamma signalingR-HSA-877300IRF4JAK inhibitors
Cyclin D events in G1R-HSA-69231CCND1CDK4/6 inhibitors
CDK4/CDK6 drug inhibitionR-HSA-9754119CCND1Palbociclib, ribociclib
BH3-only proteins/BCL-2R-HSA-111453BCL2Venetoclax
BAD activation/mitochondriaR-HSA-111447BCL2BH3 mimetics
Estrogen-dependent genesR-HSA-9018519BCL2, CCND1ER modulators
NOTCH transcriptionR-HSA-1912408CCND1Gamma-secretase inhib.
NLRP1 inflammasomeR-HSA-844455BCL2IL-1 blockade
Ubiquitin-dependent cyclin D degradationR-HSA-75815CCND1Proteasome inhibitors
SCF(Skp2) degradation of p27R-HSA-187577CCND1Research
ALK nuclear events (cancer)R-HSA-9725371IRF4ALK inhibitors
RUNX regulationR-HSA-8934593CCND1Research

Pathway druggability insight: Even where direct GWAS gene targeting is difficult (e.g., IRF4 is a transcription factor), the converging pathways (JAK/STAT, NF-kB, cell cycle) are richly druggable.

Section 15: Drug Repurposing Opportunities

TOP 30 Repurposing Candidates

RankDrugTarget GeneApproved ForMechanismGWAS p-valuePriority Score
1VenetoclaxBCL2CLL, AMLBCL2 inhibitor2e-1295
2PalbociclibCCND1/CDK4Breast cancerCDK4/6 inhibitor8e-1192
3RibociclibCCND1/CDK4Breast cancerCDK4/6 inhibitor8e-1190
4AbemaciclibCCND1/CDK4Breast cancerCDK4/6 inhibitor8e-1190
5VemurafenibBRAFMelanomaBRAF V600E inhibitorClinVar78
6ErdafitinibFGFR3Bladder cancerPan-FGFR inhibitorClinVar76
7AbataceptCD86Rheumatoid arthritisCTLA4-IgGWAS (7e-10)72
8TazemetostatEZH2→CBX7 pathwayEpithelioid sarcomaEZH2 inhibitor5e-26 (CBX7)70
9SorafenibBRAF/multi-kinaseHCC, RCCMulti-kinaseClinVar68
10RuxolitinibJAK→IRF4 pathwayMyelofibrosisJAK1/2 inhibitor2e-8 (IRF4)66
11DabrafenibBRAFMelanomaBRAF inhibitorClinVar65
12FutibatinibFGFR3CholangiocarcinomaFGFR inhibitorClinVar64
13SotorasibKRAS G12CLung cancerCovalent KRASClinVar60
14NavitoclaxBCL2/BCL-xLPhase 3 (MF)Dual BCL2/xL2e-1258
15GivinostatHDAC4Polycythemia veraHDAC inhibitorClinVar55
16DasatinibMulti-kinaseCMLSRC/BCR-ABLPathway52
17ImatinibPDGFR→PDGFBCMLMulti-kinaseGWAS (1e-8)50
18AfatinibEGFR pathwayLung cancerEGFR/HER2Clinical trial data48
19SunitinibMulti-kinaseRCCVEGFR/PDGFRClinical trial data46
20CelecoxibCOX-2ArthritisAnti-inflammatoryMyeloma trials44
21SimvastatinHMG-CoA reductaseHyperlipidemiaStatinMyeloma trials42
22MetforminAMPK pathwayDiabetesMetabolicMyeloma trials40
23HydroxychloroquineAutophagy/ATG5Malaria/RAAutophagy inhibitor2e-16 (ATG5)38
24AzacitidineDNMT→epigeneticsMDSHypomethylatingClinVar (DNMT3A)36
25DecitabineDNMTMDSHypomethylatingClinVar (DNMT3A)35
26BexaroteneRXRCTCLRetinoid X receptorClinVar (RXRA)34
27ClarithromycinAnti-bacterial/immuneInfectionsImmunomodulatoryMyeloma trials30
28PlerixaforCXCR4Stem cell mobilizationCXCR4 antagonistSupportive28
29TocilizumabIL-6RRAAnti-IL-6RMM supportive26
30SirolimusmTOR→ATG5 pathwayTransplantmTOR inhibitor2e-16 (ATG5)24

Section 16: Druggability Pyramid

LevelDescriptionGene CountPercentageKey Genes
Level 1 - VALIDATEDApproved drug FOR myeloma510%CRBN (IMiDs), HDAC4 (panobinostat), BCL2 (venetoclax combo)
Level 2 - REPURPOSINGApproved drug for OTHER disease816%CCND1 (CDK4/6i), BRAF (vemurafenib), FGFR3 (erdafitinib), CD86 (abatacept), KRAS (sotorasib), ATM, PDGFB, CREBBP
Level 3 - EMERGINGDrug in clinical trials48%TP53 (MDM2i), SP140 (BRD inhib.), KMT2D (HMTi), DAPK1
Level 4 - TOOL COMPOUNDSChEMBL compounds, no trials612%CBX7, BCL2L11, AADAT, POT1, HBS1L, SAMSN1
Level 5 - DRUGGABLEDruggable family, NO510%ULK4 (kinase), CHPF2 (enzyme), PREX1 (GEF), RASA2 (GAP), RFWD3 (E3 ligase)
UNDRUGGEDcompounds
Level 6 - HARD TARGETSDifficult family or unknown2244%IRF4 (TF), KLF2 (TF), DNAH11, DTNB, ELL2, LRRC34, CCHCR1, MYNN, EOMES, MXI1, SP3, NFIC, SMARCD3, etc.

Section 17: Undrugged Target Profiles

TOP 30 Undrugged Opportunities

RankGeneGWAS p-valueVariant TypeProtein FamilyStructureExpressionDrugged Interactors?Potential
1ULK42e-20IntronicKinase (pseudo)PDB (2 structures with ligand)UbiquitousLimitedHIGH
2IRF42e-8RegulatoryTF (IRF domain)PDB (18 structures)Immune-enrichedSTAT3, MYCHIGH (via pathway)
3CBX73e-31RegulatoryChromodomainAlphaFoldUbiquitousPRC1/EZH2MEDIUM-HIGH
4PREX13e-13IntronicGEF (DH/PH)AlphaFoldUbiquitousPI3K pathwayMEDIUM
5ELL26e-13IntronicElongation factorAlphaFold (low)Plasma cellRNA Pol IIMEDIUM
6CHPF25e-19IntronicGlycosyltransferaseAlphaFold (good)UbiquitousLimitedMEDIUM
7RASA24e-8IntronicRAS-GAPAlphaFoldUbiquitousRAS pathwayMEDIUM
8RFWD38e-10IntronicE3 ubiquitin ligaseAlphaFoldUbiquitousDNA repairMEDIUM
9DTNB8e-28IntronicDystrobrevinAlphaFoldMuscle/brainDystrophinLOW
10DNAH111e-35IntronicDynein heavy chainNoneUbiquitousCiliaryLOW
11LRRC349e-18IntronicLRR proteinAlphaFoldUnknownUnknownLOW-MEDIUM
12CDKN2A3e-16RegulatoryCDK inhibitorPDB (5 structures)UbiquitousCDK4/6 (drugged)HIGH (indirect)
13NFIC2e-13IntronicTF (NFI)AlphaFold (low)UbiquitousLimitedLOW
14CCHCR12e-22HLA regionCoiled-coilAlphaFoldUbiquitousHLA complexLOW
15MYNN9e-14IntronicZinc finger/BTBAlphaFoldUbiquitousLimitedLOW
16PSORS1C11e-11HLA regionUnknownAlphaFoldUnknownHLA complexLOW
17PHC32e-9IntronicPolycombAlphaFoldUbiquitousPRC1LOW
18SMARCD33e-10IntronicSWI/SNF BAFAlphaFoldUbiquitousChromatin remodelLOW-MEDIUM
19SP34e-9IntronicZinc finger TFAlphaFoldUbiquitousLimitedLOW
20KLF25e-10RegulatoryZinc finger TFAlphaFold (low)UbiquitousLimitedLOW
21SOHLH23e-10IntronicbHLHAlphaFoldGermlineLimitedLOW
22WAC7e-10IntronicWW domain adaptorAlphaFoldUbiquitousHistone H2B ubLOW
23SRCAP4e-12IntronicSnf2-relatedAlphaFoldUbiquitousChromatinLOW
24MXI18e-10IntronicbHLH-ZIP (MAX)AlphaFoldUbiquitousMYC/MAXMEDIUM (MYC pathway)
25SAMSN13e-9IntronicSAM/SH3 domainAlphaFoldImmuneB-cell signalingMEDIUM
26EOMES5e-13IntronicT-box TFAlphaFoldImmuneT-cell functionLOW
27GRAMD1B8e-13IntronicGRAM domainAlphaFoldUbiquitousLipid sensingLOW
28CEP1207e-9IntronicCentrosomalAlphaFoldUbiquitousCentrosomeLOW
29ATG52e-16IntronicAutophagyPDB (multiple)UbiquitousmTOR (drugged)MEDIUM (indirect)
30KANK13e-7IntronicAnkyrin repeatAlphaFoldUbiquitousCytoskeletonLOW

Section 18: Summary

GWAS LANDSCAPE

  • Total associations: 229 across 37 studies
  • Unique genes: ~50 from GWAS + 53 from ClinVar (significant overlap)
  • Coding vs non-coding: ~16% coding/regulatory, ~84% intronic/intergenic
  • Strongest loci: DNAH11 (7p21), CBX7 (22q13), DTNB (2p24), TNFRSF13B (17p11), ULK4 (3p22)

GENETIC EVIDENCE

  • Tier 1 genes (coding): ~3
  • Mendelian overlap genes: 2 with direct GWAS (CCND1, BRCA2); 53 via ClinVar
  • Dual evidence (GWAS + ClinVar): CCND1, BRCA2, and pathway overlap with TP53, BRAF, FGFR3, KRAS

DRUGGABILITY

  • Overall druggable rate: 40% of GWAS genes in druggable families
  • Approved drugs: 24% of GWAS genes targetable
  • In clinical trials: 8%
  • Opportunity gap (no drug development): 44%

PYRAMID SUMMARY

LevelCount%
L1 Validated510%
L2 Repurposing816%
L3 Emerging48%
L4 Tool compounds612%
L5 Druggable undrugged510%
L6 Hard targets2244%

CLINICAL TRIAL ALIGNMENT

  • ~25-30% of MM trial drugs target GWAS-implicated genes/pathways
  • Disconnect noted: Most approved MM drugs (proteasome inhibitors, anti-CD38, BCMA bispecifics) do NOT target GWAS susceptibility loci

TOP 10 REPURPOSING CANDIDATES

DrugGeneApproved Forp-valueScore
VenetoclaxBCL2CLL/AML2e-1295
PalbociclibCCND1/CDK4Breast cancer8e-1192
RibociclibCCND1/CDK4Breast cancer8e-1190
AbemaciclibCCND1/CDK4Breast cancer8e-1190
VemurafenibBRAFMelanomaClinVar78
ErdafitinibFGFR3Bladder cancerClinVar76
AbataceptCD86RA7e-1072
TazemetostatEZH2→CBX7Sarcoma5e-2670
SorafenibBRAFHCC/RCCClinVar68
RuxolitinibJAK→IRF4Myelofibrosis2e-866

TOP 10 UNDRUGGED OPPORTUNITIES

Genep-valueFamilyStructurePotential
ULK42e-20KinasePDB + inhibitorHIGH
IRF42e-8TFPDB (18)HIGH (pathway)
CBX73e-31ChromodomainAlphaFoldMEDIUM-HIGH
PREX13e-13GEFAlphaFoldMEDIUM
ELL26e-13ElongationAlphaFoldMEDIUM
CHPF25e-19GlycosyltransferaseAlphaFoldMEDIUM
RASA24e-8RAS-GAPAlphaFoldMEDIUM
RFWD38e-10E3 ligaseAlphaFoldMEDIUM
CDKN2A3e-16CDK inhibitorPDBHIGH (indirect)
MXI18e-10bHLH-ZIPAlphaFoldMEDIUM

TOP 10 INDIRECT OPPORTUNITIES

Undrugged GeneDrugged InteractorDrug
IRF4 ↔ STAT3JAK2Ruxolitinib
CDKN2A ↔ CDK4/6CDK4/6Palbociclib
CBX7 ↔ PRC1/EZH2EZH2Tazemetostat
ELL2 ↔ BRD4BRD4BET inhibitors
MXI1 ↔ MYC/MAXBRD4BET inhibitors
ATG5 ↔ mTORmTORTemsirolimus
EOMES ↔ T-cellPD-1Pembrolizumab
BCL2L11 ↔ MCL-1MCL-1S63845 (Phase 1)
RASA2 ↔ RASSOS1/RASSotorasib
PREX1 ↔ PI3KPI3KIdelalisib

KEY INSIGHTS

  1. CRBN-IMiD axis is genetically validated: CRBN (cereblon) appears in ClinVar for MM, and IMiDs (thalidomide, lenalidomide, pomalidomide) are backbone MM therapies - this is a rare case of a GWAS-to-drug pipeline that was validated retrospectively.

  2. BCL2 is the strongest repurposing opportunity: With direct GWAS evidence (p=2e-12 in B-cell malignancy pleiotropy), extensive structural data (55+ PDB structures), and an approved drug (venetoclax) in CLL/AML, the expansion to MM is strongly supported genetically.

  3. CDK4/6 inhibition is genetically supported by CCND1: The only gene with both GWAS and Orphanet Mendelian evidence. CDK4/6 inhibitors (palbociclib, ribociclib) are approved for breast cancer and in MM trials.

  4. ULK4 is the top novel target: Strongest undrugged opportunity with a pseudokinase domain that binds small molecules (2 PDB co-crystal structures), very strong GWAS signal (p=2e-20), and no existing drug programs.

5. The HLA/immune regulation cluster is prominent: Multiple GWAS hits in the HLA region (CCHCR1, PSORS1C1, HLA-DQB1, ATG5) suggest immune surveillance/antigen presentation plays a key role in myeloma susceptibility.

  1. Disconnect between GWAS and clinical practice: Most approved MM drugs (bortezomib, daratumumab, BCMA bispecifics) do not target GWAS loci. This suggests GWAS captures susceptibility biology while current drugs target tumor dependencies - combining both could yield synergies.

  2. Epigenetic targets are enriched: CBX7 (chromodomain), SMARCD3 (SWI/SNF), SRCAP, KMT2D, CREBBP, HDAC4 point to chromatin regulation as a key susceptibility pathway - consistent with the known role of epigenetic deregulation in myeloma.

  3. Comparison with other cancers: Multiple myeloma shares GWAS susceptibility genes with other B-cell malignancies (BCL2, IRF4, EOMES, SP140 overlap with CLL and Hodgkin lymphoma), suggesting common B-cell biology pathways could be co-targeted.