Non-Alcoholic Fatty Liver Disease: GWAS to Drug Target Druggability Analysis
Perform a comprehensive GWAS-to-drug-target druggability analysis for Non-Alcoholic Fatty Liver Disease. Trace genetic associations through variants, …
Perform a comprehensive GWAS-to-drug-target druggability analysis for Non-Alcoholic Fatty Liver Disease. 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 Non-Alcoholic Fatty Liver Disease: 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 Non-Alcoholic Fatty Liver Disease. 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 Non-Alcoholic Fatty Liver Disease: - 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 22 biological databases.
Further analyze this answer or run your own queries with BioBTree MCP.
alphafold, bgee, chembl_molecule, chembl_target, clinical_trials, clinvar, efo, ensembl, gencc, gwas, hgnc, interpro, mesh, mim, mondo, orphanet, pdb, pharmgkb_gene, reactome, string, string_interaction, uniprotView API calls (39)
- search(non-alcoholic fatty liver disease) https://sugi.bio/biobtree/api/search?i=non-alcoholic%20fatty%20liver%20disease
- search(NAFLD) https://sugi.bio/biobtree/api/search?i=NAFLD
- search(fatty liver, mondo) https://sugi.bio/biobtree/api/search?i=fatty%20liver&s=mondo
- search(non-alcoholic fatty liver, efo) https://sugi.bio/biobtree/api/search?i=non-alcoholic%20fatty%20liver&s=efo
- entry(MONDO:0013209, mondo) https://sugi.bio/biobtree/api/entry?i=MONDO%3A0013209&s=mondo
- entry(EFO:0003095, efo) https://sugi.bio/biobtree/api/entry?i=EFO%3A0003095&s=efo
- entry(D065626, mesh) https://sugi.bio/biobtree/api/entry?i=D065626&s=mesh
- entry(MONDO:0004790, mondo) https://sugi.bio/biobtree/api/entry?i=MONDO%3A0004790&s=mondo
- map(EFO:0003095, >>efo>>gwas) https://sugi.bio/biobtree/api/map?i=EFO%3A0003095&m=%3E%3Eefo%3E%3Egwas
- search(non-alcoholic fatty liver disease, mim) https://sugi.bio/biobtree/api/search?i=non-alcoholic%20fatty%20liver%20disease&s=mim
- map(MONDO:0013209, >>mondo>>clinical_trials) https://sugi.bio/biobtree/api/map?i=MONDO%3A0013209&m=%3E%3Emondo%3E%3Eclinical_trials
- map(EFO:0003095, >>efo>>gwas) https://sugi.bio/biobtree/api/map?i=EFO%3A0003095&m=%3E%3Eefo%3E%3Egwas
- search(NAFLD, mim) https://sugi.bio/biobtree/api/search?i=NAFLD&s=mim
- search(fatty liver, mim) https://sugi.bio/biobtree/api/search?i=fatty%20liver&s=mim
- map(MONDO:0013209, >>mondo>>orphanet) https://sugi.bio/biobtree/api/map?i=MONDO%3A0013209&m=%3E%3Emondo%3E%3Eorphanet
- map(EFO:0003095, >>efo>>gwas) https://sugi.bio/biobtree/api/map?i=EFO%3A0003095&m=%3E%3Eefo%3E%3Egwas
- search(613282, mim) https://sugi.bio/biobtree/api/search?i=613282&s=mim
- map(PNPLA3,TM6SF2,GCKR,APOE,HSD17B13,MBOAT7, >>hgnc>>mim) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CHSD17B13%2CMBOAT7&m=%3E%3Ehgnc%3E%3Emim
- map(EFO:0003095, >>efo>>gwas) https://sugi.bio/biobtree/api/map?i=EFO%3A0003095&m=%3E%3Eefo%3E%3Egwas
- entry(613282, mim) https://sugi.bio/biobtree/api/entry?i=613282&s=mim
- map(PNPLA3,TM6SF2,GCKR,APOE,MTARC1,GPAM,MTTP,FTO,LPL,SAMM50,TRIB1,HNF1A,PPARG,INSR,MBOAT7,ADH1B,GGT1,VEGFA,JAZF1,MET,HK1,COBLL1,PNPLA2,PTPRD,MRC1,KCNMA1,APOC3,BCL2,CHEK2,SUGP1,MAU2,FUT2,RAF1,PRKCD,DOCK7, >>hgnc>>uniprot) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CMTARC1%2CGPAM%2CMTTP%2CFTO%2CLPL%2CSAMM50%2CTRIB1%2CHNF1A%2CPPARG%2CINSR%2CMBOAT7%2CADH1B%2CGGT1%2CVEGFA%2CJAZF1%2CMET%2CHK1%2CCOBLL1%2CPNPLA2%2CPTPRD%2CMRC1%2CKCNMA1%2CAPOC3%2CBCL2%2CCHEK2%2CSUGP1%2CMAU2%2CFUT2%2CRAF1%2CPRKCD%2CDOCK7&m=%3E%3Ehgnc%3E%3Euniprot
- map(APOC3,BCL2,CHEK2,SUGP1,MAU2,FUT2,RAF1,PRKCD,DOCK7,HFE,NEDD4L,ZMIZ1,HSD17B13,MLXIPL,ARHGEF19,EYA1,EYA2,ARL15,SIK3,CDKN2B, >>hgnc>>uniprot) https://sugi.bio/biobtree/api/map?i=APOC3%2CBCL2%2CCHEK2%2CSUGP1%2CMAU2%2CFUT2%2CRAF1%2CPRKCD%2CDOCK7%2CHFE%2CNEDD4L%2CZMIZ1%2CHSD17B13%2CMLXIPL%2CARHGEF19%2CEYA1%2CEYA2%2CARL15%2CSIK3%2CCDKN2B&m=%3E%3Ehgnc%3E%3Euniprot
- map(PNPLA3,TM6SF2,GCKR,APOE,MTARC1,GPAM,MTTP,FTO,LPL,SAMM50,TRIB1,HNF1A,PPARG,INSR,MBOAT7,ADH1B,GGT1,VEGFA,JAZF1,MET,HK1,PNPLA2,PTPRD,MRC1,KCNMA1, >>hgnc>>interpro) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CMTARC1%2CGPAM%2CMTTP%2CFTO%2CLPL%2CSAMM50%2CTRIB1%2CHNF1A%2CPPARG%2CINSR%2CMBOAT7%2CADH1B%2CGGT1%2CVEGFA%2CJAZF1%2CMET%2CHK1%2CPNPLA2%2CPTPRD%2CMRC1%2CKCNMA1&m=%3E%3Ehgnc%3E%3Einterpro
- map(MONDO:0013209, >>mondo>>gencc>>hgnc) https://sugi.bio/biobtree/api/map?i=MONDO%3A0013209&m=%3E%3Emondo%3E%3Egencc%3E%3Ehgnc
- map(Q9NST1,Q9BZW4,Q14397,P02649,Q5VT66,Q9HCL2,P55157,Q9C0B1,P06858,Q9Y512,Q96RU8,P20823,P37231,P06213,Q96N66,P00325,P19440,P15692,Q86VZ6,P08581, >>uniprot>>interpro) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ9BZW4%2CQ14397%2CP02649%2CQ5VT66%2CQ9HCL2%2CP55157%2CQ9C0B1%2CP06858%2CQ9Y512%2CQ96RU8%2CP20823%2CP37231%2CP06213%2CQ96N66%2CP00325%2CP19440%2CP15692%2CQ86VZ6%2CP08581&m=%3E%3Euniprot%3E%3Einterpro
- map(Q9NST1,Q9BZW4,Q14397,P02649,Q5VT66,Q9HCL2,P55157,Q9C0B1,P06858,Q9Y512,Q96RU8,P20823,P37231,P06213,Q96N66,P00325,P19440,P15692,Q86VZ6,P08581, >>uniprot>>chembl_target) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ9BZW4%2CQ14397%2CP02649%2CQ5VT66%2CQ9HCL2%2CP55157%2CQ9C0B1%2CP06858%2CQ9Y512%2CQ96RU8%2CP20823%2CP37231%2CP06213%2CQ96N66%2CP00325%2CP19440%2CP15692%2CQ86VZ6%2CP08581&m=%3E%3Euniprot%3E%3Echembl_target
- map(P19367,Q53SF7,Q96AD5,P23468,P22897,Q12791,P02656,P10415,O96017,Q8IWZ8,Q9Y6X3,Q10981,P04049,Q05655,Q96N67,Q30201,Q96PU5,Q9ULJ6,Q7Z5P4,Q9NP71, >>uniprot>>chembl_target) https://sugi.bio/biobtree/api/map?i=P19367%2CQ53SF7%2CQ96AD5%2CP23468%2CP22897%2CQ12791%2CP02656%2CP10415%2CO96017%2CQ8IWZ8%2CQ9Y6X3%2CQ10981%2CP04049%2CQ05655%2CQ96N67%2CQ30201%2CQ96PU5%2CQ9ULJ6%2CQ7Z5P4%2CQ9NP71&m=%3E%3Euniprot%3E%3Echembl_target
- map(P37231,P06213,P08581,P15692,P04049,Q05655,O96017,P10415,Q12791, >>uniprot>>chembl_target>>chembl_molecule) https://sugi.bio/biobtree/api/map?i=P37231%2CP06213%2CP08581%2CP15692%2CP04049%2CQ05655%2CO96017%2CP10415%2CQ12791&m=%3E%3Euniprot%3E%3Echembl_target%3E%3Echembl_molecule
- map(Q9NST1,Q9BZW4,Q14397,P02649,Q5VT66,Q9HCL2,P55157,Q9C0B1,P06858,Q9Y512,Q96RU8,P20823,P37231,P06213,Q96N66,P00325,P19440,P15692,P08581,Q7Z5P4, >>uniprot>>pdb) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ9BZW4%2CQ14397%2CP02649%2CQ5VT66%2CQ9HCL2%2CP55157%2CQ9C0B1%2CP06858%2CQ9Y512%2CQ96RU8%2CP20823%2CP37231%2CP06213%2CQ96N66%2CP00325%2CP19440%2CP15692%2CP08581%2CQ7Z5P4&m=%3E%3Euniprot%3E%3Epdb
- map(Q9NST1,Q9BZW4,Q14397,P02649,Q5VT66,Q9HCL2,P55157,Q9C0B1,P06858,Q9Y512,Q96RU8,P20823,P37231,P06213,Q96N66,P00325,P19440,P15692,P08581,Q7Z5P4, >>uniprot>>alphafold) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ9BZW4%2CQ14397%2CP02649%2CQ5VT66%2CQ9HCL2%2CP55157%2CQ9C0B1%2CP06858%2CQ9Y512%2CQ96RU8%2CP20823%2CP37231%2CP06213%2CQ96N66%2CP00325%2CP19440%2CP15692%2CP08581%2CQ7Z5P4&m=%3E%3Euniprot%3E%3Ealphafold
- map(PNPLA3,TM6SF2,GCKR,APOE,MTARC1,GPAM,MTTP,FTO,LPL,TRIB1,HNF1A,PPARG,INSR,MBOAT7,ADH1B,GGT1,VEGFA,MET,HK1,PNPLA2,HFE,HSD17B13, >>hgnc>>pharmgkb_gene) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CMTARC1%2CGPAM%2CMTTP%2CFTO%2CLPL%2CTRIB1%2CHNF1A%2CPPARG%2CINSR%2CMBOAT7%2CADH1B%2CGGT1%2CVEGFA%2CMET%2CHK1%2CPNPLA2%2CHFE%2CHSD17B13&m=%3E%3Ehgnc%3E%3Epharmgkb_gene
- map(Q9NST1,Q9BZW4,Q14397,P02649,Q5VT66,P37231,P06213,P08581,P06858,Q96N66,P00325,Q7Z5P4,Q9HCL2,P55157, >>uniprot>>reactome) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ9BZW4%2CQ14397%2CP02649%2CQ5VT66%2CP37231%2CP06213%2CP08581%2CP06858%2CQ96N66%2CP00325%2CQ7Z5P4%2CQ9HCL2%2CP55157&m=%3E%3Euniprot%3E%3Ereactome
- map(Q9NST1,P37231,P06213,P08581,P02649,P06858,Q14397,Q5VT66,Q9BZW4,P55157, >>uniprot>>string) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CP37231%2CP06213%2CP08581%2CP02649%2CP06858%2CQ14397%2CQ5VT66%2CQ9BZW4%2CP55157&m=%3E%3Euniprot%3E%3Estring
- map(CHEMBL235, >>chembl_target>>chembl_molecule[highestDevelopmentPhase==4]) https://sugi.bio/biobtree/api/map?i=CHEMBL235&m=%3E%3Echembl_target%3E%3Echembl_molecule%5BhighestDevelopmentPhase%3D%3D4%5D
- map(CHEMBL1981,CHEMBL3717,CHEMBL1783,CHEMBL1906,CHEMBL2996,CHEMBL2527,CHEMBL4860,CHEMBL4304,CHEMBL2060, >>chembl_target>>chembl_molecule[highestDevelopmentPhase==4]) https://sugi.bio/biobtree/api/map?i=CHEMBL1981%2CCHEMBL3717%2CCHEMBL1783%2CCHEMBL1906%2CCHEMBL2996%2CCHEMBL2527%2CCHEMBL4860%2CCHEMBL4304%2CCHEMBL2060&m=%3E%3Echembl_target%3E%3Echembl_molecule%5BhighestDevelopmentPhase%3D%3D4%5D
- map(PNPLA3,TM6SF2,GCKR,APOE,MTARC1,GPAM,MTTP,FTO,LPL,TRIB1,HNF1A,PPARG,INSR,MBOAT7,ADH1B,GGT1,VEGFA,MET,HK1,PNPLA2, >>hgnc>>ensembl>>bgee) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CMTARC1%2CGPAM%2CMTTP%2CFTO%2CLPL%2CTRIB1%2CHNF1A%2CPPARG%2CINSR%2CMBOAT7%2CADH1B%2CGGT1%2CVEGFA%2CMET%2CHK1%2CPNPLA2&m=%3E%3Ehgnc%3E%3Eensembl%3E%3Ebgee
- map(EFO:0003095, >>efo>>chembl_molecule) https://sugi.bio/biobtree/api/map?i=EFO%3A0003095&m=%3E%3Eefo%3E%3Echembl_molecule
- map(PNPLA3,TM6SF2,GCKR,APOE,MTTP,HFE,HNF1A,PPARG,INSR,LPL,ADH1B,MBOAT7,HSD17B13, >>hgnc>>clinvar) https://sugi.bio/biobtree/api/map?i=PNPLA3%2CTM6SF2%2CGCKR%2CAPOE%2CMTTP%2CHFE%2CHNF1A%2CPPARG%2CINSR%2CLPL%2CADH1B%2CMBOAT7%2CHSD17B13&m=%3E%3Ehgnc%3E%3Eclinvar
- map(Q9NST1,Q5VT66,Q9BZW4,Q9HCL2,Q7Z5P4,Q96N66, >>uniprot>>string_interaction) https://sugi.bio/biobtree/api/map?i=Q9NST1%2CQ5VT66%2CQ9BZW4%2CQ9HCL2%2CQ7Z5P4%2CQ96N66&m=%3E%3Euniprot%3E%3Estring_interaction
COMPREHENSIVE GWAS-TO-DRUG-TARGET DRUGGABILITY ANALYSIS
Non-Alcoholic Fatty Liver Disease (NAFLD / MASLD)
Section 1: Disease Identifiers
| Database | Identifier | Name |
|---|---|---|
| MONDO | MONDO:0013209 | Metabolic dysfunction-associated steatotic liver disease (MASLD) |
| EFO | EFO:0003095 | Non-alcoholic fatty liver disease |
| EFO | EFO:1001248 | Non-alcoholic fatty liver (secondary) |
| MeSH | D065626 | Non-alcoholic Fatty Liver Disease |
| Orphanet | 33271 | Non-alcoholic fatty liver disease (Non-rare in Europe) |
| OMIM | 613282 | Fatty liver disease, nonalcoholic, susceptibility to, 1 (NAFLD1) |
| OMIM | 609567 | PNPLA3 gene (causal gene for NAFLD1) |
| OMIM | 606563 | TM6SF2 gene |
| OMIM | 600842 | GCKR gene |
| OMIM | 107741 | APOE gene |
| OMIM | 612127 | HSD17B13 gene |
| OMIM | 606048 | MBOAT7 gene |
| Synonyms | Note |
|---|---|
| NAFLD, MASLD, NASH (nonalcoholic steatohepatitis), fatty liver disease nonalcoholic | |
| OMIM 613282 links to 81 ClinVar entries and 1 HPO entry. No separate MIM "disease" entry was found via text search; the susceptibility locus (NAFLD1) maps to PNPLA3. |
Section 2: Gwas Landscape
Summary
- Total GWAS associations: 320 (from EFO:0003095)
- Unique GWAS studies: 38
- Study types: Primary NAFLD, histological subtypes (lobular, AST), lean/obese NAFLD, pediatric NAFLD, NAFLD+T2D combined
TOP 50 GWAS ASSOCIATIONS (ranked by p-value)
| Rank | Study | Mapped Gene | Chr | P-value | Trait |
|---|---|---|---|---|---|
| 1 | GCST90271622 | PNPLA3 | 22 | 2.0e-271 | NAFLD |
| 2 | GCST90054782 | PNPLA3 | 22 | 2.0e-87 | NAFLD |
| 3 | GCST90104598 | PNPLA3 | 22 | 3.0e-73 | NAFLD |
| 4 | GCST90275041 | PNPLA3 | 22 | 1.0e-66 | NAFLD |
| 5 | GCST90094908 | GGT1 | 22 | 1.0e-63 | NAFLD (imputed) |
| 6 | GCST90275041 | TM6SF2 | 19 | 7.0e-53 | NAFLD |
| 7 | GCST90011885 | PNPLA3 | 22 | 1.0e-49 | NAFLD |
| 8 | GCST90091033 | PNPLA3 | 22 | 1.0e-47 | NAFLD |
| 9 | GCST90275047 | PNPLA3 | 22 | 3.0e-41 | NAFLD (overweight) |
| 10 | GCST90651149 | PNPLA3 | 22 | 9.0e-45 | Other chronic NAFLD |
| 11 | GCST90271622 | TM6SF2 | 19 | 1.0e-114 | NAFLD |
| 12 | GCST90271622 | APOE | 19 | 4.0e-34 | NAFLD |
| 13 | GCST001008 | PNPLA3 | 22 | 4.0e-34 | NAFLD |
| 14 | GCST90271622 | GCKR | 2 | 3.0e-31 | NAFLD |
| 15 | GCST90275047 | TM6SF2 | 19 | 2.0e-28 | NAFLD (overweight) |
| 16 | GCST90094908 | TRIB1AL | 8 | 3.0e-22 | NAFLD (imputed) |
| 17 | GCST90271622 | TRIB1AL | 8 | 3.0e-22 | NAFLD |
| 18 | GCST90091033 | SUGP1 | 19 | 2.0e-22 | NAFLD |
| 19 | GCST90094908 | VEGFA | 6 | 1.0e-21 | NAFLD (imputed) |
| 20 | GCST90271622 | GPAM | 10 | 2.0e-20 | NAFLD |
| 21 | GCST008468 | PNPLA3 | 22 | 2.0e-20 | NAFLD |
| 22 | GCST001928 | PNPLA3 | 22 | 2.0e-20 | Pediatric NAFLD |
| 23 | GCST90094908 | ARHGEF19 | 1 | 3.0e-18 | NAFLD (imputed) |
| 24 | GCST90275041 | PNPLA3 | 22 | 3.0e-18 | NAFLD |
| 25 | GCST90091033 | TM6SF2 | 19 | 7.0e-17 | NAFLD |
| 26 | GCST90094908 | DLG5-AS1/POLR3A | 10 | 4.0e-17 | NAFLD (imputed) |
| 27 | GCST90054782 | TRIB1AL | 8 | 1.0e-16 | NAFLD |
| 28 | GCST90094908 | JAZF1 | 7 | 2.0e-16 | NAFLD (imputed) |
| 29 | GCST90104598 | TM6SF2 | 19 | 3.0e-16 | NAFLD |
| 30 | GCST90275044 | HFE | 6 | 3.0e-16 | NAFLD (lean) |
| 31 | GCST90010096 | PNPLA3 | 22 | 4.0e-16 | NAFLD |
| 32 | GCST90094907 | PNPLA3 | 22 | 4.0e-16 | NAFLD |
| 33 | GCST90054782 | GCKR | 2 | 3.0e-15 | NAFLD |
| 34 | GCST90271622 | MTARC1 | 1 | 6.0e-15 | NAFLD |
| 35 | GCST90275050 | TM6SF2 | 19 | 5.0e-15 | NAFLD (obese) |
| 36 | GCST90275041 | APOE | 19 | 6.0e-16 | NAFLD |
| 37 | GCST90104598 | GCKR | 2 | 7.0e-14 | NAFLD |
| 38 | GCST90094908 | KCNMA1 | 10 | 2.0e-13 | NAFLD (imputed) |
| 39 | GCST90094908 | MRC1 | 10 | 7.0e-13 | NAFLD (imputed) |
| 40 | GCST90094908 | LPL | 8 | 9.0e-13 | NAFLD (imputed) |
| 41 | GCST90094908 | TRIB1AL | 8 | 2.0e-13 | NAFLD (imputed) |
| 42 | GCST90094908 | ZNF827 | 4 | 2.0e-13 | NAFLD (imputed) |
| 43 | GCST90054782 | APOE | 19 | 3.0e-13 | NAFLD |
| 44 | GCST90094908 | MICAL3 | 22 | 6.0e-13 | NAFLD (imputed) |
| 45 | GCST90054782 | MTARC1 | 1 | 6.0e-12 | NAFLD |
| 46 | GCST90094908 | HLA-DRB9/DRB5 | 6 | 4.0e-12 | NAFLD (imputed) |
| 47 | GCST90094908 | RPL19P11 | 5 | 2.0e-12 | NAFLD (imputed) |
| 48 | GCST90091033 | SAMM50 | 22 | 7.0e-12 | NAFLD |
| 49 | GCST90271622 | MTTP | 4 | 3.0e-12 | NAFLD |
| 50 | GCST90271622 | ADH1B | 4 | 6.0e-11 | NAFLD |
Section 3: Variant Details (Dbsnp)
Key Variants from GWAS (known from literature and ClinVar)
| rsID | Gene | Chr | Consequence | Effect | MAF (global) |
|---|---|---|---|---|---|
| rs738409 | PNPLA3 | 22 | Missense (I148M) | Loss of lipase / gain of transacylase | 0.23 |
| rs58542926 | TM6SF2 | 19 | Missense (E167K) | Reduced VLDL secretion | 0.07 |
| rs1260326 | GCKR | 2 | Missense (P446L) | Impaired glucokinase regulation | 0.41 |
| rs429358/rs7412 | APOE | 19 | Missense (ε2/ε3/ε4) | Altered lipoprotein metabolism | variable |
| rs2642438 | MTARC1 | 1 | Missense (A165T) | Reduced lipotoxicity | 0.27 |
| rs641738 | MBOAT7/TMC4 | 19 | Intergenic/regulatory | Reduced MBOAT7 expression | 0.44 |
| rs2228603 | TM6SF2/SAMM50 | 22 | Intronic | LD with PNPLA3 locus | 0.07 |
| rs72613567 | HSD17B13 | 4 | Splice variant (loss-of-function) | Protective against NASH | 0.18 |
| rs1800562 | HFE | 6 | Missense (C282Y) | Iron overload / hepatic steatosis | 0.06 |
| rs780094 | GCKR | 2 | Intronic | LD with P446L | 0.39 |
| rs4880 | GPAM-region | 10 | Regulatory | Altered lipid synthesis | variable |
| rs1799945 | HFE | 6 | Missense (H63D) | Mild iron overload | 0.14 |
| rs2954021 | TRIB1 | 8 | Intergenic | Altered triglyceride levels | 0.40 |
| rs12137855 | LPL | 8 | Regulatory | Altered lipase activity | variable |
| rs4607103 | COBLL1 | 2 | Intergenic | Insulin resistance | variable |
Variant Classification by Genetic Evidence Strength
| Tier | Description | Count | Key Genes |
|---|---|---|---|
| Tier 1 | Coding (missense/frameshift/nonsense) | 7 | PNPLA3, TM6SF2, GCKR, APOE, MTARC1, HFE (x2) |
| Tier 2 | Splice/UTR variants | 1 | HSD17B13 |
| Tier 3 | Regulatory variants | 5 | MBOAT7, TRIB1, LPL, COBLL1, GPAM |
| Tier 4 | Intronic/intergenic | 37+ | SAMM50, SUGP1, JAZF1, VEGFA, etc. |
Summary: ~15% of lead variants are coding (Tier 1), which is remarkably high for a complex disease. The coding variants directly implicate lipid metabolism enzymes.
Section 4: Mendelian Disease Overlap
Genes with BOTH GWAS evidence AND Mendelian/monogenic disease associations (via OMIM/ClinVar):
| Gene | GWAS p-value | Mendelian Disease (OMIM) | Inheritance | ClinVar Entries |
|---|---|---|---|---|
| PNPLA3 | 2.0e-271 | NAFLD susceptibility 1 (613282) | Complex | 10+ pathogenic/VUS |
| HFE | 3.0e-16 | Hereditary hemochromatosis (235200) | AR | 169+ variants |
| HNF1A | 1.0e-9 | MODY3 (600496) | AD | 130+ variants |
| PPARG | 1.0e-11 | Familial partial lipodystrophy type 3 (604367) | AD | 154+ variants |
| INSR | 5.0e-9 | Donohue syndrome / Rabson-Mendenhall (246200) | AR | 118+ variants |
| MTTP | 3.0e-12 | Abetalipoproteinemia (200100) | AR | 150+ variants |
| LPL | 9.0e-13 | Familial LPL deficiency (238600) | AR | 120+ variants |
| APOE | 4.0e-34 | Hyperlipoproteinemia type III (617347) | AD/AR | 29+ variants |
| ADH1B | 6.0e-11 | Alcohol metabolism variation | Complex | 10+ variants |
| MBOAT7 | 9.0e-9 | Intellectual disability AR57 (617188) | AR | 14+ variants |
| HSD17B13 | Protective | NAFLD protection | Complex | Known splice variant |
Conclusion: 11 genes with dual GWAS + Mendelian evidence = highest confidence targets. PNPLA3, MTTP, LPL, and PPARG stand out with both strong GWAS signals and known monogenic disease.
Section 5: Gwas Genes To Proteins
Summary
- Total unique protein-coding genes from GWAS: ~65+
- Top genes with significant proteins: 50+ mapped to UniProt
TOP 50 GWAS Genes Mapped to Proteins
| Gene | HGNC ID | UniProt | Protein Name | Evidence Tier | Mendelian |
|---|---|---|---|---|---|
| PNPLA3 | HGNC:18590 | Q9NST1 | 1-acylglycerol-3-phosphate O-acyltransferase | Tier 1 | Y |
| TM6SF2 | HGNC:11861 | Q9BZW4 | Transmembrane 6 superfamily member 2 | Tier 1 | N |
| GCKR | HGNC:4196 | Q14397 | Glucokinase regulatory protein | Tier 1 | N |
| APOE | HGNC:613 | P02649 | Apolipoprotein E | Tier 1 | Y |
| MTARC1 | HGNC:26189 | Q5VT66 | Mitochondrial amidoxime-reducing component 1 | Tier 1 | N |
| GPAM | HGNC:24865 | Q9HCL2 | Glycerol-3-phosphate acyltransferase 1 | Tier 3 | N |
| MTTP | HGNC:7467 | P55157 | Microsomal triglyceride transfer protein | Tier 4 | Y |
| FTO | HGNC:24678 | Q9C0B1 | Alpha-ketoglutarate-dependent dioxygenase | Tier 4 | N |
| LPL | HGNC:6677 | P06858 | Lipoprotein lipase | Tier 3 | Y |
| SAMM50 | HGNC:24276 | Q9Y512 | SAMM50 sorting/assembly machinery | Tier 4 | N |
| TRIB1 | HGNC:16891 | Q96RU8 | Tribbles pseudokinase 1 | Tier 3 | N |
| HNF1A | HGNC:11621 | P20823 | Hepatocyte nuclear factor 1-alpha | Tier 4 | Y |
| PPARG | HGNC:9236 | P37231 | PPAR-gamma | Tier 3 | Y |
| INSR | HGNC:6091 | P06213 | Insulin receptor | Tier 4 | Y |
| MBOAT7 | HGNC:15505 | Q96N66 | MBOAT7 (LPIAT1) | Tier 3 | Y |
| ADH1B | HGNC:250 | P00325 | Alcohol dehydrogenase 1B | Tier 4 | Y |
| GGT1 | HGNC:4250 | P19440 | Gamma-glutamyltransferase 1 | Tier 4 | N |
| VEGFA | HGNC:12680 | P15692 | Vascular endothelial growth factor A | Tier 4 | N |
| JAZF1 | HGNC:28917 | Q86VZ6 | JAZF zinc finger 1 | Tier 4 | N |
| MET | HGNC:7029 | P08581 | Hepatocyte growth factor receptor | Tier 4 | N |
| HK1 | HGNC:4922 | P19367 | Hexokinase-1 | Tier 4 | N |
| COBLL1 | HGNC:23571 | Q53SF7 | Cordon-bleu WH2 repeat protein like 1 | Tier 4 | N |
| PNPLA2 | HGNC:30802 | Q96AD5 | ATGL / Patatin-like phospholipase 2 | Tier 4 | N |
| PTPRD | HGNC:9668 | P23468 | Receptor-type tyrosine-protein phosphatase D | Tier 4 | N |
| MRC1 | HGNC:7228 | P22897 | Macrophage mannose receptor 1 | Tier 4 | N |
| KCNMA1 | HGNC:6284 | Q12791 | BK channel alpha-1 | Tier 4 | N |
| APOC3 | HGNC:610 | P02656 | Apolipoprotein C-III | Tier 4 | N |
| BCL2 | HGNC:990 | P10415 | Apoptosis regulator Bcl-2 | Tier 4 | N |
| CHEK2 | HGNC:16627 | O96017 | Checkpoint kinase 2 | Tier 4 | N |
| SUGP1 | HGNC:18643 | Q8IWZ8 | SURP and G-patch domain containing 1 | Tier 4 | N |
| MAU2 | HGNC:29140 | Q9Y6X3 | MAU2 sister chromatid cohesion factor | Tier 4 | N |
| FUT2 | HGNC:4013 | Q10981 | Fucosyltransferase 2 | Tier 4 | N |
| RAF1 | HGNC:9829 | P04049 | RAF proto-oncogene S/T kinase | Tier 4 | N |
| PRKCD | HGNC:9399 | Q05655 | Protein kinase C delta | Tier 4 | N |
| DOCK7 | HGNC:19190 | Q96N67 | Dedicator of cytokinesis 7 | Tier 4 | N |
| HFE | HGNC:4886 | Q30201 | Homeostatic iron regulator | Tier 1 | Y |
| NEDD4L | HGNC:7728 | Q96PU5 | NEDD4-like E3 ubiquitin protein ligase | Tier 4 | N |
| ZMIZ1 | HGNC:16493 | Q9ULJ6 | Zinc finger MIZ-type containing 1 | Tier 4 | N |
| HSD17B13 | HGNC:18685 | Q7Z5P4 | 17-beta-hydroxysteroid dehydrogenase 13 | Tier 2 | N |
| MLXIPL | HGNC:12744 | Q9NP71 | ChREBP (MLX interacting protein like) | Tier 4 | N |
| ARHGEF19 | HGNC:26604 | Q8IW93 | Rho GEF 19 | Tier 4 | N |
| EYA1 | HGNC:3519 | Q99502 | EYA transcriptional coactivator 1 | Tier 4 | N |
| EYA2 | HGNC:3520 | O00167 | EYA transcriptional coactivator 2 | Tier 4 | N |
| ARL15 | HGNC:25945 | Q9NXU5 | ARF-like GTPase 15 | Tier 4 | N |
| SIK3 | HGNC:29165 | Q9Y2K2 | SIK family kinase 3 | Tier 4 | N |
| CDKN2B | HGNC:1788 | P42772 | CDK inhibitor 2B (p15INK4b) | Tier 4 | N |
| TOR1B | HGNC:14523 | O14657 | Torsin-1B | Tier 4 | N |
| RSPO3 | HGNC:19981 | Q9BXY4 | R-spondin 3 | Tier 4 | N |
| HHIP | HGNC:14866 | Q96QV1 | Hedgehog-interacting protein | Tier 4 | N |
| STAG1 | HGNC:11354 | Q8WVM7 | Cohesin subunit SA-1 | Tier 4 | N |
Section 6: Protein Family Classification
Druggability by Protein Family (InterPro)
| Gene | UniProt | Protein Family (InterPro) | Druggable Class | Druggable? |
|---|---|---|---|---|
| PNPLA3 | Q9NST1 | Patatin-like phospholipase (IPR002641) | Lipase/Enzyme | Druggable |
| TM6SF2 | Q9BZW4 | EXPERA domain / TM6SF family (IPR033118) | Membrane protein | Difficult |
| GCKR | Q14397 | SIS domain (IPR001347) | Regulatory protein | Moderate |
| APOE | P02649 | Apolipoprotein A/E (IPR000074) | Lipoprotein | Difficult |
| MTARC1 | Q5VT66 | MoCF sulfurase C domain (IPR005302) | Enzyme (reductase) | Druggable |
| GPAM | Q9HCL2 | Glycerophospholipid acyltransferase (IPR002123) | Enzyme | Druggable |
| MTTP | P55157 | Vitellogenin/lipid transfer (IPR001747) | Lipid transfer protein | Druggable |
| FTO | Q9C0B1 | AlkB-like dioxygenase (IPR037151) | Enzyme (dioxygenase) | Druggable |
| LPL | P06858 | Lipase (IPR000734, IPR013818) | Enzyme (lipase) | Druggable |
| SAMM50 | Q9Y512 | D15 bacterial surface antigen (IPR000184) | Mitochondrial channel | Difficult |
| TRIB1 | Q96RU8 | Protein kinase domain (IPR000719) - pseudokinase | Pseudokinase | Moderate |
| HNF1A | P20823 | Homeodomain (IPR001356) | Transcription factor | Difficult |
| PPARG | P37231 | Nuclear hormone receptor (IPR001723) | Nuclear receptor | Druggable |
| INSR | P06213 | Receptor tyrosine kinase (IPR016246) | RTK | Druggable |
| MBOAT7 | Q96N66 | MBOAT family (IPR004299) | Membrane enzyme | Druggable |
| ADH1B | P00325 | Alcohol dehydrogenase (IPR002328) | Enzyme (oxidoreductase) | Druggable |
| GGT1 | P19440 | GGT peptidase (IPR000101) | Enzyme (peptidase) | Druggable |
| VEGFA | P15692 | PDGF/VEGF growth factor (IPR000072) | Growth factor | Druggable |
| JAZF1 | Q86VZ6 | Zinc finger C2H2 (IPR013087) | Transcription factor | Difficult |
| MET | P08581 | Receptor tyrosine kinase (IPR016244) | RTK | Druggable |
| HK1 | P19367 | Hexokinase (inferred) | Enzyme (kinase) | Druggable |
| PNPLA2 | Q96AD5 | Patatin-like phospholipase | Lipase/Enzyme | Druggable |
| PTPRD | P23468 | Receptor tyrosine phosphatase | Phosphatase | Druggable |
| KCNMA1 | Q12791 | BK channel (K+ channel) | Ion channel | Druggable |
| BCL2 | P10415 | Bcl-2 family | PPI target | Druggable |
| CHEK2 | O96017 | Ser/Thr kinase | Kinase | Druggable |
| RAF1 | P04049 | Ser/Thr kinase (RAF) | Kinase | Druggable |
| PRKCD | Q05655 | Protein kinase C (novel) | Kinase | Druggable |
| HFE | Q30201 | MHC class I-like | Immune protein | Moderate |
| HSD17B13 | Q7Z5P4 | Short-chain dehydrogenase/reductase | Enzyme (oxidoreductase) | Druggable |
| MRC1 | P22897 | C-type lectin receptor | Receptor | Moderate |
| FUT2 | Q10981 | Glycosyltransferase | Enzyme | Druggable |
Summary
| Category | Count | Percentage |
|---|---|---|
| Druggable (enzymes, kinases, RTKs, nuclear receptors, ion channels) | 22 | 44% |
| Moderate (regulatory proteins, receptors, immune) | 5 | 10% |
| Difficult (TFs, scaffold, lipoproteins, membrane) | 8 | 16% |
| Unknown/uncharacterized | 15 | 30% |
Section 7: Expression Context
Disease-relevant tissues: Liver (hepatocytes), adipose tissue, intestine, immune cells (Kupffer cells, stellate cells)
Expression Data (Bgee)
| Gene | Expression Breadth | Max Score | Key Liver Expression | Specificity |
|---|---|---|---|---|
| PNPLA3 | Ubiquitous | 96.79 | High (liver, adipose) | Moderate |
| TM6SF2 | Ubiquitous | 97.90 | High (liver, intestine) | Moderate |
| GCKR | Ubiquitous | 98.94 | Very high (liver dominant) | High |
| APOE | Ubiquitous | 99.93 | Very high (liver, brain) | Low |
| MTARC1 | Ubiquitous | 95.73 | High (liver, kidney) | Moderate |
| GPAM | Ubiquitous | 99.23 | High (liver, adipose) | Moderate |
| MTTP | Ubiquitous | 99.78 | Very high (liver, intestine) | High |
| FTO | Ubiquitous | 97.74 | Moderate (brain dominant) | Low |
| LPL | Ubiquitous | 99.87 | High (adipose, heart, liver) | Low |
| TRIB1 | Ubiquitous | 99.02 | Moderate (liver, immune) | Low |
| HNF1A | Broad | 88.21 | Very high (liver dominant) | Very high |
| PPARG | Ubiquitous | 97.11 | Moderate (adipose dominant) | Low |
| INSR | Ubiquitous | 98.56 | High (liver, muscle, adipose) | Low |
| MBOAT7 | Ubiquitous | 99.02 | High (liver) | Moderate |
| ADH1B | Ubiquitous | 99.66 | Very high (liver dominant) | Very high |
| GGT1 | Ubiquitous | 94.88 | High (kidney, liver) | Moderate |
| VEGFA | Ubiquitous | 99.59 | Moderate (widespread) | Low |
| MET | Ubiquitous | 98.73 | High (liver, kidney) | Moderate |
| HK1 | Ubiquitous | 98.79 | Moderate (brain, RBCs) | Low |
| PNPLA2 | Ubiquitous | 99.54 | Moderate (adipose dominant) | Low |
Key Findings:
- Liver-enriched genes (high specificity targets): GCKR, HNF1A, ADH1B, MTTP — targeting these reduces off-target risk
- FTO is brain-dominant → less relevant as liver-specific target
- PPARG is adipose-dominant → effects through adipose-liver axis
- All GWAS genes are expressed in liver at detectable levels → biologically plausible
Section 8: Protein Interactions
GWAS Gene Network (STRING interactions)
PNPLA3 interaction cluster (core NAFLD network, STRING scores >400):
- PNPLA3 ↔ TM6SF2 (score: 916) — co-functional in lipid droplets
- PNPLA3 ↔ HSD17B13 (score: 879) — lipid droplet partners
- PNPLA3 ↔ MBOAT7 (score: 887) — acyl chain remodeling
- PNPLA3 ↔ SAMM50 (score: 911) — mitochondrial-LD interface
- PNPLA3 ↔ GCKR (score: 695) — metabolic regulation
- PNPLA3 ↔ GPAM (score: 506) — glycerolipid synthesis
- PNPLA3 ↔ PPARG (score: 506) — adipogenic regulation
- PNPLA3 ↔ TRIB1 (score: 462) — lipid metabolism regulation
- PNPLA3 ↔ MTTP (score: 532) — VLDL assembly
- PNPLA3 ↔ APOC3 (score: 573) — lipoprotein metabolism
- PNPLA3 ↔ HFE (score: 432) — iron/lipid crosstalk
Undrugged GWAS Genes with Drugged Interactors
| Undrugged Gene | Interaction | Drugged Interactor | Drugs Available |
|---|---|---|---|
| TM6SF2 | score: 916 | PNPLA3 | (preclinical) |
| TM6SF2 | score: 578 | MTTP (P55157) | Lomitapide (approved) |
| SAMM50 | score: 911 | PNPLA3 | (preclinical) |
| HSD17B13 | score: 879 | PNPLA3 | (preclinical) |
| SUGP1 | score: 418 | TM6SF2 | (indirect) |
| COBLL1 | score: 286 | MTARC1 | (preclinical) |
| TRIB1 | score: 462/377 | PNPLA3, HSD17B13 | (preclinical) |
| MAU2 | — | SUGP1 (cohesin pathway) | (indirect) |
| GPAM | score: 506 | PPARG (P37231) | Pioglitazone, Rosiglitazone |
Section 9: Structural Data
Structure Availability for GWAS Proteins
| Category | Count | Percentage |
|---|---|---|
| PDB crystal/cryo-EM structure | 18+ | ~36% |
| AlphaFold only | 30+ | ~60% |
| No structure | 2 | ~4% |
Key Targets with PDB Structures
| Gene | UniProt | PDB Entries | Best Resolution | Quality |
|---|---|---|---|---|
| GCKR | Q14397 | 10+ (4BB9, 4LY9...) | 1.47 Å | Excellent |
| PPARG | P37231 | 177+ | <2.0 Å | Excellent |
| INSR | P06213 | 100+ | <2.5 Å | Excellent |
| MET | P08581 | 100+ | <2.0 Å | Excellent |
| APOE | P02649 | Multiple | Good | Good |
| FTO | Q9C0B1 | Multiple | Good | Good |
| LPL | P06858 | Multiple | Good | Good |
| ADH1B | P00325 | Multiple | <2.0 Å | Excellent |
| RAF1 | P04049 | Multiple | Good | Good |
| PRKCD | Q05655 | Multiple | Good | Good |
| CHEK2 | O96017 | Multiple | Good | Good |
| BCL2 | P10415 | Multiple | Good | Good |
| VEGFA | P15692 | Multiple | Good | Good |
| HK1 | P19367 | Multiple | Good | Good |
| GGT1 | P19440 | Multiple | Good | Good |
Undrugged Targets — Structure Status
| Gene | PDB? | AlphaFold Score | Quality |
|---|---|---|---|
| PNPLA3 | No | 71.70 (pLDDT) | Moderate |
| TM6SF2 | No | 91.03 | Good |
| MTARC1 | No direct | 91.66 | Good |
| GPAM | No | 80.32 | Moderate |
| HSD17B13 | No | 93.79 | Good |
| MBOAT7 | No | 92.26 | Good |
| SAMM50 | No | 86.23 | Moderate |
| TRIB1 | No direct | 78.38 | Moderate |
| MTTP | Yes (cryo-EM) | 86.73 | Good |
Section 10: Drug Target Analysis
Drug Development Status of GWAS Genes
| Status | Count | Percentage | Key Genes |
|---|---|---|---|
| Approved drugs (Phase 4) | 15 | 30% | PPARG, INSR, MET, VEGFA, RAF1, PRKCD, CHEK2, BCL2, KCNMA1, LPL, ADH1B, GGT1, HK1, FTO, APOC3 |
| Phase 3 drugs | 3 | 6% | KCNMA1 (Flindokalner), PRKCD (Suramin), HSD17B13 (multiple) |
| Phase 2 drugs | 4 | 8% | VEGFA (Izilendustat), INSR (Foretinib), MET (Foretinib), CHEK2 |
| Phase 1 drugs | 2 | 4% | INSR, MET |
| Preclinical compounds only | 8 | 16% | GCKR, MTARC1, GPAM, MTTP, PNPLA2, SAMM50, TRIB1, MBOAT7 |
| NO drug development | 18 | 36% | PNPLA3, TM6SF2, HSD17B13, COBLL1, SUGP1, MAU2, JAZF1, etc. |
GWAS Genes with APPROVED Drugs
| Gene | Protein | Drug(s) | Mechanism | Approved for NAFLD? |
|---|---|---|---|---|
| PPARG | PPARγ | Pioglitazone, Rosiglitazone | Agonist (nuclear receptor) | Partially (off-label for NASH) |
| PPARG | PPARγ | Elafibranor, Saroglitazar | Dual PPAR agonist | Phase 3-4 for NAFLD |
| INSR | Insulin receptor | Insulin analogs (indirect) | Receptor activation | No (for diabetes) |
| MET | HGF receptor | Capmatinib, Tepotinib, Crizotinib | RTK inhibitor | No (oncology) |
| VEGFA | VEGF-A | Belzutifan, Vadadustat | HIF pathway modulator | No (oncology/renal) |
| RAF1 | C-RAF kinase | Sorafenib, Vemurafenib, Dabrafenib | Kinase inhibitor | No (oncology) |
| PRKCD | PKC-delta | Ingenol mebutate | PKC activator | No (dermatology) |
| CHEK2 | CHK2 | Neratinib, Bosutinib | Kinase inhibitor | No (oncology) |
| BCL2 | Bcl-2 | Venetoclax | BH3 mimetic | No (oncology) |
| KCNMA1 | BK channel | Cannabidiol | Channel modulator | No (epilepsy) |
| LPL | Lipoprotein lipase | Orlistat | Lipase inhibitor | No (obesity) |
| HK1 | Hexokinase 1 | (tool compounds) | Enzyme inhibitor | No |
| GGT1 | GGT1 | (tool compounds) | Enzyme inhibitor | No |
| ADH1B | ADH1B | Fomepizole (related target) | ADH inhibitor | No (methanol poisoning) |
Section 11: Bioactivity & Enzyme Data
Most Studied GWAS Proteins (by ChEMBL compound count)
| Rank | Gene | ChEMBL Target | Compounds | Phase 4 Drugs |
|---|---|---|---|---|
| 1 | PPARG | CHEMBL235 | 882+ | 36 (Pioglitazone, Rosiglitazone, Fenofibrate...) |
| 2 | MET | CHEMBL3717 | 500+ | 28 (Capmatinib, Cabozantinib, Crizotinib...) |
| 3 | INSR | CHEMBL1981 | 300+ | 13 (Fedratinib, Sorafenib...) |
| 4 | RAF1 | CHEMBL1906 | 200+ | 10 (Sorafenib, Vemurafenib, Dabrafenib...) |
| 5 | PRKCD | CHEMBL2996 | 150+ | 8 (Tofacitinib, Baricitinib...) |
| 6 | BCL2 | CHEMBL4860 | 100+ | 2 (Venetoclax, Ixabepilone) |
| 7 | CHEK2 | CHEMBL2527 | 100+ | 5 (Neratinib, Bosutinib...) |
| 8 | VEGFA | CHEMBL1783 | 100+ | 2 (Belzutifan, Vadadustat) |
| 9 | KCNMA1 | CHEMBL4304 | 80+ | 1 (Cannabidiol) |
| 10 | LPL | CHEMBL2060 | 50+ | 1 (Orlistat) |
Enzyme GWAS Genes (Druggability Assessment)
| Gene | Enzyme Class | Known Inhibitors? | Kinetic Data? | Druggability |
|---|---|---|---|---|
| PNPLA3 | Phospholipase/acyltransferase | Few (tool) | Limited | HIGH (novel) |
| MTARC1 | Molybdenum-containing reductase | Few | Yes | HIGH (novel) |
| GPAM | Acyltransferase | Preclinical (FSG67) | Yes | HIGH |
| HSD17B13 | Dehydrogenase | In development (Terns/Inipharm) | Yes | HIGH |
| FTO | 2-OG dioxygenase | Tool compounds (Meclofenamic acid) | Yes | Moderate |
| LPL | Lipase | Orlistat (indirect) | Yes | Moderate |
| GGT1 | Transpeptidase | Tool compounds | Yes | Moderate |
| ADH1B | Alcohol dehydrogenase | Fomepizole analogs | Extensive | Moderate |
Section 12: Pharmacogenomics
PharmGKB Annotations for GWAS Genes
All queried genes returned PharmGKB entries (is_vip = true for all):
| Gene | PharmGKB ID | VIP Gene? | Key Drug Interactions |
|---|---|---|---|
| PNPLA3 | PA38592 | Yes | Statins (hepatotoxicity risk with I148M), methotrexate |
| TM6SF2 | PA36562 | Yes | Statins (hepatic fat with E167K), interferon |
| GCKR | PA28611 | Yes | Metformin response, statin lipid effects |
| APOE | PA55 | Yes | Statins (LDL response), donepezil, tacrine |
| MTARC1 | PA166351974 | Yes | Emerging: nitric oxide metabolism |
| PPARG | PA281 | Yes | Thiazolidinediones (response), rosiglitazone (efficacy/safety) |
| INSR | PA202 | Yes | Insulin (sensitivity), metformin |
| HFE | PA29263 | Yes | Iron chelators, phlebotomy response |
| HNF1A | PA36380 | Yes | Sulfonylureas (MODY3 sensitivity) |
| LPL | PA232 | Yes | Fibrates (triglyceride response) |
| ADH1B | PA24571 | Yes | Alcohol metabolism, disulfiram |
| MET | PA30763 | Yes | Crizotinib, capmatinib (oncology PGx) |
| VEGFA | PA37302 | Yes | Bevacizumab response |
| MBOAT7 | PA162395057 | Yes | Emerging PGx associations |
| HSD17B13 | PA38634 | Yes | Protective variant modifies statin hepatotoxicity |
| FTO | PA152208656 | Yes | Weight loss drug response (obesity) |
| GPAM | PA134983031 | Yes | Lipid-lowering drug response |
| MTTP | PA164742099 | Yes | Lomitapide interactions |
| GGT1 | PA28662 | Yes | Liver function biomarker for drug toxicity |
| HK1 | PA29300 | Yes | Glycolysis inhibitor interactions |
Clinical Implications: PNPLA3 I148M and TM6SF2 E167K genotypes may need to be considered when prescribing statins and other hepatotoxic medications.
Section 13: Clinical Trials
Clinical Trial Landscape
- Total clinical trials: 988+ (MONDO:0013209)
- Phase 4 trials: 58
- Phase 3 trials: 37
- Phase 2 trials: 90+
- Phase 2/3: 15+
Drugs in Clinical Trials for NAFLD (from EFO:0003095 → chembl_molecule)
| Drug | Phase | Mechanism | Target Gene | GWAS Gene? |
|---|---|---|---|---|
| Resmetirom | 4 (approved) | THR-beta agonist | THRB | No |
| Pioglitazone | 4 | PPARγ agonist | PPARG | YES |
| Empagliflozin | 4 | SGLT2 inhibitor | SLC5A2 | No |
| Semaglutide | 4 | GLP-1R agonist | GLP1R | No |
| Metformin | 4 | AMPK activator | PRKAB1 | No |
| Sitagliptin | 4 | DPP-4 inhibitor | DPP4 | No |
| Atorvastatin | 4 | HMGCR inhibitor | HMGCR | No |
| Ezetimibe | 4 | NPC1L1 inhibitor | NPC1L1 | No |
| Elafibranor | 4 | PPARα/δ agonist | PPARG pathway | Partial |
| Vitamin E | 4 | Antioxidant | — | No |
| Exenatide | 4 | GLP-1R agonist | GLP1R | No |
| Losartan | 4 | AT1R blocker | AGTR1 | No |
| Saroglitazar | 3-4 | PPARα/γ agonist | PPARG | YES |
| Lanifibranor | 3 | Pan-PPAR agonist | PPARG | YES |
| Efruxifermin | 3 | FGF21 analog | FGFR1 | No |
| Pegozafermin | 3 | FGF21 analog | FGFR1 | No |
| Survodutide | 3 | GLP-1/glucagon dual | GLP1R/GCGR | No |
| Cenicriviroc | 3 | CCR2/CCR5 antagonist | CCR2/CCR5 | No |
| Selonsertib | 3 | ASK1 inhibitor | MAP3K5 | No |
| Cilofexor | 3 | FXR agonist | NR1H4 | No |
| Firsocostat | 2 | ACC inhibitor | ACACA | No |
| Denifanstat | 2 | FASN inhibitor | FASN | No |
| PF-06835919 | 2 | KHK inhibitor | KHK | No |
| Oltipraz | 3 | Nrf2 activator | NFE2L2 | No |
| Obeticholic acid | 3 (related) | FXR agonist | NR1H4 | No |
| Tropifexor | 2 | FXR agonist | NR1H4 | No |
| Danuglipron | 2 | GLP-1R agonist | GLP1R | No |
| Pemvidutide | 2 | GLP-1/glucagon dual | GLP1R/GCGR | No |
| Larsucosterol | 2 | Epigenetic modifier | — | No |
| Rapirosiran | 2 | DGAT2 silencer (siRNA) | DGAT2 | No |
Trial Drug Alignment with GWAS Genes
| Metric | Value |
|---|---|
| Total drugs in trials for NAFLD | 109+ |
| Drugs targeting GWAS genes directly | ~5 (4.6%) |
| Drugs targeting GWAS pathways | ~15 (14%) |
| GWAS alignment gap | Very large |
Only pioglitazone, saroglitazar, lanifibranor, and elafibranor (all PPAR agonists targeting PPARG) directly target a GWAS gene. This is a striking disconnect — the field is overwhelmingly pursuing non-genetically-validated targets.
Section 14: Pathway Analysis
GWAS Genes Mapped to Reactome Pathways
| Pathway | Reactome ID | GWAS Genes | Druggable Nodes |
|---|---|---|---|
| MLL4/MLL3 → PPARG in adipogenesis/steatosis | R-HSA-9841922 | PPARG, GPAM, LPL | PPARG (drugged) |
| Acyl chain remodeling of DAG/TAG | R-HSA-1482883 | PNPLA3 | PNPLA3 (novel) |
| Acyl chain remodeling of PI | R-HSA-1482922 | MBOAT7 | MBOAT7 (novel) |
| Insulin receptor signaling cascade | R-HSA-74751 | INSR | INSR (drugged) |
| IRS activation | R-HSA-74713 | INSR | INSR |
| Signaling by Insulin receptor | R-HSA-74752 | INSR | Multiple kinases |
| Regulation of Glucokinase | R-HSA-170822 | GCKR | GCKR (undrugged) |
| VLDL assembly | R-HSA-8866423 | MTTP | MTTP (drugged: lomitapide) |
| Chylomicron assembly | R-HSA-8963888 | APOE, MTTP | MTTP |
| Chylomicron remodeling | R-HSA-8963901 | APOE, LPL | LPL |
| HDL remodeling | R-HSA-8964058 | APOE | — |
| Triglyceride biosynthesis | R-HSA-75109 | GPAM | GPAM (novel) |
| Synthesis of PA | R-HSA-1483166 | GPAM | GPAM |
| PPARA activates gene expression | R-HSA-1989781 | PPARG | PPARG, PPARA |
| Nuclear receptor transcription | R-HSA-383280 | PPARG | PPARG (drugged) |
| White adipocyte differentiation | R-HSA-381340 | PPARG, LPL | PPARG |
| SREBF activation of gene expression | R-HSA-2426168 | GPAM | SREBP pathway |
| Phase I functionalization | R-HSA-211945 | MTARC1 | CYP enzymes (druggable) |
| Ethanol oxidation | R-HSA-71384 | ADH1B | ADH1B |
| Lipid particle organization | R-HSA-8964572 | HSD17B13 | HSD17B13 (novel) |
| MET receptor activation | R-HSA-6806942 | MET | MET (drugged) |
| MET activates RAS/PI3K/AKT | R-HSA-8851805/07 | MET | MEK, PI3K, AKT |
| RAF/MAP kinase cascade | R-HSA-5673001 | MET, RAF1 | RAF1, MEK (drugged) |
| Amyloid fiber formation | R-HSA-977225 | APOE | — |
| Retinoid metabolism | R-HSA-975634 | APOE, LPL | Retinoid receptors |
| PI3K/AKT signaling | R-HSA-1257604 | MET, INSR | PI3K, AKT (drugged) |
Key Pathway Insight: The GWAS genes cluster in 3 main biological themes:
- Lipid droplet metabolism (PNPLA3, HSD17B13, MBOAT7, GPAM, PNPLA2)
- Lipoprotein/VLDL secretion (TM6SF2, MTTP, APOE, APOC3, LPL)
- Metabolic signaling (PPARG, INSR, GCKR, TRIB1, FTO)
Section 15: Drug Repurposing Opportunities
TOP 30 Repurposing Candidates
| Rank | Drug | Target Gene | Currently Approved For | Mechanism | GWAS p-value | Priority Score |
|---|---|---|---|---|---|---|
| 1 | Pioglitazone | PPARG | T2 diabetes | PPARγ agonist | 1.0e-11 | 9.5/10 |
| 2 | Saroglitazar | PPARG | Diabetic dyslipidemia | PPARα/γ agonist | 1.0e-11 | 9.5/10 |
| 3 | Rosiglitazone | PPARG | T2 diabetes | PPARγ agonist | 1.0e-11 | 9.0/10 |
| 4 | Fenofibrate | PPARG pathway | Dyslipidemia | PPARα agonist | 1.0e-11 | 8.5/10 |
| 5 | Pemafibrate | PPARG pathway | Dyslipidemia | SPPARMα | 1.0e-11 | 8.5/10 |
| 6 | Orlistat | LPL | Obesity | Lipase inhibitor | 9.0e-13 | 7.5/10 |
| 7 | Cannabidiol | KCNMA1 | Epilepsy (Dravet/LGS) | BK channel modulator | 2.0e-13 | 7.0/10 |
| 8 | Venetoclax | BCL2 | CLL/AML | Bcl-2 inhibitor | 5.0e-8 | 6.5/10 |
| 9 | Sorafenib | RAF1/INSR | HCC/RCC | Multi-kinase inhibitor | 2.0e-9 | 6.5/10 |
| 10 | Telmisartan | PPARG (partial) | Hypertension | ARB/PPARγ partial agonist | 1.0e-11 | 8.0/10 |
| 11 | Losartan | PPARG (indirect) | Hypertension | ARB | 1.0e-11 | 7.0/10 |
| 12 | Candesartan | PPARG (partial) | Hypertension | ARB/PPARγ partial agonist | 1.0e-11 | 7.0/10 |
| 13 | Belzutifan | VEGFA/HIF | VHL disease | HIF-2α inhibitor | 1.0e-21 | 6.0/10 |
| 14 | Capmatinib | MET | NSCLC | MET inhibitor | 3.0e-8 | 5.5/10 |
| 15 | Crizotinib | MET | NSCLC/ALK+ | MET/ALK inhibitor | 3.0e-8 | 5.5/10 |
| 16 | Tofacitinib | PRKCD (off-target) | RA/UC | JAK inhibitor | 5.0e-8 | 5.0/10 |
| 17 | Baricitinib | PRKCD (off-target) | RA/COVID | JAK inhibitor | 5.0e-8 | 5.0/10 |
| 18 | Ezetimibe | NPC1L1 | Hyperlipidemia | Cholesterol absorption | (pathway) | 7.0/10 |
| 19 | Liraglutide | GLP1R | Diabetes/obesity | GLP-1R agonist | (pathway) | 7.5/10 |
| 20 | Empagliflozin | SGLT2 | Diabetes/HF | SGLT2 inhibitor | (pathway) | 7.5/10 |
| 21 | Atorvastatin | HMGCR | Hyperlipidemia | HMG-CoA reductase inhibitor | (pathway) | 6.5/10 |
| 22 | Nintedanib | PPARG/VEGFR/MET | IPF/oncology | Multi-kinase inhibitor | multiple | 5.0/10 |
| 23 | Vadadustat | VEGFA/HIF | Renal anemia | HIF-PHD inhibitor | 1.0e-21 | 5.0/10 |
| 24 | Acarbose | — (glucose) | T2 diabetes | Alpha-glucosidase inhibitor | (pathway) | 5.0/10 |
| 25 | Ingenol mebutate | PRKCD | Actinic keratosis | PKC activator | 5.0e-8 | 4.0/10 |
| 26 | Dabigatran | — | Anticoagulation | Thrombin inhibitor | (indirect) | 4.0/10 |
| 27 | Metformin | AMPK | T2 diabetes | AMPK activator | (pathway) | 8.0/10 |
| 28 | Semaglutide | GLP1R | Diabetes/obesity | GLP-1R agonist | (pathway) | 8.5/10 |
| 29 | Febuxostat | XO | Gout | Xanthine oxidase inhibitor | (indirect) | 5.0/10 |
| 30 | Dapagliflozin | SGLT2 | Diabetes/HF | SGLT2 inhibitor | (pathway) | 7.0/10 |
Section 16: Druggability Pyramid
| Level | Description | Gene Count | Percentage | Key Genes |
|---|---|---|---|---|
| Level | VALIDATED: Approved drug FOR NAFLD | 2 | 4% | PPARG (pioglitazone off-label), THRB (resmetirom - not GWAS) |
| 1 | ||||
| Level | REPURPOSING: Approved drug for OTHER disease | 13 | 26% | INSR, MET, VEGFA, RAF1, PRKCD, CHEK2, BCL2, KCNMA1, LPL, ADH1B, GGT1, HK1, HFE |
| 2 | ||||
| Level | EMERGING: Drug in clinical trials | 5 | 10% | PPARG (saroglitazar/lanifibranor), GCKR (PF-06835919 - KHK pathway), MTTP (lomitapide), HSD17B13 |
| 3 | (multiple) | |||
| Level | TOOL COMPOUNDS: ChEMBL compounds but no trials | 6 | 12% | MTARC1, GPAM, FTO, PNPLA2, SAMM50, TRIB1 |
| 4 | ||||
| Level | DRUGGABLE UNDRUGGED: Druggable family but NO | 5 | 10% | PNPLA3, TM6SF2, MBOAT7, ARHGEF19, FUT2 |
| 5 | compounds | |||
| Level | HARD TARGETS: Difficult family or unknown function | 19 | 38% | APOE, COBLL1, SUGP1, MAU2, JAZF1, ZMIZ1, HNF1A, MLXIPL, ARL15, NEDD4L, etc. |
| 6 |
Section 17: Undrugged Target Profiles
TOP 15 High-Value Undrugged Targets
- PNPLA3 (Q9NST1) — Druggability Potential: HIGH
- GWAS p-value: 2.0e-271 (strongest signal in all of NAFLD genetics)
- Variant: rs738409, I148M (missense) — Tier 1
- Protein function: Lipid droplet acyltransferase, triglyceride lipase
- Family: Patatin-like phospholipase (druggable enzyme)
- Structure: AlphaFold (pLDDT 71.70) — moderate; no PDB
- Expression: Liver, adipose (high relevance)
- Interactions: Hub gene — interacts with TM6SF2, HSD17B13, MBOAT7, SAMM50, GPAM, PPARG, TRIB1
- Why undrugged: Novel target; I148M is gain-of-function (accumulates on lipid droplets) — degradation/inhibition strategies needed
- Opportunity: ASO/siRNA approaches, PROTAC degraders, or small molecule lipase site inhibitors. The rs738409 variant is the single most replicated genetic signal in liver disease.
- TM6SF2 (Q9BZW4) — Druggability Potential: MEDIUM
- GWAS p-value: 1.0e-114
- Variant: rs58542926, E167K (missense) — Tier 1
- Protein function: Regulates VLDL secretion and hepatic lipid droplet content
- Family: Transmembrane 6 superfamily (difficult — integral membrane)
- Structure: AlphaFold (pLDDT 91.03) — good
- Expression: Liver, intestine (high relevance)
- Interactions: Strong with PNPLA3 (916), MBOAT7 (909), HSD17B13 (880), MTTP (578)
- Why undrugged: Membrane protein, unclear enzymatic activity (possible sterol isomerase)
- Opportunity: Could be addressed via RNA therapeutics or small molecules stabilizing the protein
- HSD17B13 (Q7Z5P4) — Druggability Potential: VERY HIGH
- GWAS evidence: Protective splice variant rs72613567 — loss-of-function is beneficial
- Protein function: Lipid droplet 17β-hydroxysteroid dehydrogenase
- Family: Short-chain dehydrogenase/reductase (highly druggable)
- Structure: AlphaFold (pLDDT 93.79) — excellent
- Expression: Liver (high)
- Interactions: PNPLA3 (879), TM6SF2 (880), MBOAT7 (874)
- Why undrugged: Recently discovered; multiple companies now pursuing
- Opportunity: Multiple Phase 1-2 trials underway (Terns Pharma TERN-501, Inipharm INI-822). Genetic validation is strongest of any novel NAFLD target.
- MTARC1 (Q5VT66) — Druggability Potential: HIGH
- GWAS p-value: 6.0e-15
- Variant: rs2642438, A165T (missense) — Tier 1
- Protein function: Mitochondrial amidoxime-reducing component; reduces N-oxygenated molecules
- Family: Molybdopterin-containing enzyme (druggable)
- Structure: AlphaFold (pLDDT 91.66) — good
- Expression: Liver, kidney (high relevance)
- Interactions: HSD17B13 (667), TM6SF2 (582), PNPLA3 (541), MBOAT7 (507)
- Why undrugged: Recently identified as NAFLD gene; biology still being elucidated
- Opportunity: Loss-of-function A165T is protective → inhibitor strategy. Enzyme has cofactor-binding pocket amenable to small molecules.
- GPAM (Q9HCL2) — Druggability Potential: HIGH
- GWAS p-value: 2.0e-20
- Protein function: Glycerol-3-phosphate acyltransferase 1; rate-limiting step of de novo triglyceride synthesis
- Family: Acyltransferase (druggable enzyme)
- Structure: AlphaFold (pLDDT 80.32) — moderate
- Expression: Liver, adipose (high relevance)
- Interactions: PPARG (693), PNPLA3 (506)
- Pathway: Triglyceride biosynthesis (R-HSA-75109), SREBP signaling
- Why undrugged: Preclinical tool compounds exist (FSG67) but no clinical development
- Opportunity: GPAM inhibition reduces hepatic TG synthesis. Enzyme has clear active site.
- MBOAT7 (Q96N66) — Druggability Potential: MEDIUM-HIGH
- GWAS p-value: 9.0e-9
- Variant: rs641738 (regulatory) — Tier 3
- Protein function: Phosphatidylinositol acyltransferase; remodels PI acyl chains
- Family: MBOAT family (membrane-bound O-acyltransferase) — druggable enzyme
- Structure: AlphaFold (pLDDT 92.26) — good
- Expression: Liver (high)
- Mendelian: Also causes intellectual disability (AR) — safety consideration
- Interactions: TM6SF2 (909), PNPLA3 (887), HSD17B13 (874)
- Why undrugged: Membrane enzyme, complex biology
- Opportunity: MBOAT7 loss of function increases risk → activator/stabilizer approach needed
- GCKR (Q14397) — Druggability Potential: MEDIUM
- GWAS p-value: 3.0e-31
- Variant: rs1260326, P446L (missense) — Tier 1
- Protein function: Regulates glucokinase activity and hepatic glucose metabolism
- Family: SIS domain regulatory protein
- Structure: PDB 4BB9 (1.47 Å) — excellent
- Expression: Liver (high specificity)
- Interactions: PNPLA3 (695), MBOAT7 (596), TM6SF2 (695)
- Why somewhat undrugged: Regulatory protein, not classic enzyme; compounds exist (AMG-3969, AMG-1694) in crystal structures but no clinical development for NAFLD
- Opportunity: Crystal structures with bound compounds demonstrate druggability; fructose-phosphate binding site is a clear target pocket
- MTTP (P55157) — Druggability Potential: HIGH (already drugged for other indication)
- GWAS p-value: 3.0e-12
- Protein function: Lipid transfer protein for VLDL assembly
- Structure: PDB available (cryo-EM)
- Drug: Lomitapide (approved for homozygous FH) — MTTP inhibitor
- Opportunity: Dose-adjusted MTTP inhibition for NAFLD; hepatic steatosis is the known side effect of inhibition, requiring careful dose finding
- TRIB1 (Q96RU8) — Druggability Potential: MEDIUM
- GWAS p-value: 3.0e-22
- Protein function: Pseudokinase; regulates lipogenesis via COP1-mediated degradation of C/EBPα
- Family: Pseudokinase (kinase fold without catalytic activity)
- Structure: AlphaFold (pLDDT 78.38) — moderate
- Interactions: PNPLA3 (462), MBOAT7 (317), HSD17B13 (377)
- Why undrugged: Pseudokinase — no catalytic pocket; functions as a scaffold/adaptor
- Opportunity: PPI disruptors or allosteric modulators; challenging but feasible
- SAMM50 (Q9Y512) — Druggability Potential: LOW-MEDIUM
- GWAS p-value: 7.0e-12
- Protein function: Mitochondrial outer membrane sorting/assembly machinery
- Expression: Ubiquitous
- Interactions: PNPLA3 (911) — very high
- Why undrugged: Mitochondrial channel protein; unclear if modulation would be beneficial
11-15. Additional Undrugged Targets
| Rank | Gene | p-value | Family | Structure | Potential |
|---|---|---|---|---|---|
| 11 | APOC3 | 1.0e-8 | Apolipoprotein | Known | HIGH (volanesorsen ASO approved) |
| 12 | SUGP1 | 2.0e-22 | RNA splicing factor | AlphaFold | LOW |
| 13 | COBLL1 | 3.0e-9 | WH2 domain protein | AlphaFold | LOW |
| 14 | ARHGEF19 | 3.0e-18 | Rho GEF (druggable) | AlphaFold | MEDIUM |
| 15 | JAZF1 | 2.0e-16 | Zinc finger TF | AlphaFold | LOW |
Section 18: Summary
GWAS LANDSCAPE
- Total associations: 320 | Studies: 38 | Unique genes: 65+
- Coding variants: ~15% (Tier 1) — unusually high for a complex disease
- Non-coding variants: ~85% (Tiers 2-4)
- Strongest signal: PNPLA3 rs738409 (p = 2.0e-271) — one of the strongest GWAS signals in any disease
GENETIC EVIDENCE
- Tier 1 (coding) genes: 7 (PNPLA3, TM6SF2, GCKR, APOE, MTARC1, HFE x2)
- Mendelian overlap genes: 11
- Both Tier 1 + Mendelian: PNPLA3, HFE, APOE
DRUGGABILITY
- Overall druggable rate: 44% of GWAS proteins in druggable families
- Approved drugs for other diseases: 26%
- In clinical trials for NAFLD: 10%
- Opportunity gap (no drugs at all): 36%
PYRAMID SUMMARY
| Level | Description | Count | % |
|---|---|---|---|
| 1 | Validated (approved for NAFLD) | 2 | 4% |
| 2 | Repurposing (approved elsewhere) | 13 | 26% |
| 3 | Emerging (in trials) | 5 | 10% |
| 4 | Tool compounds only | 6 | 12% |
| 5 | Druggable but undrugged | 5 | 10% |
| 6 | Hard targets | 19 | 38% |
CLINICAL TRIAL ALIGNMENT
- Only ~4.6% of trial drugs target GWAS genes directly — massive disconnect
- Almost all GWAS-validated drug development is through PPARG agonists
- The field is dominated by non-genetically-validated targets (FXR, GLP-1, ACC, FASN, FGF21, ASK1)
TOP 10 REPURPOSING CANDIDATES
| Drug | Gene | Approved For | p-value | Score |
|---|---|---|---|---|
| 1. Pioglitazone | PPARG | T2 diabetes | 1.0e-11 | 9.5 |
| 2. Saroglitazar | PPARG | Dyslipidemia | 1.0e-11 | 9.5 |
| 3. Rosiglitazone | PPARG | T2 diabetes | 1.0e-11 | 9.0 |
| 4. Semaglutide | GLP1R (pathway) | Obesity/T2D | pathway | 8.5 |
| 5. Fenofibrate | PPARG pathway | Dyslipidemia | 1.0e-11 | 8.5 |
| 6. Telmisartan | PPARG (partial) | Hypertension | 1.0e-11 | 8.0 |
| 7. Metformin | AMPK (pathway) | T2 diabetes | pathway | 8.0 |
| 8. Orlistat | LPL | Obesity | 9.0e-13 | 7.5 |
| 9. Empagliflozin | SGLT2 (pathway) | Diabetes/HF | pathway | 7.5 |
| 10. Cannabidiol | KCNMA1 | Epilepsy | 2.0e-13 | 7.0 |
TOP 10 UNDRUGGED OPPORTUNITIES
| Gene | p-value | Family | Structure | Potential |
|---|---|---|---|---|
| 1. PNPLA3 | 2.0e-271 | Lipase/acyltransferase | AlphaFold | VERY HIGH |
| 2. HSD17B13 | Protective LOF | SDR enzyme | AlphaFold (93.8) | VERY HIGH |
| 3. MTARC1 | 6.0e-15 | Mo-containing enzyme | AlphaFold (91.7) | HIGH |
| 4. GPAM | 2.0e-20 | Acyltransferase | AlphaFold (80.3) | HIGH |
| 5. GCKR | 3.0e-31 | Regulatory (SIS domain) | PDB 1.47Å | HIGH |
| 6. MBOAT7 | 9.0e-9 | Membrane acyltransferase | AlphaFold (92.3) | MEDIUM-HIGH |
| 7. APOC3 | 1.0e-8 | Apolipoprotein | Known | HIGH (ASO exists) |
| 8. TM6SF2 | 1.0e-114 | TM6SF family | AlphaFold (91.0) | MEDIUM |
| 9. TRIB1 | 3.0e-22 | Pseudokinase | AlphaFold (78.4) | MEDIUM |
| 10. ARHGEF19 | 3.0e-18 | Rho GEF | AlphaFold | MEDIUM |
TOP 10 INDIRECT OPPORTUNITIES
| Undrugged Gene | Drugged Interactor | Drug Available |
|---|---|---|
| PNPLA3 ↔ PPARG | Pioglitazone, Rosiglitazone | |
| TM6SF2 ↔ MTTP | Lomitapide | |
| GPAM ↔ PPARG | Pioglitazone | |
| TRIB1 ↔ PPARG (pathway) | TZDs | |
| HSD17B13 ↔ PNPLA3 → PPARG | TZDs (indirect) | |
| SAMM50 ↔ PNPLA3 → PPARG | TZDs (indirect) | |
| MBOAT7 ↔ TM6SF2 → MTTP | Lomitapide (indirect) | |
| COBLL1 ↔ INSR | Insulin pathway drugs | |
| APOC3 ↔ LPL | Orlistat (indirect) | |
| MAU2 ↔ SUGP1 → TM6SF2 | (3rd degree) |
KEY INSIGHTS
NAFLD has the strongest single-gene GWAS signal of any complex liver disease — PNPLA3 rs738409 at p=2.0e-271 with a clear functional mechanism (I148M missense). Yet PNPLA3 remains completely undrugged.
Massive clinical trial disconnect — Only 4.6% of drugs in NAFLD trials target GWAS genes. The field is pursuing FXR agonists, GLP-1 agonists, and FGF21 analogs — none of which have direct genetic validation. This represents a significant opportunity if GWAS-backed targets can be drugged.
The “lipid droplet proteome” is the genetic epicenter — PNPLA3, HSD17B13, TM6SF2, MBOAT7, SAMM50, and GPAM all localize to or regulate lipid droplets. This organelle is the convergence point.
HSD17B13 is the most actionable novel target — protective loss-of-function variant, druggable enzyme family, excellent AlphaFold structure, multiple companies in clinical development. This is the model GWAS-to-drug-target story.
MTARC1 A165T is an emerging high-value target — protective missense variant in an enzyme with a clear cofactor-binding pocket. Inhibitor strategy is straightforward.
Comparison with other diseases: NAFLD has ~44% druggable GWAS genes (higher than many psychiatric/autoimmune diseases at ~25-30%), but an unusually low clinical translation rate. The lipid metabolism focus means many targets are enzymes — intrinsically more druggable than the transcription factors and signaling molecules dominating other disease GWAS.
7. The PPARG pathway is the only genetically validated, clinically active target pathway — pioglitazone and related PPAR agonists (saroglitazar, lanifibranor, elafibranor) are the only drugs in trials that directly target a GWAS gene. Resmetirom (THR-beta) was the first FDA-approved drug for NASH/MASLD but targets a non-GWAS gene.
- Iron metabolism crossover — HFE variants (hemochromatosis gene) show strong association with lean NAFLD (p=3.0e-16), suggesting iron-lipid crosstalk as an underexplored mechanism.