ID: h-bb7a863d9b
Hypothesis
AD fine-mapping identifies causal variants in microglia-specific enhancers with small credible sets
Bayesian fine-mapping of the top 25 AD GWAS loci will identify credible sets significantly enriched for variants disrupting microglia-specific regulatory elements, reflecting microglial dysfunction as a central AD pathogenic mechanism.
neurodegeneration
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
Bayesian fine-mapping of the top 25 AD GWAS loci will identify credible sets significantly enriched for variants disrupting microglia-specific regulatory elements, reflecting microglial dysfunction as a central AD pathogenic mechanism. Credible sets at loci with known effector genes (APOE, TREM2, PLCG2) will be smaller (<10 variants) due to stronger functional constraints, while novel loci will have larger sets requiring integration with epigenomic data to prioritize causal variants. The highest posterior probability variants will predominantly map to non-coding regulatory regions active in myeloid cells rather than neuronal or astrocytic enhancers.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["AD Fine-Mapping<br/>Microglia-Specific Enhancers"]
B["TREM2 Causal<br/>Variants Identified"]
C["Small Credible Sets<br/>Variant Refinement"]
D["Microglial Activation<br/>Phagocytosis Impact"]
E["TREM2 Variant<br/>as LOAD Risk Modifier"]
F["Enhancer-Based<br/>Therapeutic Targeting"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
⚖️ Evidence Matrix5 supports2 contradicts
Contradicts
Systematic CRISPRi fine-mapping of AD GWAS loci reveals heterogeneous causal cell types across loci; multiple risk genes implicate non-microglial mechanisms including neuronal and oligodendrocyte functions, challenging the prediction that most AD loci harbour microglia-specific enhancer variants
PMID:41427057strong
Contradicts
Genetic drivers of Alzheimer's disease progression are largely distinct from disease-risk loci and involve neuronal pathways; this dichotomy suggests that relying on risk GWAS loci to infer microglial-enhancer causality may miss substantial non-microglial genetic architecture
PMID:41332834moderate
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TREM2
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for TREM2 from GTEx v10.
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TREM2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF credible set sizes are compared between the three known effector gene loci (APOE, TREM2, PLCG2) and the remaining 22 novel AD loci after Bayesian fine-mapping, THEN the median 95% credible set at e | Mean 95% credible set size at APOE/TREM2/PLCG2 = 6.3 variants (range 3-9); mean 95% credible set size at novel loci = 31.7 variants (range 18-89); ratio of nove | — no observation — | pending | 0.72 |
| IF Bayesian fine-mapping is performed on the top 25 AD GWAS loci using multi-ancestry summary statistics and high-resolution microglia ATAC-seq chromatin accessibility data, THEN the credible set vari | At least 18 of 25 loci (72%) will show enrichment scores for microglia-specific enhancer disruption > 2 standard deviations above genomic background null distri | — no observation — | pending | 0.78 |
🔮 Falsifiable Predictions (2)
pendingconf 78%
IF Bayesian fine-mapping is performed on the top 25 AD GWAS loci using multi-ancestry summary statistics and high-resolution microglia ATAC-seq chromatin accessibility data, THEN the credible set variants at these loci will show significant enrichment (OR > 2.0, p < 0.001) for disruption of microgli
Predicted outcome: At least 18 of 25 loci (72%) will show enrichment scores for microglia-specific enhancer disruption > 2 standard deviations above genomic background n
Falsification: Enrichment OR ≤ 1.0 or p > 0.05 for microglia-specific enhancer disruption among credible set variants; OR < 1.5 if nominally significant; or fewer than 12 of 25 loci showing any directional enrichmen
pendingconf 72%
IF credible set sizes are compared between the three known effector gene loci (APOE, TREM2, PLCG2) and the remaining 22 novel AD loci after Bayesian fine-mapping, THEN the median 95% credible set at effector gene loci will contain <10 variants while novel loci will have median sets >25 variants (Man
Predicted outcome: Mean 95% credible set size at APOE/TREM2/PLCG2 = 6.3 variants (range 3-9); mean 95% credible set size at novel loci = 31.7 variants (range 18-89); rat
Falsification: No significant size difference (p > 0.05) between effector and novel loci credible sets; median effector gene credible set size ≥15 variants; or >50% of known effector loci showing credible sets large
▸Metadatasource: v1_phase_c_backfill · origin_type: audit_hypothesis_generator
| source | v1_phase_c_backfill |
| origin_type | audit_hypothesis_generator |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
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Certainty
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Debates
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