Concise Statement: In Parkinson's disease, different epigenetic clock algorithms (Horvath, Hannum, PhenoAge, GrimAge) generate systematically divergent age estimates from the same DNA sample — and this inter-clock discordance score (IDS) is a novel, specific PD prodrome biomarker that reflects the cell-type-skewed aging pattern caused by dopaminergic neuron loss and compensatory glial proliferation.
Curated pathway from expert analysis
flowchart TD
A["Epigenetic Clock<br/>Ensemble Panel"]
B["Horvath Hannum PhenoAge<br/>GrimAge Divergence"]
C["Inter-Clock Discordance<br/>Score (IDS)"]
D["Dopaminergic Neuron Loss<br/>Cell Composition Shift"]
E["Neuroinflammatory Signaling<br/>Monocyte Lymphocyte Methylome"]
F["Peripheral Blood Methylome<br/>Altered Clock Training Signals"]
G["Systematic Clock Output<br/>Divergence From Same Sample"]
H["IDS as PD Prodromal<br/>Biomarker Signal"]
A --> B
B --> C
D --> E
E --> F
F --> G
G --> H
D --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No curated PDB or AlphaFold mapping for DNA yet. Search RCSB →
Median TPM across 13 brain regions for DNA, IDS, PD from GTEx v10.
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 DNA, IDS, PD.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF epigenetic asynchrony precedes PD symptoms, THEN discordance between GrimAge, PhenoAge, and mitotic clocks will correlate with DAT-SPECT decline at r >=0.30 over 24 months in prodromal PD cohorts. | Baseline or change in clock discordance predicts striatal DAT-SPECT loss with partial r >=0.30 and FDR <0.05. | — no observation — | pending | 0.56 |
| IF multi-clock epigenetic asynchrony is a Parkinson prodrome signal, THEN REM sleep behavior disorder participants who convert to PD will show a >=1.5 SD increase in cross-clock age discordance at lea | Clock-discordance z score is >=1.5 SD higher in converters than non-converters before motor conversion, with AUC >=0.72. | — no observation — | pending | 0.60 |