parkinson-celloracle-ko-r1

Does CellOracle's in-silico knock-out (KO) of the top PD-risk genes from the Kim 2024 multi-ancestry GWAS — LRRK2, GBA, SNCA, VPS13C, GAK, MAPT, BST1, CTSB, DDC, SCARB2 (10 genes ranked by fine-mapping posterior probability) — in Fullard 2024 SNpc dopaminergic neurons produce predicted cell-state vector shifts that align with the observed PD-vs-control DA state shift?

The CellOracle framework (Kamimoto et al. 2023 Nature) lets one combine a scATAC-derived base-GRN with snRNA-seq to predict counter-factual cell-state shifts in response to TF / target perturbation. The mechanistic-content claim — that the inferred GRN encodes enough biology to predict disease-state shifts — has not been formally tested in human PD with public data.

Hypotheses (pre-registered):

H1 (primary — KO-vs-disease alignment): The mean cosine similarity between the CellOracle-predicted post-KO state-shift vector (averaged across the 10 GWAS genes) and the observed PD-minus-control SNpc DA centroid shift is > 0.30, with a permutation-null p < 0.01 (10,000 random gene-label permutations).

H2 (secondary — fine-mapping PIP correlation): Per-gene KO cosine alignment with PD-minus-control shift correlates positively (Spearman ρ > 0.4, p < 0.05) with the gene's posterior probability of causal association from Kim 2024 fine-mapping (Supp Table S5).

H3 (secondary — LRRK2-KO target enrichment): The CellOracle-predicted top-100 up-regulated targets of LRRK2-KO are enriched (q < 0.05 by hypergeometric) for the Hemedan 2024 Boolean-PD "prodromal-cluster" regulatory-module gene list.

H4 (secondary — SNCA protective + HBB null control): SNCA-KO simulation predicts a protective shift (cosine with PD-vs-ctrl vector > 0 with permutation p < 0.05), consistent with α-syn loss-of-function reducing aggregation; control gene HBB (red-blood-cell marker, irrelevant) predicts a null shift (|cosine| < 0.1).

H5 (secondary — base-GRN robustness): Repeat the analysis with the published CellOracle midbrain reference base-GRN (Zenodo 7755357) vs. the Adams-2024- derived ATAC base-GRN. The H1 cosine-similarity changes by ≤ 0.1 between the two base-GRN sources (network-source sensitivity test).

Null payoff. A null cosine alignment (H1 ≤ 0.15) means GWAS- implicated genes do not in-silico recapitulate PD cellular phenotypes — sharpening the long-standing field critique that risk-variant biology is not cell-autonomous and may be glia-mediated.

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