parkinson-scenic-regulons-r1

Which transcription-factor (TF) regulons, inferred de novo by pySCENIC from the Fullard 2024 multi-region snRNA-seq atlas (CELLxGENE d5d0df8f-...) on substantia-nigra pars compacta (SNpc) dopaminergic (DA) neurons, are differentially active between Parkinson's-disease (PD) and age-matched control donors — and do those regulon-activity shifts replicate in the independent Smajic / Wang / Adams SNpc atlases when the same regulon dictionary is scored zero-shot via AUCell?

Selective-vulnerability biology in PD has so far been read at the cluster + marker-gene resolution (Kamath 2022 AGTR1+; Wang 2024 RIT2+/CALB1-). The TF-network layer above the markers has not been formally tested for cross-atlas reproducibility — i.e., is the dysregulation a coherent regulon shift, or only an apparent marker-gene shift that scrambles when the network is recomputed from a different atlas? This OmiCairn run pre-registers that test.

Hypotheses (pre-registered):

H1 (primary — regulon replication across three independent atlases): Let R = the top-20 SNpc-DA PD-vs-control differentially active regulons in the Fullard atlas (FDR < 0.05, limma-voom on the donor × regulon-AUCell matrix with age + sex + post-mortem interval covariates). At least 3 of those 20 regulons recover a same-sign log-fold-change in regulon- AUCell score in all three held-out atlases (Smajic GSE157783, Wang GSE184950, Adams GSE193688), with a binomial test p < 0.01 against a null of 0.5 sign-agreement for each regulon × atlas combination.

H2 (secondary — TF gene-level GWAS enrichment): The PD-up-regulated regulon set (FDR < 0.05 in Fullard, same-sign in ≥ 2 of 3 replication atlases) is enriched by hypergeometric test (q < 0.05) for TFs whose genes carry PD-risk fine-mapped variants in the Kim 2024 multi-ancestry GWAS (GCST90275127 Supplementary Table S5).

H3 (secondary — alignment with AGTR1+ depletion): Per-donor AUCell scores of the consensus PD-up regulons rank-correlate (Spearman ρ > 0.3, p < 0.05) with the AGTR1+ DA depletion score derived in the v1 parkinson-da-vulnerability workspace (read from prior workspace results record), at the donor level inside Fullard SNpc.

H4 (secondary — donor-level classification): Leave-one-atlas-out donor-level random forest using only the top-50 SNpc DA regulon AUCell scores as features achieves an AUC ≥ 0.70 for PD-vs-control classification (95% bootstrap CI excluding 0.5).

H5 (secondary — clustering-resolution robustness): Re-run the top-level Leiden clustering at γ ∈ {0.4, 0.8, 1.2}; the H1 same-sign replication count varies by ≤ 1 regulon across the three resolutions (the dominant failure mode the v1 parkinson-da-vulnerability case logged).

Null payoff. If consensus regulons fail to replicate across atlases (H1 = 0/20 same-sign in ≥ 2 atlases), the field's TF-level mechanistic claim is at the cluster-resolution layer, not the regulon-network layer. That is an informative Tier-A negative.

The research question comes from the topic's current research brief. All attempts at a topic share it; earlier attempts may have started from an earlier wording.