alzheimer-gwas-snatac-celltype-r1

Direction d3 from the Alzheimer's-mechanism IDEATE run.

Cell-type-resolved functional dissection of AD GWAS variants in microglial vs neuronal cis-regulatory elements via snATAC-seq.

Which of the 75+ AD GWAS loci harbor causal variants within microglia-specific enhancers controlled by SPI1, ELF2, or RUNX1 (vs. excitatory neuron-specific circuits), what are the effector genes and their direction of effect, and do these cell-type-specific regulatory circuits operate differently across AD disease stages in existing multi-omic atlases?

AD GWAS hits are enriched in microglial enhancers (Tsai/Kellis Cell 2023, SPI1/ELF2/RUNX1), but most of the 75+ loci remain functionally uncharacterized at cell-type resolution, and neuronal regulatory circuits may mediate risk through synaptic gene programs independently of microglia. This OmiCairn run re-analyses open human snATAC-seq (the Morabito 2021 multiome ATAC arm) against AD GWAS loci to ask which loci fall in microglia- vs neuron-specific cis-regulatory elements, identify candidate effector genes and the direction of effect, and test whether the microglial regulatory circuits are stage-dependent.

Hypotheses (pre-registered, lifted from d3):

H1 (primary — SPI1/microglial enhancer dominance of AD GWAS loci): SPI1 (PU.1) binding motif accessibility in microglia snATAC-seq is the single strongest predictor of causal AD GWAS variant activity, with at least 15 of the top 75 GWAS loci having their strongest chromatin-accessibility QTL (or peak overlap / motif disruption signal) in microglia rather than neurons, astrocytes, or oligodendrocytes. Decision rule: for each AD GWAS lead/credible-set variant, compute cell-type-resolved snATAC peak overlap and SPI1 motif accessibility per cell type; rank cell types per locus; report the count of loci whose strongest microglial signal exceeds the other cell types, with effect size + p-value + 95% CI for the microglia-vs-other enrichment. H1 passes if ≥15 of the top 75 loci are microglia-dominant AND SPI1 motif accessibility is the top predictor (significant at p<0.05) of microglial variant activity.

H2 (secondary — DAM-stage timing of microglial GWAS circuits): Microglial GWAS-variant regulatory circuits are most active at the DAM stage (mid-disease), not at homeostatic or late-disease stages, suggesting the therapeutic window for GWAS-linked microglial targets is the early-to-mid Braak period. Decision rule: stratify microglia by activation state (homeostatic / DAM / late) using marker programs and/or Braak stage; compute GWAS-variant-overlapping peak accessibility per stage; report the stage contrast (DAM vs homeostatic and DAM vs late) as effect size + p-value + 95% CI. H2 passes if peak accessibility at GWAS-overlapping microglial loci is significantly higher at the DAM/mid stage than at both homeostatic and late stages (p<0.05, 95% CI excluding 0).

IMPORTANT — feasibility caveat (snATAC is heavy): snATAC peak-calling and peak-to-variant integration is substantially heavier than the RNA-only AD cases and depends on the snATAC arm being present and parseable in the fetched object, plus a usable AD GWAS variant list. EXECUTE MUST verify, BEFORE asserting H1/H2: (1) the snATAC fragment/ peak matrix is fetchable and parseable; (2) a public AD GWAS lead/credible-set variant list is obtained (ADGC public summary statistics / published supplementary tables — never fabricated accessions or coordinates); (3) variant-to-peak overlap can actually be computed against a stated genome build. If peak calls cannot be computed, the variant overlap cannot be performed, or cell-type labels are absent, EXECUTE MUST report that honestly in analysis summary § Limitations and fall back to whatever partial analysis is supportable (e.g. cell-type marker-gene accessibility, or the RNA arm only) rather than fabricating peak/variant overlaps. Do NOT impute peaks, QTLs, or genotypes.

A negative or partial result is fully informative. If AD GWAS loci are NOT preferentially microglia-/SPI1-resolved, or the circuits are not stage-dependent, that must be the headline rather than re-tuning peak definitions or variant sets until H1/H2 pass.

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.