Fig. 4: TREM2 reduced activation variant carriers (p.R47H, p.R62H, and p.H157Y) have distinct microglia and oligodendrocyte profiles.
From: Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
a–d Microglia (Mic-reduced = cluster 2). e–g Oligodendrocytes (Oligo-TFEB = cluster 5). a, e Proportion plots show a significant (p < 0.05) enrichment (*) of cell states in TREM2 reduced activation carriers (TREM2R) compared to all other samples as determined by linear regression. Exact p values can be found in Supplementary Dataset 6. The proportion was calculated for each sample (see Methods). For visualization, sample proportions are averaged by group. “Other” represents all sAD non-TREM2 reduced activation carriers, including carriers of other TREM2 variants. b Barplot shows the expression of both resting and activated microglia marker genes in Mic-reduced (mic.2) compared to the Mic-resting (mic.0) and Mic-activated cell states (mic.1). Expression was corrected for the age of death and sex using partial residuals. c UMAP plots showing the integrated nuclei from the discovery cohort and ROSMAP, split by cohort. d Violin plot of cell state expression signatures in the ROSMAP nuclei. The signature was calculated from the upregulated genes from the discovery cohort. Differences in signature scores were calculated using linear regression. (*) = p < 0.05, (**) = p < 5.0 × 10−3, (***) = p < 5.0 × 10−20; exact p values can be found in the Source Data file. f Barplot shows the log2 fold-change of TFEB by oligodendrocyte cell state. g Identification of gene regulatory networks (GRN) in Oligo-TFEB discovery and replication cohorts. Regulons were filtered to include only those identified in both cohorts (p = 9.98 × 10−41; hypergeometric analysis) with significant differential expression in Oligo-TFEB. Then those regulons with significant (Benjamini–Hochberg p < 0.05; hypergeometric analysis and Benjamini–Hochberg multiple testing correction) coincidence in the underlying target genes between cohorts were selected. h Gene regulatory network for transcription factors (TF; shown in blue) replicated in both discovery (purple edges) and ROSMAP (orange edges) datasets for oligo-TFEB. Replicated target genes and edges are shown in yellow and green respectively. Genes within AD GWAS loci are highlighted in red. g, h (*) = Benjamini–Hochberg p < 0.05, (**) = Benjamini–Hochberg p < 0.01. Source data are provided as a Source Data file.
