Fig. 5: scMORE uncovers aging-relevant eRegulons associated with PD.
a, UMAP visualization of single nuclei, colored by cell types. b, UMAP plot of single nuclei, colored by three groups (young, aged and PD). c, UMAP plot of single nuclei, colored by sex (male (M) and female (F)). d, Cell proportions of seven brain cell types across the three groups, stratified by sex. Cell composition of seven cell types across different group × sex categories (top). Spearman correlation (two-sided) between the proportion of each cell type and donor age (n = 31) (bottom). Only cell types corresponding to FDR-adjusted P < 0.05 are marked by an asterisk. e, Distribution of eRegulon sizes identified by scMORE in a human midbrain single-cell multiomic dataset. Among these detected eRegulons, 74.13% contain 20 or more genes. f, Heatmap illustrating the top-ranked PD-associated eRegulons identified by scMORE across seven brain cell types. **Denotes PCTS < 0.05, PGRS < 0.05, PTRS < 0.05 and TRS > 3. *Denotes PCTS < 0.05, PGRS < 0.05, PTRS < 0.05 and TRS > 1.5. Significance was assessed by an MC permutation test (one-sided, upper tail; n = 1,000 iterations; no multiple correction). g, Proportion of PD-associated eRegulons in each brain cell type. h, Scatter-plots demonstrating significant eRegulons associated with PD in ASs and OPCs. Each dot represents an eRegulon, with −log-transformed GRS P values (−log10(P)) shown on the y axis and −log-transformed CTS P values (−log10(P)) shown on the x axis. Gray dots denote nonsignificant eRegulons, and red dots indicate significant eRegulons. Significance was assessed by an MC permutation test (one-sided, upper tail; n = 1,000 iterations; no multiple correction). i, Representative examples showing differential eRegulon activity across the young (n = 9), aged (n = 8) and PD groups (n = 14). A two-sided Wilcoxon test was used to assess statistical significance. Boxplot shows the median (center line), IQR (box) and 1.5 × IQR bounds (whiskers). Minima and maxima are represented by the whiskers. Outliers are shown as individual points. j, Regulatory network of PD-associated genes in the ZFPM2-eRegulon that harbors strong genetic signals (SNPs and corresponding P values from GWAS summary data; no multiple correction). k, Functional enrichment analysis of the ZFPM2-eRegulon. Pathway enrichment results from Metascape (top) and Gene Ontology (GO) Biological Process (BP) term enrichment results from WebGestlat (bottom).
