Fig. 5
Identification of cis co-accessible networks and associated DEGs in LOAD nuclei. a and b, Diagrams of example unidirectional CCANs—in which all overlapping DAPs and DEGs are regulated in the same direction in LOAD nuclei (e.g. more accessible peaks and higher gene expression) and mixed CCANs—in which at least one DAP/DEG pair are regulated in the same direction and at least one pair are regulated in opposite directions. Vertical lines at the top of each diagram indicate chromatin peaks and regulatory linkages of accessibility between peak pairs and associated co-accessibility scores are indicated by Bezier curves. Only CCAN-associated peaks are shown. DAPs with greater accessibility in LOAD are shown in salmon, while those with reduced accessibility in LOAD are shown in blue. Non-differentially-accessible peaks are shown in grey. Below the peak linkage plots, gene exons overlapping CCAN regions are depicted as arrows indicating the directionality of transcription. DEGs are labeled with gene names, and LOAD-upregulated DEGs are shown in salmon while non-differentially-expressed genes are shown in grey (no downregulated DEGs depicted). At the bottom of each diagram, a Manhattan plot is shown indicating -log10 of p-values for LOAD-association of chromosome loci within CCAN region as calculated by Kunkle et al. [7] Dotted lines in Manhattan plots indicate statistical significance threshold (p = 0.05). Panel a depicts example CCANs that do not overlap GWAS-identified LOAD-associated SNPs, while panel b depicts example CCANs that do overlap LOAD-associated SNP loci, indicated via orange dots and labeled on Manhattan plots. c, Table showing total number of CCANs identified for each snATAC-seq nuclei cluster, as well as the number of unidirectional and mixed CCANs, and the mean number of DAPs and DEGs identified per CCAN for each cluster in both the unidirectional and mixed categories, along with the standard deviation (SD) and maximum and minimum values. d, Table listing DEGs linked to cCREs in unidirectional and mixed CCANs for each applicable cluster, as well a functional annotation of specific DEGs with known associations to neurodegenerative disease. Number of cCREs linked to each DEG is shown in parentheses. e, Diagram of potential DEG/cCRE associations in which (i) one DAP is coaccessible with one peak overlapping the DEG, (ii) one DAP is coaccessible with multiple DEG peaks, (iii) two DAPs are coaccessible with one DEG peak, and (iv) two DAPs are coaccessible with two DEG peaks. f, Gene ontological analysis of biological processes for cCRE-linked DEGs associated with CCANs in the indicated cell subtype clusters. Up to the top ten significantly enriched biological processes involving a minimum of three DEGs are listed. Statistical significance of category enrichment (p < 0.05) indicated by vertical lines