Fig. 2

Network-based validation of predicted risk genes for Alzheimer’s disease (AD). a A subnetwork highlighting disease module formed by predicted AD risk genes (ARGs) in the human protein–protein interactome. This disease module includes 128 protein–protein interactions (PPIs) (edges or links) connecting 70 ARGs (nodes). Larger node size highlighting the high expression level in brain compared to other tissues. b–k Discovery of genomic features of 103 predicted ARGs implicated in AD. ARGs capture strong distal gene regulatory elements in Hi-C (b) and FANTOM5 data (c) compared to a set of local background genes (LBGs). d–k AGRs are more likely to be differentially expressed across 4 single-cell/nucleus RNA sequencing datasets (Table S3): d, e brain microglia cell of 5XFAD mouse model (GSE98969 [d] and GSE140511 [e]); f,g a human single-cell atlas (GSE147528) of entorhinal cortex (f) and the superior frontal gyrus (g) from individuals spanning the neuropathological progression of AD patient brain astrocyte cells; and a single-cell atlas (GSE138852) of entorhinal cortex from AD patients across four brain cell types: microglia [h], neuron [i], oligodendrocyte [j], oligodendrocyte progenitor cell (OPC) [k]. P value was computed by one-tail T-test. Adjusted P value (adj-P) was calculated based on the Benjamini−Hochberg approach. LCC: largest connected component; EC: entorhinal cortex; SFG: superior frontal gyrus