Fig 1.
142 GWAS-identified AD genes were included as the seed genes of the AD disease module, and propagated to an expanded network consisting of another 646 predicted proximal genes based on the background protein-protein interactome (STRING). The expanded AD module was used for further functional annotation, pathway clustering and gene expression analyses integrating with transcriptomic data.
Fig 2.
Expanded AD disease module and highlighted distinctive clusters annotating different biological pathways possibly involved in AD.
Clusters identified in the expanded AD module labeled in the center. Genes comprising 5 selected clusters are depicted around the edges of the figure. The temporal cortex RNAseq beta statistic is mapped to the gene color, and shape indicates AD GWAS seed gene (triangle) or network proximal gene (z > 2, circle). Bold black outlines indicate AGORA proposed drug targets (e.g. CHRNA2, PTK2B). Seed genes or genes with AGORA targets are labeled with a larger font, while other genes identified by network propagation are labeled with a smaller font.
Fig 3.
Annotations of Mammalian Phenotype Ontology on the AD network genes.
The figure shows the odds ratios and 95% confidence intervals for the 9 significantly enriched brain-related phenotypes, and one negative control phenotype (abnormal skeleton physiology). The circle size indicates the number of genes which result in that phenotype when knocked out in mice.
Fig 4.
Hierarchical graph of the AD gene network.
Pie charts indicate fractions of up- (red) and down- (blue) regulated genes.
Table 1.
Clusters in the expanded AD disease module.
Fig 5.
Cell-specific gene expression across clusters and schematic model.
A) Mean expression (FPKM) from brain cell-types averaged across genes in each cluster (functional annotations for identified clusters are 1: Immunoregulatory interactions between a lymphoid and non-lymphoid cell, 2: RNA metabolic process, 3: Complement activation, 4: Protein modification by small protein conjugation, 5: Clathrin-mediated endocytosis, 6: SNARE binding, 7: Regulation of plasma lipoprotein particle levels, 8: EPH-Ephrin signaling, 9: DNA-binding transcription factor activity, 10: Acetylcholine-gated cation-selected channel activity, 11: Interleukin-1 signaling, 12: GABAergic synapse). B) Classes of identified pathways that are functionally related are presented as inner circles, with circle size roughly indicating relative class sizes. The overlying outer circle illustrates the types of cells in the central nervous system with overall preferential gene expression in each major class (e.g., microglia overlay the classes of Immune reactions and Substance metabolism because genes in multiple clusters of these two classes were highly expressed in microglia).