Refining known associations is important to translate results into functional studies, but the newly validated Alzheimer’s disease genes (Figs. 6a and 6b) also offer new insights into disease: we used GeNets42 to evaluate the connectivity of our new Alzheimer’s disease genes with the network of known susceptibility genes that are interconnected by protein-protein interaction (PPI)43. These new and known Alzheimer’s disease susceptibility genes are directly connected (i.e., they form shared ‘communities’) (P < 0.006) (Fig. 6c). Further, this joint network is enriched for endocytosis pathways (P < 0.0002), highlighting the existing narrative of endocytosis pathways as being preferentially targeted in Alzheimer’s disease. The enrichment for autophagy-lysosomal related pathway (P < 0.003) is more interesting (Fig. 6c). The genes in the autophagy-lysosomal related pathway (AP2A2, AP2A1, and MAP1B) form a statistically significant (P < 4.3×10−4) PPI sub-network with known Alzheimer’s disease genes (PTK2B, PICALM and BIN1) (Fig. 6d). Protein degradation pathways have been implicated previously in Alzheimer’s disease44. Overall, these PPI analyses suggest that our new TWAS-derived genes are not a random set of genes but are part of an Alzheimer’s disease network.
