We used the powerful TWAS approach, which leverages our splicing map and common genetic variants to test the hypothesis that the effect of such variants in Alzheimer’s disease is mediated, by altering splicing levels. These analyses confirmed many of the known Alzheimer’s disease genes (i.e., CLU and PTK2B), which supports the role of regulation of splicing levels as key mechanisms in certain loci, but also found several new loci: TBC1D7, AP2A1, AP2A2, and MAP1B (Figs. 5a and 6b; Supplementary Figs. 7, 9, and 13). These new genes reinforce the association of the Clathrin/AP2 adaptor complex with Alzheimer’s disease susceptibility45. Both AP2A2 and AP2A1, which are components of the AP2 adaptor complex that serves as a cargo receptor, selectively sorting membrane proteins involved in receptor-mediated endocytosis46. The AP2 complex and PICALM interact with APP, directing it to degradation and autophagy46.
