Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood

Abstract

AbstractBackgroundGenome‐wide association studies (GWASs) have discovered numerous risk genes for Alzheimer’s disease (AD), but how these genes confer AD risk is challenging to decipher.MethodTo efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in brain and blood by systematically applying proteome‐wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization.ResultCollectively, we identified the brain protein abundance of 7 genes (ACE, ICA1L, TOM1L2, SNX32, EPHX2, CTSH, and RTFDC1) are causal in AD (P<0.05/proteins identified for PWAS and MR; PPH4>80% for Bayesian colocalization). The proteins encoded by these genes were mainly expressed on the surface of glutamatergic neurons and astrocytes. Of them, ACE with its protein abundance was also identified in significant association with AD on the blood‐based studies and showed significance at the transcriptomic level. SNX32 was also found to be associated with AD at the blood transcriptomic level.ConclusionOur current study results on genetic, proteomic and transcriptomic approaches has identified compelling genes, which may provide important leads to design future functional studies and potential drug targets for AD.