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

Genome-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. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using p...

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Bibliographic Details
Published in:Molecular psychiatry 2021-10, Vol.26 (10), p.6065-6073
Main Authors: Ou, Ya-Nan, Yang, Yu-Xiang, Deng, Yue-Ting, Zhang, Can, Hu, Hao, Wu, Bang-Sheng, Liu, Yi, Wang, Yan-Jiang, Zhu, Ying, Suckling, John, Tan, Lan, Yu, Jin-Tai
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Alzheimer Disease - genetics
Alzheimer's disease
Astrocytes
Bayes Theorem
Bayesian analysis
Blood
Brain
Drug development
Drug targeting
Drug therapy
Genetic aspects
Genome-wide association studies
Genome-Wide Association Study
Genomes
Glutamatergic transmission
Humans
Neurodegenerative diseases
Pharmacology, Experimental
Polymorphism, Single Nucleotide
Proteome - genetics
Proteomes
Proteomics
Therapeutic targets
Transcriptomics
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Summary:Genome-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. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in the brain and blood by systematically applying proteome-wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization. Collectively, we identified the brain protein abundance of 7 genes (ACE, ICA1L, TOM1L2, SNX32, EPHX2, CTSH, and RTFDC1) are causal in AD (P 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. Collectively, our 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.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-021-01251-6