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 < 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. 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.
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Data of brain pQTL and eQTL from the ROS/MAP study are available through https://doi.org/10.7303/syn23627957 and https://www.synapse.org/#!Synapse:syn3219045, respectively. Proteomic and transcriptomic data used in this manuscript are available via the AD Knowledge Portal (https://adknowledgeportal.org). Data are available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.org/DataAccess/Instructions). Data from AGES Reykjavik study can be accessed at www.sciencemag.org/cgi/content/full/science.aaq1327/DC1. Data from the AGES Reykjavik study are available through collaboration (AGES_data_request@hjarta.is) under a data usage agreement with the IHA. GTEx can be accessed at https://gtexportal.org/home/datasets (GTEx Analysis V8). Summary statistics for the Schwartzentruber’s meta-analysis are available through the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalog under accession nos. GCST90012877 and GCST90012878 (https://www.ebi.ac.uk/gwas/downloads/summary-statistics). Summary statistics for the Jansen’s GWAS can be made available for download upon publication (https://ctg.cncr.nl/software/summary_statistics). Cell-type specificity data are available at https://portal.brain-map.org/atlases-and-data/rnaseq.
Codes associated with the current submission can be requested by contacting the corresponding author.
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This study was supported by grants from the National Natural Science Foundation of China (82071201, 91849126), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZHANGJIANG LAB, Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University. This work was made possible by the generous sharing of statistics from the public databases. We thank the participants of the ROS and MAP for their time and effort. Study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. We thank the AGES Reykjavik study, GTEx project, and Cell Types database for their kind dedication. We thank the Schwartzentruber’s GWAS meta-analysis and Jansen’s GWAS. Statistics were made possible by their generous sharing of GWAS summary statistics. Access to data is shown below. The full list of acknowledgements can be found in the Supplementary Text.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Ou, YN., Yang, YX., Deng, YT. et al. Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood. Mol Psychiatry 26, 6065–6073 (2021). https://doi.org/10.1038/s41380-021-01251-6
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