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

Molecular Psychiatry volume 26, pages 6065–6073 (2021)Cite this article

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Abstract

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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Fig. 1: The analytical pipeline for identifying genetic targets of AD using brain- and blood-based proteomics.
Fig. 2: Manhattan plots of PWAS by integrating brain pQTL and AD GWAS.
Fig. 3: MR and Bayesian colocalization analysis identified AD-associated genes.
Fig. 4: Summary of the AD significant genes with evidence for being consistent among the four approaches.

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Data availability

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.

Code availability

Codes associated with the current submission can be requested by contacting the corresponding author.

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Acknowledgements

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.

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  1. These authors contributed equally: Ya-Nan Ou, Yu-Xiang Yang.

Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China

    Ya-Nan Ou, Hao Hu, Yi Liu & Lan Tan

  2. Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

    Yu-Xiang Yang, Yue-Ting Deng, Bang-Sheng Wu & Jin-Tai Yu

  3. Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Diseases (MIND), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    Can Zhang

  4. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    Yan-Jiang Wang

  5. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China

    Ying Zhu

  6. Department of Psychiatry, University of Cambridge, Cambridge, UK

    John Suckling

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Contributions

J-TY conceptualized the study and revised the manuscript. Y-NO, Y-XY, B-SW, Y-TD, and YL analyzed and interpreted the data. Y-NO prepared all the figures and tables. Y-NO and Y-XY drafted and revised the manuscript. HH, LT, JS, CZ, YZ, and Y-JW revised the manuscript. All authors contributed to the writing and revisions of the paper and approved the final version.

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Correspondence to Jin-Tai Yu.

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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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