@article{aa1f8a42d8424b56a7c5edc367081c56,
title = "Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer's disease",
abstract = "Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome. Via NETTAG, we identified 156 AD-risk genes enriched in druggable targets. Combining network-based prediction and retrospective case-control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is associated with reduced likelihood of AD incidence. Gemfibrozil (an approved lipid regulator) is significantly associated with 43% reduced risk of AD compared with simvastatin using an active-comparator design (95% confidence interval 0.51–0.63, p < 0.0001). In summary, NETTAG offers a deep learning methodology that utilizes GWAS and multi-genomic findings to identify pathobiology and drug repurposing in AD.",
keywords = "AD, Alzheimer's disease, CP: Neuroscience, EHR, GWAS, deep learning, drug repurposing, drug target, electronic health record, gemfibrozil, genome-wide association studies, multi-omics, pathobiology, protein-protein Interactome",
author = "Jielin Xu and Chengsheng Mao and Yuan Hou and Yuan Luo and Binder, {Jessica L.} and Yadi Zhou and Bekris, {Lynn M.} and Jiyoung Shin and Ming Hu and Fei Wang and Charis Eng and Oprea, {Tudor I.} and Flanagan, {Margaret E.} and Pieper, {Andrew A.} and Jeffrey Cummings and Leverenz, {James B.} and Feixiong Cheng",
note = "Funding Information: We thank members from The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site and The Alzheimer's disease Knowledge portal to provide technical support for multi-omics data access and analysis. This work was primarily supported by the National Institute on Aging (NIA) under Award Number U01AG073323, R01AG066707 and R01AG076448 to F.C. This work was supported in part by NIA grants 3R01AG066707-01S1, 3R01AG066707-02S1, and R56AG074001 to F.C. This work was supported in part by the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center (NIH/NIA: P30AG072959) to F.C. A.A.P. J.B.L. and J.C. This work was supported in part by the Brockman Foundation, Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, and the Louis Stokes VA Medical Center resources and facilities to A.A.P. This work was supported in part by Keep Memory Alive (KMA), National Institute of General Medical Sciences (NIGMS) grant P20GM109025, National Institute of Neurological Disorders and Stroke (NINDS) grant U01NS093334, NIA grant R01AG053798, and R35AG071476, and the Alzheimer's Disease Drug Discovery Foundation (ADDF) to J.C. F.C. conceived the study. J.X. C.M. and Y.H. performed all experiments and data analysis. Y.L. J.L.B. Y.Z. M.E.F. M.H. L.B. J.S. F.W. C.E. T.I.O. A.A.P, J.C. and J.B.L. interpreted the data analysis. J.X. C.M. and F.C. drafted the manuscript. J.X. F.C. A.A.P, J.C. and J.B.L. critically revised the manuscript. All authors critically revised and gave final approval of the manuscript. J.C. has provided consultation to AB Science, Acadia, Alkahest, AlphaCognition, ALZPathFinder, Annovis, AriBio, Artery, Avanir, Biogen, Biosplice, Cassava, Cerevel, Clinilabs, Cortexyme, Diadem, EIP Pharma, Eisai, GatehouseBio, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lexeo, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PharmacotrophiX, PRODEO, Prothena, ReMYND, Renew, Resverlogix, Roche, Signant Health, Suven, Unlearn AI, Vaxxinity, VigilNeuro pharmaceutical, assessment, and investment companies. J.B.L. has received consulting fees from consulting fees from Vaxxinity, grant support from GE Healthcare and serves on a Data Safety Monitoring Board for Eisai. Funding Information: This work was primarily supported by the National Institute on Aging (NIA) under Award Number U01AG073323, R01AG066707 and R01AG076448 to F.C. This work was supported in part by NIA grants 3R01AG066707-01S1, 3R01AG066707-02S1, and R56AG074001 to F.C. This work was supported in part by the Translational Therapeutics Core of the Cleveland Alzheimer's Disease Research Center ( NIH /NIA: P30AG072959) to F.C., A.A.P., J.B.L., and J.C. This work was supported in part by the Brockman Foundation , Project 19PABH134580006-AHA/Allen Initiative in Brain Health and Cognitive Impairment, the Elizabeth Ring Mather & William Gwinn Mather Fund, S. Livingston Samuel Mather Trust, and the Louis Stokes VA Medical Center resources and facilities to A.A.P. This work was supported in part by Keep Memory Alive ( KMA ), National Institute of General Medical Sciences (NIGMS) grant P20GM109025, National Institute of Neurological Disorders and Stroke (NINDS) grant U01NS093334, NIA grant R01AG053798, and R35AG071476, and the Alzheimer{\textquoteright}s Disease Drug Discovery Foundation (ADDF) to J.C. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = nov,
day = "29",
doi = "10.1016/j.celrep.2022.111717",
language = "English (US)",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",
}
